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  • 401.
    Starokozhko, Viktoriia
    et al.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
    Vatakuti, Suresh
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
    Schievink, Bauke H.
    Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Merema, Marjolijn T.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
    Asplund, Annika
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Aspegren, Anders
    Takara Bio Europe AB, Gothenburg, Sweden.
    Groothuis, Geny M. M.
    Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
    Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days2017In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 5, p. 2079-2092Article in journal (Refereed)
    Abstract [en]

    Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and function of hPCLS to 5 days of incubation. hPCLS were incubated in two media developed for long-term culture of hepatocytes, RegeneMed(®), and Cellartis(®), and in the standard medium WME. Maintenance of phase I and II metabolism was studied both on gene expression as well as functional level using a mixture of CYP isoform-specific substrates. Albumin synthesis, morphological integrity, and glycogen storage was assessed, and gene expression was studied by transcriptomic analysis using microarrays with a focus on genes involved in drug metabolism, transport and toxicity. The data show that hPCLS retain their viability and functionality during 5 days of incubation in Cellartis(®) medium. Albumin synthesis as well as the activity and gene expression of phase I and II metabolic enzymes did not decline during 120-h incubation in Cellartis(®) medium, with CYP2C9 activity as the only exception. Glycogen storage and morphological integrity were maintained. Moreover, gene expression changes in hPCLS during incubation were limited and mostly related to cytoskeleton remodeling, fibrosis, and moderate oxidative stress. The expression of genes involved in drug transport, which is an important factor in determining the intracellular xenobiotic exposure, was also unchanged. Therefore, we conclude that hPCLS cultured in Cellartis(®) medium are a valuable human ex vivo model for toxicological and pharmacological studies that require prolonged xenobiotic exposure.

  • 402.
    Stenberg, Johan
    et al.
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    de Windt, Tommy S.
    Department of Orthopaedics, University Medical Center Utrecht, Utrecht, the Netherlands.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Hynsjö, Lars
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    van der Lee, Josefine
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Saris, Daniel B. F.
    Department of Orthopaedics, University Medical Center Utrecht, Utrecht, the Netherlands / MIRA Institute for Biotechnology and Technical Medicine, University of Twente, Enschede, the Netherlands.
    Brittberg, Mats
    Department of Orthopaedics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Peterson, Lars
    Department of Orthopaedics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Lindahl, Anders
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Clinical Outcome 3 Years After Autologous Chondrocyte Implantation Does Not Correlate With the Expression of a Predefined Gene Marker Set in Chondrocytes Prior to Implantation but Is Associated With Critical Signaling Pathways2014In: The Orthopaedic Journal of Sports Medicine, ISSN 2325-9671, Vol. 2, no 9, p. 1-14, article id 2325967114550781Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is a need for tools to predict the chondrogenic potency of autologous cells for cartilage repair.

    PURPOSE: To evaluate previously proposed chondrogenic biomarkers and to identify new biomarkers in the chondrocyte transcriptome capable of predicting clinical success or failure after autologous chondrocyte implantation.

    STUDY DESIGN: Controlled laboratory study and case-control study; Level of evidence, 3.

    METHODS: Five patients with clinical improvement after autologous chondrocyte implantation and 5 patients with graft failures 3 years after implantation were included. Surplus chondrocytes from the transplantation were frozen for each patient. Each chondrocyte sample was subsequently thawed at the same time point and cultured for 1 cell doubling, prior to RNA purification and global microarray analysis. The expression profiles of a set of predefined marker genes (ie, collagen type II α1 [COL2A1], bone morphogenic protein 2 [BMP2], fibroblast growth factor receptor 3 [FGFR3], aggrecan [ACAN], CD44, and activin receptor-like kinase receptor 1 [ACVRL1]) were also evaluated.

    RESULTS: No significant difference in expression of the predefined marker set was observed between the success and failure groups. Thirty-nine genes were found to be induced, and 38 genes were found to be repressed between the 2 groups prior to autologous chondrocyte implantation, which have implications for cell-regulating pathways (eg, apoptosis, interleukin signaling, and β-catenin regulation).

    CONCLUSION: No expressional differences that predict clinical outcome could be found in the present study, which may have implications for quality control assessments of autologous chondrocyte implantation. The subtle difference in gene expression regulation found between the 2 groups may strengthen the basis for further research, aiming at reliable biomarkers and quality control for tissue engineering in cartilage repair.

    CLINICAL RELEVANCE: The present study shows the possible limitations of using gene expression before transplantation to predict the chondrogenic and thus clinical potency of the cells. This result is especially important as the chondrogenic potential of the chondrocytes is currently part of quality control measures according to European and American legislations regarding advanced therapies.

  • 403.
    Storr-Paulsen, Marie
    et al.
    DTU Aqua - National Institute of Aquatic Resources Section for Fisheries Advice, Denmark.
    Anu, Albert
    Department of fish biology and fisheries, Estonian Marine Institute, University of Tartu.
    Arula, Timo
    University of Tartu, Estonian Marine Institute, Dept. of Ecodynamics.
    Boje, Jesper
    The National Institute of Aquatic Resources Section for Fisheries Advice, Denmark.
    Casini, Michele
    Swedish University of Agricultural Sciences, Department of Aquatic Resources, Institute of Marine Research, Lysekil.
    Degel, Henrik
    The National Institute of Aquatic Resources Section for Fisheries Advice, Denmark.
    Eero, Margit
    The National Institute of Aquatic Resources Section for Management Systems, Denmark.
    Gasyukov, Pavel
    AtlantNIRO, Kaliningrad, Russian Federation.
    Gröhsler, Tomas
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Rostock, Germany.
    Hjelm, Joakim
    Swedish University of Agricultural Sciences Institute of Marine Research, Lysekil.
    Horbowy, Jan
    Sea Fisheries Institute in Gdynia, Poland.
    Holmgren, Noél
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Bioscience.
    Jonusas, Stanislovas
    European Commission Directorate for Maritime Affairs and Fisheries, Brussels, Belgium.
    Kaljuste, Olavi
    Swedish University of Agricultural Sciences, Department of Aquatic Resources, Institute of Coastal Research, Öregrund.
    Karpushevskaia, Anastasiia
    AtlantNIRO, Kaliningrad, Russian Federation.
    Karpushevskiyi, Igor
    AtlantNIRO, Kaliningrad, Russian Federation.
    Kornilovs, Georgs
    Latvian Fish Resources Agency, Riga.
    Krumme, Uwe
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Rostock, Germany.
    Luzenczyk, Anna
    National Marine Fisheries Research Institute, Gdynia, Poland.
    Lövgren, Johan
    Swedish University of Agricultural Sciences Institute of Marine Research, Lysekil.
    Mikhaylov, Andrey
    Russian Federal Research Institute of Fisheries & Oceanography (VNIRO), Moscow.
    Norrström, Niclas
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Bioscience.
    Oeberst, Rainer
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Rostock, Germany.
    Pönni, Jukka
    Finnish Game and Fisheries Research Institute Kotka Unit.
    Raid, Tiit
    Estonian Marine Institute, University of Tartu, Tallinn.
    Raitaniemi, Jari
    Finnish Game and Fisheries Research Institute Turku.
    Statkus, Romas
    Division of fishery research and science, Fishery service under Ministry of Agriculture, Klaipeda, Lithuania.
    Stoetera, Sven
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Rostock, Germany.
    Strehlow, Harry Vincent
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Rostock, Germany.
    Ustups, Didzis
    Institute of Food Safety, Animal Health and Environment (BIOR), Fish Resources Research Department, Riga, Latvia.
    Walther, Yvonne
    Swedish University of Agricultural Sciences Institute of Marine Research, Karlskrona.
    Report of the Baltic Fisheries Assessment Working Group (WGBFAS), 3-10 April 2014, ICES HQ, Copenhagen, Denmark2014Report (Refereed)
  • 404.
    Storr-Paulsen, Marie
    et al.
    DTU Aqua - National Institute of Aquatic Resources, Denmark.
    Arula, Timo
    University of Tartu, Estonia.
    Bergenius, Mikaela
    Swedish University of Agricultural Sciences, Sweden.
    Boje, Jesper
    The National Institute of Aquatic Resources, Denmark.
    Casini, Michele
    Swedish University of Agricultural Sciences, Sweden.
    Degel, Henrik
    The National Institute of Aquatic Resources, Denmark.
    Eero, Margit
    The National Institute of Aquatic Resources, Denmark.
    Gasyukov, Pavel
    AtlantNIRO, Kaliningrad, Russian Federation.
    Gröhsler, Tomas
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Germany.
    Hjelm, Joakim
    Swedish University of Agricultural Sciences, Sweden.
    Horbowy, Jan
    Sea Fisheries Institute in Gdynia, Poland.
    Holmgren, Noél
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Jonusas, Stanislovas
    European Commission Directorate for Maritime Affairs and Fisheries, Belgium.
    Kaljuste, Olavi
    Swedish University of Agricultural Sciences, Sweden.
    Karpushevskaia, Anastasiia
    AtlantNIRO, Kaliningrad, Russian Federation.
    Karpushevskiy, Igor
    AtlantNIRO, Kaliningrad, Russian Federation.
    Kornilovs, Georgs
    Latvian Fish Resources Agency, Riga.
    Krumme, Uwe
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Germany.
    Luzenczyk, Anna
    National Marine Fisheries Research Institute, Poland.
    Lövgren, Johan
    Swedish University of Agricultural Sciences, Sweden.
    Mikhaylov, Andrey
    Russian Federal Research Institute of Fisheries & Oceanography (VNIRO), Russian Federation.
    Oeberst, Rainer
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Germany.
    Pönni, Jukka
    Finnish Game and Fisheries Research Institute, Finland.
    Raid, Tiit
    Estonian Marine Institute, University of Tartu, Estonia.
    Raitaniemi, Jari
    Finnish Game and Fisheries Research Institute, Finland.
    Sics, Ivo
    Institute of Food Safety, Animal Health and Environment (BIOR), Latvia.
    Statkus, Romas
    Fishery service under Ministry of Agriculture, Klaipeda, Lithuania.
    Stoetera, Sven
    Thünen Institute of Baltic Sea Fisheries (TI-OF), Germany.
    Ustups, Didzis
    Institute of Food Safety, Animal Health and Environment (BIOR), Latvia.
    Walther, Yvonne
    Swedish University of Agricultural Sciences, Karlskrona.
    Report of the Baltic Fisheries Assessment Working Group (WGBFAS), 10-17 April 2013, ICES Headquarters, Copenhagen2013Report (Refereed)
  • 405.
    Stratmann, Johannes
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Wang, Chao-Jie
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Gnosa, Sebastian
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Wallin, Åsa
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Hinselwood, David
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Sun, Xiao-Feng
    Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Zhang, Hong
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients2011In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, p. 345-Article in journal (Refereed)
    Abstract [en]

    Background: Dicer is aberrantly expressed in several types of cancers. Applying real-time PCR, we detected the expression of Dicer mRNA in normal mucosa (n = 162), primary colorectal cancer (CRC) (n = 162) and liver metastasis (n = 37), and analysed the relationship between Dicer expression and clinicopathological features. We also correlated the expression of Dicer mRNA to the miRNA expression of miR-141, miR-200a, miR-200b, mir-200c and miR-429 in liver metastases.

    Methods: RT-PCR and qPCR were used to analyse the Dicer expression in normal mucosa, primary tumour and liver metastasis by using the High Capacity cDNA Reverse Transcription Kit and TaqMan™® Gene Expression assays for Dicer and GAPDH. RT-PCR and qPCR were used to detect miRNA expression in liver metastases by utilizing TaqMan® MicroRNA Reverse Transcription Kit and TaqMan® miRNA Assays. Statistical analyses were performed with STATISTICA.

    Results: Dicer expression in rectal cancer (3.146 ± 0.953) was higher than in colon cancer (2.703 ± 1.204, P = 0.018). Furthermore the Dicer expression was increased in primary tumours (3.146 ± 0.952) in comparison to that in normal mucosa from rectal cancer patients (2.816 ± 1.009, P = 0.034) but this is not evident in colon cancer patients. Dicer expression in liver metastases was decreased in comparison to that of either normal mucosa or primary tumour in both colon and rectal cancers (P < 0.05). Patients with a high Dicer expression in normal mucosa had a worse prognosis compared to those with a low Dicer expression, independently of gender, age, tumour site, stage and differentiation (P < 0.001, RR 3.682, 95% CI 1.749 - 7.750). In liver metastases, Dicer was positively related to miR-141 (R = 0.419, P = 0.015).

    Conclusion: Dicer is up-regulated in the early development of rectal cancers. An increased expression of Dicer mRNA in normal mucosa from CRC patients is significantly related to poor survival independently of gender, age, tumour site, stage and differentiation.

  • 406.
    Sutkowska, Agnieszka
    et al.
    University of Agriculture in Krakow, Poland.
    Pasierbinski, Andrzej
    University of Silesia in Katowice, Poland.
    Warzecha, Tomasz
    University of Agriculture in Krakow, Poland.
    Mandal, Abul
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Mitka, Jozef
    Jagiellonian University in Krakow, Poland.
    Refugial pattern of Bromus erectus in Central Europe based on ISSR fingerprinting: Phylogeography of Bromus erectus in Central Europe2013In: Acta Biologica Cracoviensia. Series Botanica, ISSN 0001-5296, E-ISSN 1898-0295, Vol. 55, no 2, p. 107-119Article in journal (Refereed)
  • 407.
    Svala, Emilia
    et al.
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden / Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Thorfve, Anna I.
    BIOMATCELL, VINN Excellence Center of Biomaterials and Cell Therapy, Department of Biomaterials, Institute of Clinical Sciences, Sweden.
    Ley, Cecilia
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Henriksson, Helena K. Barreto
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Sweden / Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Synnergren, Jane M.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. University of Gothenburg, Sweden.
    Lindahl, Anders H.
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Sweden.
    Ekman, Stina
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Skiöldebrand, Eva S. R.
    Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden / Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, University of Gothenburg, Sweden.
    Effects of interleukin-6 and interleukin-1β on expression of growth differentiation factor-5 and Wnt signaling pathway genes in equine chondrocytes2014In: American Journal of Veterinary Research, ISSN 0002-9645, E-ISSN 1943-5681, Vol. 75, no 2, p. 132-140Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine the effects of interleukin (IL)-6 and IL-1β stimulation on expression of growth differentiation factor (GDF)-5 and Wnt signaling pathway genes in equine chondrocytes.

    SAMPLE: Macroscopically normal articular cartilage samples from 6 horses and osteochondral fragments (OCFs) from 3 horses.

    PROCEDURES: Chondrocyte pellets were prepared and cultured without stimulation or following stimulation with IL-6 or IL-1β for 1, 2, 12, and 48 hours; expression of GDF-5 was determined with a quantitative real-time PCR assay. Expression of genes in various signaling pathways was determined with microarrays for pellets stimulated for 1 and 2 hours. Immunohistochemical analysis was used to detect GDF-5, glycogen synthase kinase 3β (GSK-3β), and β-catenin proteins in macroscopically normal cartilage samples and OCFs.

    RESULTS: Chondrocytes stimulated with IL-6 had significantly higher GDF-5 expression within 2 hours versus unstimulated chondrocytes. Microarray analysis of Wnt signaling pathway genes indicated expression of GSK-3β and coiled-coil domain containing 88C increased after 1 hour and expression of β-catenin decreased after 2 hours of IL-6 stimulation. Results of immunohistochemical detection of proteins were similar to microarray analysis results. Chondrocytes in macroscopically normal articular cartilage and OCFs had immunostaining for GDF-5.

    CONCLUSION AND CLINICAL RELEVANCE: Results indicated IL-6 stimulation decreased chondrocyte expression of the canonical Wnt signaling pathway transactivator β-catenin, induced expression of inhibitors of the Wnt pathway, and increased expression of GDF-5. This suggested IL-6 may inhibit the Wnt signaling pathway with subsequent upregulation of GDF-5 expression. Anabolic extracellular matrix metabolism in OCFs may be attributable to GDF-5 expression. This information could be useful for development of cartilage repair methods.

  • 408.
    Svensson, Maria
    et al.
    University of Skövde, School of Life Sciences.
    Lundh, Dan
    University of Skövde, School of Humanities and Informatics.
    Ejdebäck, Mikael
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Mandal, Abul
    University of Skövde, School of Life Sciences.
    Functional prediction of a T-DNA tagged gene of Arabidopsis thalianaby in silico analysis2004In: Journal of Molecular Modeling, ISSN 1610-2940, E-ISSN 0948-5023, Vol. 10, no 2, p. 130-138Article in journal (Refereed)
    Abstract [en]

    We have employed a gene-knockout approach using T-DNA tagging and in vivo gene fusion in Arabidopsis thaliana for identification and isolation of specific plant genes. Screening of about 3,000 T-DNA tagged lines resulted in identification of a mutant line (no. 197) exhibiting a significant delay in flowering. From this line a 600-bp plant DNA fragment downstream of the left T-DNA junction was cloned by inverse PCR. BLAST searching in the A. thaliana genomic database indicated a putative gene, frf (flowering regulating factor), with unknown function downstream of the T-DNA insert. Bioinformatic tools were used to predict possible protein structure and function. The protein structure predicted by fold recognition indicates that frf is a transcriptional regulator, a ligand-binding receptor responsive to steroids and hormones. Analyzing the predicted results and the phenotype of the T-DNA tagged plant we hypothesized that FRF might be involved in hormone response in A. thaliana. For verification of this hypothesis we exposed the plants of line no. 197 to gibberellic acid (GA3), a potential growth regulator in higher plants. This treatment resulted in an earlier onset of flowering, almost similar to that in wild type control plants.

  • 409.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Explore transcription factor profiles in human pluripotent stem cells2014In: 6th International Conference on Bioinformatics and Computational Biology (BICoB 2014): Las Vegas, Nevada, USA, 24 – 26 March 2014 / [ed] F. Saeed, B. DasGupta, International Society for Computers and Their Applications , 2014, p. 197-202Conference paper (Refereed)
    Abstract [en]

    Human pluripotent stem cells (hPSCs) have unique properties of proliferation and self-renewal, and can be differentiated into various functional cell types. The differentiation processes are to a large extent controlled by transcription factors, which are key cellular components that control gene expression and determine how cells respond to the environment on various stimuli. Surprisingly little is known about the transcription factor activity in hPSCs, and more knowledge is needed about the transcriptional regulation during the differentiation processes. This information will be instrumental for development of efficient differentiation protocols to produce fully functional specialized cell types, for use in drug discovery and toxicity testing studies. This paper explores the expression of transcription factors in hPSCs, and gives an overview of the genomic organization of transcription factors, which likely are involved in the fate decision processes of hPSCs. In total 1,323 human transcription factors were selected from literature and further investigated for their genomic organization and their expression in hPSCs. Moreover, transcription factors that are highly expressed in undifferentiated hPSCs, compared to their differentiated progenies are identified and further investigated for protein-protein interaction activity using computational tools. The protein-protein interaction networks presented here will provide valuable information about the regulatory mechanisms, and reveal important proteins involved in the maintenance of the pluripotent state of stem cells.

  • 410.
    Synnergren, Jane
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Identification of miRNAs in Control of Aberrant Gene Transcription in Human Pluripotent Stem Cell Derived Hepatocytes2013In: Computer Applications in Industry and Engineering (CAINE-2013), 26th International Conference September 25-27, 2013, Los Angeles, California, USA / [ed] Sultan Aljahdali, International Society for Computers and Their Applications , 2013, p. 11-16Conference paper (Refereed)
  • 411.
    Synnergren, Jane
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    MicroRNA regulatory network involved in impaired functionality in cardiomyocytes derived from human embryonic stem cells2012In: 25th International Conference on Computer Applications in Industry and Engineering 2012 (CAINE-2012) Held with the 4th International Symposium on Sensor Network and Application (SNA-2012): New Orleans, Louisiana, USA 14-16 November 2012 / [ed] Gongzhu Hu, International Society for Computers and Their Applications , 2012, p. 133-138Conference paper (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESCs) have unique properties of proliferation and self-renewal, and can be differentiated into various functional cell types e.g. cardiomyocytes. However, previous studies have shown that the expression of cardiac ion channels and genes involved in the Ca2+-handling machinery is immature in the stem cell derived cardiomyocytes, and novel approaches are therefore needed to improve the differentiation protocols and produce more functional cardiomyocytes. MicroRNAs (miRNAs) are small molecules, which play key roles in regulation of cellular development and may therefore be powerful tools to improve the differentiation.

    This paper presents a method to derive a miRNA-mRNA regulatory network, which likely are important for the regulation of the functionality that currently is lacking in the hESC-derived cardiomyocytes. In total 14 ion channels and 9 calcium handling genes that have important roles in cardiac tissue and which have shown to be significantly lower expressed in hESC-derived cardiomyocytes compared to their in vivo counterpart, were investigated and scanned for putative miRNA target sites. For each of the predicted miRNAs, a combined prediction score (CPS) was calculated and a miRNA regulatory network was generated consisting of miRNAs with a high CPS and with multiple targets among the investigated genes. Results from this study propose that the miRNA network presented here is highly involved in the hampered functionality seen in hESC-derived cardiomyocytes, and that it therefore will constitute an important tool to select candidate miRNAs for future knockout- and overexpression studies.

  • 412.
    Synnergren, Jane
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Transcriptional profiling of human embryonic stem cells and their functional derivatives2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human    embryonic    stem    cells    (hESCs)    represent    populations    of    pluripotent, undifferentiated  cells  with  unlimited  replication  capacity,  and  with  the  ability  to differentiate into any functional cell type in the human body. Based on these properties, hESCs  and  their  derivatives  provide  unique  model  systems  for  basic  research  on embryonic development. Also, industrial in vitro applications of hESCs are now beginning to  find  their  way  into  the  fields  of  drug  discovery  and  toxicology.  Moreover,  hESC-derivatives are anticipated to be promising resources for future cell replacement therapies. However, in order to fully utilize the potential of hESCs it is necessary to increase our knowledge about the processes that govern the differentiation of these cells. At present, some  of  the  major  challenges  in  stem  cell  research  are  heterogeneous  cell  populations, insufficient  yield  of  the  differentiated  cell  types  and  immature  derivatives  with  limited functionality.  To  address  these  problems,  a  better  understanding  of  the  regulatory mechanisms  that  control  the  lineage  commitment  is  needed.  The  aim  of  this  thesis  has been to increase the knowledge of the global transcriptional programs which are activated when  cells  differentiate  along  specific  pathways,  and  to  identify  key  genes  that  show differential expression at specific stages of differentiation. The results indicate that hESCs express a unique set of housekeeping genes that are stably expressed in this specific cell type  and  in  their  derivatives,  which  highlights  the  importance  of  proper  validation  of reference genes for usage in hESCs. Furthermore, an extensive characterization of hESCs and differentiated progenies of the cardiac and hepatic lineages has been conducted, and sets  of  differentially  expressed  genes  were  identified.  Two  different  protocols,  which mediate  definitive  and  primitive  endoderm  respectively,  were  studied,  and  important discrepancies  between  these  two  cell  types  were  identified.  Moreover,  the  global expression profile of hESC-derived cardiomyocyte clusters were thoroughly investigated and compared to that of foetal and adult heart. To further study regulatory mechanisms of  importance  during  stem  cell  differentiation,  the  global  expression  of  microRNAs (miRNAs) was also investigated. Putative target genes of differentially expressed miRNAs were  identified  using  computational  predictions,  and  their  mRNA  expression  was analysed. Notably, an interesting correlation between the miRNA and mRNA expression was observed, which supports the general notion that miRNAs bind to and degrade their target mRNAs, and thus act as fine-tuning regulators of gene expression. Taken together, the results described in this thesis provide important information for further studies on regulatory mechanisms that control the differentiation of hESCs into functional cell types such as cardiomyocytes and hepatocytes. 

  • 413.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital.
    Ameen, Caroline
    Cellartis, Göteborg, Sweden.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis, Göteborg, Sweden.
    Global transcriptional profiling reveals similarities and differences between human stem cell-derived cardiomyocyte clusters and heart tissue2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 4, p. 245-258Article in journal (Refereed)
    Abstract [en]

    It is now well documented that human embryonic stem cells (hESCs) can differentiate into functional cardiomyocytes. These cells constitute a promising source of material for use in drug development, toxicity testing, and regenerative medicine. To assess their utility as replacement or complement to existing models, extensive phenotypic characterization of the cells is required. In the present study, we used microarrays and analyzed the global transcription of hESC-derived cardiomyocyte clusters (CMCs) and determined similarities as well as differences compared with reference samples from fetal and adult heart tissue. In addition, we performed a focused analysis of the expression of cardiac ion channels and genes involved in the Ca2+-handling machinery, which in previous studies have been shown to be immature in stem cell-derived cardiomyocytes. Our results show that hESC-derived CMCs, on a global level, have a highly similar gene expression profile compared with human heart tissue, and their transcriptional phenotype was more similar to fetal than to adult heart. Despite the high similarity to heart tissue, a number of significantly differentially expressed genes were identified, providing some clues toward understanding the molecular difference between in vivo sourced tissue and stem cell derivatives generated in vitro. Interestingly, some of the cardiacrelated ion channels and Ca2+-handling genes showed differential expression between the CMCs and heart tissues. These genes may represent candidates for future genetic engineering to create hESC-derived CMCs that better mimic the phenotype of the cardiomyocytes present in the adult human heart.

  • 414.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Améen, Caroline
    Cellartis, Gothenburg, Sweden.
    Lindahl, Anders
    Dept of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital, Sweden.
    Olsson, Björn
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis, Gothenburg, Sweden .
    Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue2011In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 10, p. 581-594Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue-like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation.

  • 415.
    Synnergren, Jane
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Drowley, Lauren
    Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Plowright, Alleyn T.
    Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Brolén, Gabriella
    Discovery Sciences, AstraZeneca Gothenburg, Mölndal, Sweden.
    Goumans, Marie-Josè
    Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
    Gittenberger-de Groot, Adriana C.
    Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Cardiovascular and Metabolic Disease Global Medicines Development Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Wang, Qing-Dong
    Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden.
    Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitors and hiPSC-derived cardiac progenitors2016In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 48, no 11, p. 771-784Article in journal (Refereed)
    Abstract [en]

    Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitor cells and hiPSC-derived cardiac progenitor cells: effects of hypoxic vs normoxic culture conditions.

  • 416.
    Synnergren, Jane
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Dönnes, Pierre
    SciCross AB, Skövde, Sweden.
    Current Perspectives on Multi-Omics Data Integration With Application on Toxicity Biomarkers Discovery2018In: Open Access journal of Toxicology, ISSN 2474-7599, Vol. 2, no 5, p. 1-2, article id OAJT.MS.ID.555597Article, review/survey (Refereed)
  • 417.
    Synnergren, Jane
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Ghosheh, Nidal
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Dönnes, Pierre
    SciCross AB.
    Integration of Biomedical Big Data Requires Efficient Batch Effect Reduction2018In: 10th International Conference on Bioinformatics and Computational Biology (BICOB): Las Vegas, Nevada, USA 19 – 21 March 2018 / [ed] Hisham Al-Mubaid, Qin Ding, Oliver Eulenstein, 2018, p. 76-82Conference paper (Refereed)
    Abstract [en]

     Efficiency in dealing with batch effects will be the next frontier in large-scale biological data analysis, particularly when involving the integration of different types of datasets. Large-scale omics techniques have quickly developed during the last decade and huge amounts of data are now generated, which has started to revolutionize the area of medical research. With the increase in the volume of data across the whole spectrum of biology, problems related to data analytics are continuously increasing as analysis and interpretation of these large volumes of molecular data has become a real challenge. Tremendous efforts have been made to obtain data from various molecular levels and the most recent trends show that more and more researchers now are trying to integrate data of various molecular types to inform hypotheses and biological questions. Tightly connected to this work are the batch-related biases that commonly are apparent between different datasets, but these problems are often not tackled. In present study the ComBat algorithm was applied and evaluated on two different data integration problems. Results show that the batch effects present in the integrated datasets efficiently could be removed by applying the ComBat algorithm.

  • 418.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Heins, Nico
    Cellartis AB, Göteborg.
    Brolén, Gabriella
    Cellartis AB, Göteborg.
    Eriksson, Gustav
    Cellartis AB, Göteborg.
    Lindahl, Anders
    Sahlgrenska University Hospital.
    Hyllner, Johan
    Cellartis AB, Göteborg.
    Olsson, Björn
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis AB, Göteborg.
    Björnquist, Petter
    Cellartis AB, Göteborg.
    Transcriptional profiling of human embryonic stem cells differentiating to definitive and primitive endoderm and further towards the hepatic lineage2010In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 19, no 7, p. 961-978Article in journal (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESC) can differentiate into a variety of specialized cell types, and they constitute a useful model system to study embryonic development in vitro. In order to fully utilize the potential of these cells, the mechanisms that regulate the developmental processes of specific lineage differentiation need to be better defined. The aim of this study was to explore the molecular program involved in the differentiation of hESC towards definitive endoderm (DE) and further into the hepatic lineage, and to compare that to primitive endoderm (PrE) differentiation. To that end, we applied two protocols, a specific DE differentiation protocol and an intrinsic differentiation protocol that mainly mediates PrE formation. We collected hESC, hESC-derived DE, DE-derived hepatocyte-progenitors (DE-Prog), DE-derived hepatocyte-like cells (DE-Hep), and the corresponding PrE-derivatives. The samples were analyzed using microarrays, and we identified sets of genes which were exclusively up-regulated in DE-derivatives (compared to PrE-derivatives) at discrete developmental stages. We also investigated known protein interactions among the set of up-regulated genes in DE-Hep. The results demonstrate important differences between DE- and PrE-differentiation on the transcriptional level. In particular, our results identify a unique molecular program, exclusively activated during development of DE and the subsequent differentiation of DE towards the hepatic lineage. We identified key-genes and pathways of potential importance for future efforts to improve hepatic differentiation from hESC. These results reveal new opportunities for rational design of specific interventions with the purpose of generating enriched populations of DE derivatives, including functional hepatocytes.

  • 419.
    Synnergren, Jane Marie
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Ameén, Caroline
    Takara Bio Europe, Gothenburg, Sweden.
    Åkesson, Karolina
    Takara Bio Europe, Gothenburg, Sweden.
    Karlsson, Alexander
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Riveiro, Maria
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Andersson, Christian X.
    Takara Bio Europe, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Transcriptional profiling of human embryonic stem cells during mesodermal- and cardiac differentiation2016Conference paper (Refereed)
  • 420.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Olsson, Björn
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Gamalielsson, Jonas
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    A Data Integration Method for Exploring Gene Regulatory Mechanisms2008In: Conference on Information and Knowledge Management: Proceedings of the 2nd international workshop on Data and text mining in bioinformatics, ACM Press, 2008, p. 81-84Conference paper (Refereed)
    Abstract [en]

    Systems biology aims to understand the behavior of and interaction between various components of the living cell, such as genes, proteins, and metabolites. A large number of components are involved in these complex systems and the diversity of relationships between the components can be overwhelming, and there is therefore a need for analysis methods incorporating data integration. We here present a method for exploring gene regulatory mechanisms which integrates various types of data to assist the identification of important components in gene regulation mechanisms. By first analyzing gene expression data, a set of differentially expressed genes is selected. These genes are then further investigated by combining various types of biological information, such as clustering results, promoter sequences, binding sites, transcription factors and other previously published information regarding the selected genes. Inspired by Information Fusion research, we also mapped functions of the proposed method to the well-known OODA-model to facilitate application of this data integration method in other research communities. We have successfully applied the method to genes identified as differentially expressed in human embryonic stem cells at different stages of differentiation towards cardiac cells. We identified 15 novel motifs that may represent important binding sites in the cardiac cell linage.

  • 421.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Olsson, Björn
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Gamalielsson, Jonas
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Classification of information fusion methods in systems biology2009In: In Silico Biology, ISSN 1386-6338, Vol. 9, no 3, p. 65-76Article, review/survey (Refereed)
    Abstract [en]

    Biological systems are extremely complex and often involve thousands of interacting components. Despite all efforts, many complex biological systems are still poorly understood. However, over the past few years high-throughput technologies have generated large amounts of biological data, now requiring advanced bioinformatic algorithms for interpretation into valuable biological information. Due to these high-throughput technologies, the study of biological systems has evolved from focusing on single components (e.g. genes) to encompassing large sets of components (e.g. all genes in an entire genome), with the aim to elucidate their interdependences in various biological processes. In addition, there is also an increasing need for integrative analysis, where knowledge about the biological system is derived by data fusion, using heterogeneous data sets as input. We here review representative examples of bioinformatic methods for fusion-oriented interpretation of multiple heterogeneous biological data, and propose a classification into three categories of tasks that they address: data extraction, data integration and data fusion. The aim of this classification is to facilitate the exchange of methods between systems biology and other information fusion application areas.

  • 422.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis AB, Sweden.
    Microarray Analysis of Undifferentiated and Differentiated Human Pluripotent Stem Cells2011In: Methodological Advances in the Culture, Manipulation and Utilization of Embryonic Stem Cells for Basic and Practical Applications / [ed] Craig Atwood, Rijeka, Croatia: INTECH, 2011, p. 343-366Chapter in book (Refereed)
  • 423.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Sartipy, Peter
    Cellartis AB, Sweden.
    Transcriptional analysis of messenger-RNA and micro-RNA array data reveals global negative correlation in human stem cell derived cardiomyocyte clusters2012In: 4th International Conference on Bioinformatics and Computational Biology / [ed] F. Saeed H. Al-Mubaid, Curran Associates, Inc., 2012, p. 178-183Conference paper (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are small non-coding molecules that have been shown to play key roles in regulating cellular development and to be involved in various diseases. By interfering with their target mRNAs, these molecules inhibit the expression of proteins, either by de-stabilizing the messenger RNA (mRNA) molecule or by preventing its translation. Each miRNA can target hundreds of mRNAs, and one mRNA can be targeted by several miRNAs.This makes it extremely complex to determine the regulatory functions of specific miRNAs in the transcription and translation processes. However, important advancements in microarray technology have made large scale monitoring of miRNA expression possible. This opens the possibility to move from studies of single molecules to studies of complex molecular processes, pathways, and biological systems. Recent studies have indicated important roles for miRNAs in stem cell differentiation in general and in cardiac development in particular. This paper presents a global transcriptional study where putativecorrelation between miRNA and mRNA expression in fetal- and adult heart tissues samples and in clusters of cardiomyocytes derived from human embryonic stem cells (hESCs) were investigated. Target genes of miRNAs expressed in cardiac tissue have been predicted and their transcriptional profiles investigated in tissue specimen. By using a statistical algorithm, up- and down-regulated miRNAs and mRNAs have been identified in four different cardiac related samples. In total, 17 cardiac related miRNAs have been analyzed and for each of these, clusters of negatively correlated target genes were identified. This supports the hypothesis that sets of miRNAs play an important role in modulating the expression of genes, which are important for cardiac development. Interestingly, the results from this study also indicate a global negative correlation between miRNA expression and mRNA expression, which previously has not been reported.

  • 424.
    Synnergren, Jane
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Özdogan, Alper
    Yildiz Technical University, Turkey.
    Olsson, Björn
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Sartipy, Peter
    Cellartis AB, Göteborg, Sweden.
    Clustering micro-RNA array data using an information fusion based approach with multiple types of input data2010In: Proceedings of the ISCA 2nd International Conference on Bioinformatics and Computational Biology, BICoB-2010, March 24-26, 2010, Sheraton Waikiki Hotel, Honolulu, Hawaii, USA / [ed] Hisham Al-Mubaid, International Society for Computers and Their Applications , 2010, p. 151-158Conference paper (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are small non-coding molecules that have been shown to play key roles in regulating cellular development and to be involved in various diseases. By interfering with their target mRNAs, these molecules inhibit the expression of proteins, either by destabilizing the mRNA molecule or by preventing its translation. It has been suggested that each miRNA can target hundreds of mRNAs, and that one mRNA can be targeted by several miRNAs. This makes it extremely complex to determine the roles of specific miRNAs in the regulation of translation of mRNA. Recent advancements in microarray technology have made large-scale monitoring of miRNA expression possible. However, the size and complexity of these data sets make them challenging to analyze, and improved algorithms are therefore required to facilitate the analysis. In this paper, we present a novel clustering algorithm that uses an Information Fusion (IF) approach to cluster miRNA data, allowing for multiple types of input data to guide the clustering. For evaluation of the algorithm, we used miRNA expression data from human embryonic stem cells and cardiomyocyte-like cells derived thereof. Clusters obtained when using the multiple input data approach were compared to those generated when using only the expression data. Our results show that it is beneficial to include various types of genomic data as input to the clustering process, since it results in clusters of increased biological relevance.

  • 425.
    Säterberg, Torbjörn
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Division of Theoretical Biology, Sweden / Swedish University of Agricultural Sciences, Department of Aquatic Resources, Öregrund, Sweden.
    Jonsson, Tomas
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Swedish University of Agricultural Sciences, Department of Ecology, Uppsala, Sweden.
    Yearsley, Jon
    University College Dublin, School of Biology & Environmental Science, Ireland / UCD Earth Institute, Belfield, Dublin 4, Ireland.
    Berg, Sofia
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Ebenman, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Division of Theoretical Biology, Sweden / Stockholm University, SRC, Sweden.
    A potential role for rare species in ecosystem dynamics2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, p. 1-12, article id 11107Article in journal (Refereed)
    Abstract [en]

    The ecological importance of common species for many ecosystem processes and functions is unquestionably due to their high a bundance.Yet, the importance of rare species is much less understood. Here we take a theoretical approach, exposing dynamical models of ecological networks to small perturbations, to explore the dynamical importance of rare and common species. We find that both species types contribute to the recovery of communities following generic perturbations (i.e. perturbations affecting all species).Yet, when perturbations are selective (i.e. affects only one species), perturbations to rare species have the most pronounced effect on community stability. We show that this is due to the strong indirect effects induced by perturbations to rare species. Because indirect effects typically set in at longer timescales, our results indicate that the importance of rare species may be easily overlooked and thus underrated. Hence, our study provides a potential ecological motive for the management and protection of rare species.

  • 426.
    Sögaard, Peter
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Szekeres, Ferenc
    Department of Molecular Medicine and Surgery, Section og Integrative Physiology, Karolinska Institutet.
    Holmström, Maria
    Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet.
    Larsson, Dennis
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Harlén, Mikael
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Garcia-Roves, Pablo
    Section of Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet.
    Chibalin, Alexander V.
    Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet.
    Effects of fibre type and diffusion distance on mouse skeletal muscle glycogen content in vitro2009In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 107, no 6, p. 1189-1197Article in journal (Refereed)
    Abstract [en]

    In vitro incubation of isolated rodent skeletal muscle is a widely used procedure in metabolic research. One concern with this method is the development of an anoxic state during the incubation period that can cause muscle glycogen depletion. Our aim was to investigate whether in vitro incubation conditions influence glycogen concentration in glycolytic extensor digitorum longus (EDL) and oxidative soleus mouse muscle. Quantitative immunohistochemistry was applied to assess glycogen content in incubated skeletal muscle. Glycogen concentration was depleted, independent of insulin-stimulation in the incubated skeletal muscle. The extent of glycogen depletion was correlated with the oxidative fibre distribution and with the induction of hypoxia-induced-factor-1-alpha. Insulin exposure partially prevented glycogen depletion in soleus, but not in EDL muscle, providing evidence that glucose diffusion is not a limiting step to maintain glycogen content. Our results provide evidence to suggest that the anoxic milieu and the intrinsic characteristics of the skeletal muscle fibre type play a major role in inducing glycogen depletion in during in vitro incubations.

  • 427.
    Sögård, Peter
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Mathematical Modelling of Insulin Signalling: Effects on Glucose Metabolism in Skeletal Muscle2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The use of models to understand complex phenomena is indispensable to the scientific community. The advantage of a model is that it simplifies the phenomena under study. However, a model should be only as complex as required, no more, no less. Furthermore, a model should avoid known or unknown confounding variables that might obscure the interpretations of observations. Within biology, models can be set up in many different ways, such as mathematical, graphical or verbal descriptions of the system under study. In physiology, the systems under study can be the entire animal or organs or cell cultures from it. To study some aspects of the regulation of glucose and energy homeostasis, skeletal muscles is a preferable model, as it is the main consumer of post-prandial glucose, and thus, important for maintaining whole body glucose and energy homeostasis. Incubation of skeletal muscle specimens in a suitable solution is a model-system that has been used during the last century. The availability of oxygen for energy transformation has been of major concern. Therefore, the experimental system has been validated several times with different methods, both experimentally and mathematically.

    The result from experimental validations indicates that glycogen content is unequally distributed within the incubated muscle specimens, with the core depleted of glycogen. Furthermore, validation done with the mathematical models describing the experimental systems indicates that oxygen diffusion is sufficient if the following assumptions are valid; homogeneous structure and that the critical value of oxygen pressure is above zero throughout the entire muscle. However, if those assumptions are invalid, the observations of some metabolic and/or signalling data might be invalid. In this thesis, those assumption are validated, with the specific aim to derive mathematical models that can be used to further analyse the metabolic data generated.

    Set of ordinary differential equation was used to describe the metabolic data derived from incubation of mouse extensor digitorum longus skeletal muscles preparations, paper 1. The parameters and constants were identified within the mathematical model, which then, was further analysed. The results indicated that the experimental system suffered from anoxia and that glycogen was depleted during the incubation time. An immunohistochemical approach was used to verify the predictions from the mathematical model on glycogen depletion, paper 2. A statistical approach was developed herein that made quantitative studies possible and the results verified the prediction from the mathematical model in paper 1. Furthermore, a correlation between fibre type distribution and glycogen depletion was observed, indicating that the assumption on homogeneous glucose handling might be too hard. The existence of anoxia within the incubated muscle specimens was revealed. A novel hypothesis regarding deficient insulin diffusion into the centre of the incubated muscle preparation as the cause for quasi-depletion of glycogen was tested, paper 3. The hypothesis was falsified; instead increased insulin signalling was observed in the core of the muscle, correlating with fibre types on the single-cell-level.

    In conclusion, the studies presented in this thesis provide evidence that muscle preparations are suffering of anoxia after incubation leading to depletion of glycogen. Furthermore, the assumption on homogeneous glucose handling is falsified. Finally, a mathematical model is provided that can be used to estimate the un-measurable glycogen concentrations and estimate the glucose uptake rate in the superficial fibres.

  • 428.
    Sögård, Peter
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences. Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Long, Yun Chau
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Szekeres, Ferenc
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Barnes, Brian R.
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Chibalin, Alexander V.
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Zierath, Juleen R.
    Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
    Validation of the in vitro incubation of extensor digitorum longus muscle from mice with a mathematical model2010In: Journal of biological systems, ISSN 0218-3390, Vol. 18, no 3, p. 687-707Article in journal (Refereed)
    Abstract [en]

    In vitro incubation of tissues; in particular, skeletal muscles from rodents, is a widely-used experimental method in diabetes research. This experimental method has previously been validated, both experimentally and theoretically. However, much of the method's experimental data remains unclear, including the high-rate of lactate production and the lack of an observable increase in glycogen content, within a given time. The predominant hypothesis explaining the high-rate of lactate production is that this phenomenon is dependent on a mechanism in glycolysis that works as a safety valve, producing lactate when glucose uptake is super-physiological. Another hypothesis is that existing anoxia forces more ATP to be produced from glycolysis, leading to an increased lactate concentration. The lack of an observable increase in glycogen content is assumed to be dependent on limitations in sensitivity of the measuring method used. We derived a mathematical model to investigate which of these hypotheses is most likely to be correct. Using our model, data analysis indicates that the in vitro incubated muscle specimens, most likely are sensing the presence of existing anoxia, rather than an overflow in glycolysis. The anoxic milieu causes the high lactate production. The model also predicts an increased glycogenolysis. After mathematical analyses, an estimation of the glycogen concentration could be made with a reduced model. In conclusion, central anoxia is likely to cause spatial differences in glycogen concentrations throughout the entire muscle. Thus, data regarding total glycogen levels in the incubated muscle do not accurately represent the entire organ. The presented model allows for an estimation of total glycogen, despite spatial differences present in the muscle specimen.

  • 429.
    Takahashi, Yuki
    et al.
    Karolinska Inst, Stockholm, Sweden / Japanese Red Cross Toyota Coll Nursing, Aichi, Japan.
    Jonas, Wibke
    Karolinska Inst, Stockholm, Sweden / Univ Toronto, Canada.
    Ransjo-Arvidson, Anna-Berit
    Karolinska Inst, Stockholm, Sweden.
    Lidfors, Lena
    Swedish University of Agricultural Sciences, Skara, Sweden.
    Uvnäs Moberg, Kerstin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Swedish University of Agricultural Sciences, Skara, Sweden.
    Nissen, Eva
    Karolinska Institutet, Stockholm, Sweden.
    Weight loss and low age are associated with intensity of rooting behaviours in newborn infants2015In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no 10, p. 1018-1023Article in journal (Refereed)
    Abstract [en]

    Aim: Little is known about the developing breastfeeding behaviour of newborn infants. This study describes infants' prebreastfeeding behaviour during the second day of life and explores possible associations with infant characteristics. Methods: We studied 13 mothers and healthy full-term infants after normal births. At 2448 hours of life, the newborns were placed in skin-to-skin contact with their mothers for breastfeeding and were video-filmed. The order, frequency and duration of predefined infant prefeeding behaviours and suckling were coded and analysed using computer-based video software. Results: Prefeeding behaviours occurred in the following order: rooting, hand to mouth movements, licking of the nipple and hand to breast to mouth movements. The infants started to suckle at a median of one to two minutes. Rooting was the most common behaviour, observed in 12 infants. The duration of rooting movements during the last minute before breastfeeding was inversely related to neonatal age (p = 0.001) and positively related to neonatal weight loss (p = 0.02) after birth. Conclusion: Infants exhibited a distinct sequence of prefeeding behaviours during the second day of life, and our findings suggest that rooting movements were governed by mechanisms involved in the regulation of food intake and weight gain.

  • 430.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Long-term effects of penicillin resistance and fitness cost on pneumococcal transmission dynamics in a developed setting2016In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 6, article id 31234Article in journal (Refereed)
    Abstract [en]

    Background: The increasing prevalence of penicillin non-susceptible pneumococci (PNSP) throughout the world threatens successful treatment of infections caused by this important bacterial pathogen. The rate at which PNSP clones spread in the community is thought to mainly be determined by two key determinants; the volume of penicillin use and the magnitude of the fitness cost in the absence of treatment. The aim of the study was to determine the impacts of penicillin consumption and fitness cost on pneumococcal transmission dynamics in a developed country setting.

    Methods: An individual-based network model based on real-life demographic data was constructed and applied in a developed country setting (Sweden). A population structure with transmission of carriage taking place within relevant mixing groups, i.e. families, day care groups, school classes, and other close contacts, was considered to properly assess the transmission dynamics for susceptible and PNSP clones. Several scenarios were simulated and model outcomes were statistically analysed.

    Results: Model simulations predicted that with an outpatient penicillin use corresponding to the sales in Sweden 2010 (118 recipes per 1,000 inhabitants per year), the magnitude of a fitness cost for resistance must be at least 5% to offset the advantage of penicillin resistance. Moreover, even if there is a fitness cost associated with penicillin resistance, a considerable reduction of penicillin usage appears to be required to significantly decrease the incidence of PNSP in a community.

    Conclusion: The frequency of PNSP clones is hard to reverse by simply reducing the penicillin consumption even if there is a biological cost associated with resistance. However, because penicillin usage does promote further spread of PNSP clones, it is important to keep down penicillin consumption considering future resistance problems.

  • 431.
    Tina, Elisabet
    et al.
    Clinical Research Centre, Örebro University Hospital, Örebro, Sweden / School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Malakkaran Lindqvist, Breezy
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Gabrielson, Marike
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Lubovac, Zelmina
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Wegman, Pia
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Wingren, Sten
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. Article number 350-Article in journal (Refereed)
    Abstract [en]

    Background: Overexpression of the human epidermal growth factor receptor (HER) 2 is associated with poor prognosis and shortened survival in breast cancer patients. HER2 is a potent activator of several signaling pathways that support cell survival, proliferation and metabolism. In HER2- positive breast cancer there are most likely unexplored proteins that act directly or indirectly downstream of well established pathways and take part in tumor development and treatment response.

    Methods: In order to identify novel copy number variations (CNVs) in HER2-positive breast cancer whole-genome single nucleotide polymorphism (SNP) arrays were used. A PCR-based loss of heterozygosis (LOH) assay was conducted to verify presence of deletion in HER2-positive breast cancer cases but also in HER2 negative breast cancers, cervical cancers and lung cancers. Screening for mutations was performed using single-strand conformation polymorphism (SSCP) followed by PCR sequencing. Protein expression was evaluated with immunohistochemistry (IHC).

    Results: A common deletion at chromosome Xq24 was found in 80% of the cases. This locus harbors the gene solute carrier (SLC) family 25A member 43 (SLC25A43) encoding for a mitochondrial transport protein. The LOH assay revealed presence of SLC25A43 deletion in HER2-positive (48%), HER2-negative (9%), cervical (42%) and lung (67%) cancers. HER2- positive tumors with negative or low SLC25A43 protein expression had significantly lower S-phase fraction compared to tumors with medium or high expression (P = 0.024).

    Conclusions: We have found deletion in the SLC25A43 gene to be a common event in HER2-positive breast cancer as well as in other cancers. In addition, the SLC25A43 protein expression was shown to be related to S-phase fraction in HER2-positive breast cancer. Our results indicate a possible role of SLC25A43 in HER2-positive breast cancer and support the hypothesis of altered mitochondrial function in cancer.

  • 432.
    Torra, Vicenç
    et al.
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Jonsson, Annie
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Navarro‐Arribas, Guillermo
    Universitat Autònoma de Barcelona, Spain / Center for Cybersecurity Research of Catalonia (CYBERCAT), Spain.
    Salas, Julián
    Center for Cybersecurity Research of Catalonia (CYBERCAT), Spain / Universitat Oberta de Catalunya (UOC), Barcelona, Spain.
    Synthetic generation of spatial graphs2018In: International Journal of Intelligent Systems, ISSN 0884-8173, E-ISSN 1098-111X, Vol. 32, no 12, p. 2364-2378Article in journal (Refereed)
    Abstract [en]

    Graphs can be used to model many different types of interaction networks, for example, online social networks or animal transport networks. Several algorithms have thus been introduced to build graphs according to some predefined conditions. In this paper, we present an algorithm that generates spatial graphs with a given degree sequence. In spatial graphs, nodes are located in a space equiped with a metric. Our goal is to define a graph in such a way that the nodes and edges are positioned according to an underlying metric. More particularly, we have constructed a greedy algorithm that generates nodes proportional to an underlying probability distribution from the spatial structure, and then generates edges inversely proportional to the Euclidean distance between nodes. The algorithm first generates a graph that can be a multigraph, and then corrects multiedges. Our motivation is in data privacy for social networks, where a key problem is the ability to build synthetic graphs. These graphs need to satisfy a set of required properties (e.g., the degrees of the nodes) but also be realistic, and thus, nodes (individuals) should be located according to a spatial structure and connections should be added taking into account nearness.

  • 433.
    Torra, Vicenç
    et al.
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Karlsson, Alexander
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Steinhauer, H. Joe
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Berglund, Stefan
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Artificial Intelligence2019In: Data Science in Practice / [ed] Alan Said, Vicenç Torra, Springer, 2019, p. 9-26Chapter in book (Refereed)
    Abstract [en]

    This chapter gives a brief introduction to what artificial intelligence is. We begin discussing some of the alternative definitions for artificial intelligence and introduce the four major areas of the field. Then, in subsequent sections we present these areas. They are problem solving and search, knowledge representation and knowledge-based systems, machine learning, and distributed artificial intelligence. The chapter follows with a discussion on some ethical dilemma we find in relation to artificial intelligence. A summary closes this chapter.

  • 434.
    Toräng, Per
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Bioscience. Department of Plant Ecology and Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
    Vikström, Linus
    Department of Plant Ecology and Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
    Wunder, Jörg
    Department of Plant Developmental Biology, Max Planck Institute for Plant Breeding Research, Cologne, Germany.
    Wötzel, Stefan
    Department of Plant Developmental Biology, Max Planck Institute for Plant Breeding Research, Cologne, Germany.
    Coupland, George
    Department of Plant Developmental Biology, Max Planck Institute for Plant Breeding Research, Cologne, Germany.
    Ågren, Jon
    Department of Plant Ecology and Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
    Evolution of the selfing syndrome: Anther orientation and herkogamy together determine reproductive assurance in a self-compatible plant2017In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 71, no 9, p. 2206-2218Article in journal (Refereed)
    Abstract [en]

    Capacity for autonomous self-fertilization provides reproductive assurance, has evolved repeatedly in the plant kingdom, and typically involves several changes in flower morphology and development (the selfing syndrome). Yet, the relative importance of different traits and trait combinations for efficient selfing and reproductive success in pollinator-poor environments is poorly known. In a series of experiments, we tested the importance of anther-stigma distance and the less studied trait anther orientation for efficiency of selfing in the perennial herb Arabis alpina. Variation in flower morphology among eight self-compatible European populations was correlated with efficiency of self-pollination and with pollen limitation in a common-garden experiment. To examine whether anther-stigma distance and anther orientation are subject to directional and/or correlational selection, and whether this is because these traits affect pollination success, we planted a segregating F2 population at two native field sites. Selection strongly favored a combination of introrse anthers and reduced anther-stigma distance at a site where pollinator activity was low, and supplemental hand-pollination demonstrated that this was largely because of their effect on securing self-pollination. The results suggest that concurrent shifts in more than one trait can be crucial for the evolution of efficient self-pollination and reproductive assurance in pollinator-poor habitats.

  • 435.
    Toto, Robert D.
    et al.
    University of Texas Southwestern Medical Center, Dallas, TX, USA.
    Goldenberg, Ronald
    LMC Diabetes & Endocrinology, Thornhill, ON, Canada.
    Chertow, Glenn M.
    Stanford University School of Medicine, CA, USA.
    Cain, Valerie
    Bogier Clinical and IT Solutions, Raleigh, NC, USA.
    Stefánsson, Bergur V.
    Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Sjöström, Carl David
    Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Correction of hypomagnesemia by dapagliflozin in patients with type 2 diabetes: A post hoc analysis of 10 randomized, placebo-controlled trials2019In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 33, no 10, article id 107402Article in journal (Refereed)
    Abstract [en]

    Aims: Hypomagnesemia (serum magnesium [Mg] <0.74 mmol/L [<1.8 mg/dL]) is commonly observed in patients with type 2 diabetes (T2D). This study investigated the effect of treatment with dapagliflozin 10 mg on Mg concentrations in patients with T2D. Methods: In this post hoc analysis, we used pooled data from 10 placebo-controlled studies of dapagliflozin over 24 weeks of treatment in patients with T2D. We evaluated the change in Mg in patients receiving dapagliflozin vs. placebo overall, and in subgroups with baseline hypomagnesemia and normal/hypermagnesemia (≥0.74 mmol/L [≥1.8 mg/dL]). We determined the proportion of patients with baseline hypomagnesemia who achieved Mg ≥0.74 mmol/L (≥1.8 mg/dL). Results: A total of 4398 patients with T2D were included. The mean change from baseline to week 24 in Mg was significantly larger with dapagliflozin vs. placebo; difference, 0.06 mmol/L (95% confidence interval [CI]: 0.05, 0.06). The proportion of patients with Mg within the population reference range after 24 weeks of treatment was significantly higher with dapagliflozin vs. placebo; difference, 47.8% (95% CI: 41.4, 53.9). The proportion of patients displaying hypermagnesemia did not increase with dapagliflozin treatment. Conclusions: Treatment with dapagliflozin 10 mg resulted in correction of Mg concentrations in patients with T2D and hypomagnesemia. 

  • 436.
    Tuominen, Jarno
    et al.
    Department of Psychology and Speech-Language Pathology, University of Turku, Finland.
    Peltola, Karoliina
    Department of Psychology and Speech-Language Pathology, University of Turku, Finland.
    Saaresranta, Tarja
    Division of Medicine, Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland / Sleep Research Centre, Department of Pulmonary Diseases and Clinical Allergology, University of Turku, Finland.
    Valli, Katja
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Psychology, University of Turku, Turku, Finland /Turku Brain and Mind Center, University of Turku, Turku, Finland.
    Sleep Parameter Assessment Accuracy of a Consumer Home Sleep Monitoring Ballistocardiograph Beddit Sleep Tracker: A Validation Study2019In: Journal of Clinical Sleep Medicine (JCSM), ISSN 1550-9389, E-ISSN 1550-9397, Vol. 15, no 3, p. 483-487, article id PII jc-18-00561Article in journal (Refereed)
    Abstract [en]

    Study Objectives: Growing interest in monitoring sleep and well-being has created a market for consumer home sleep monitoring devices. Additionally, sleep disorder diagnostics, and sleep and dream research would benefit from reliable and valid home sleep monitoring devices. Yet, majority of currently available home sleep monitoring devices lack validation. In this study, the sleep parameter assessment accuracy of Beddit Sleep Tracker (BST), an unobtrusive and non-wearable sleep monitoring device based on ballistocardiography, was evaluated by comparing it with polysomnography (PSG) measures. We measured total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), and sleep efficiency (SE). Additionally, we examined whether BST can differentiate sleep stages. Methods: We performed sleep studies simultaneously with PSG and BST in ten healthy young adults (5 female/5 male) during two non-consecutive nights in a sleep laboratory. Results: BST was able to distinguish SOL with some accuracy. However, it underestimated WASO and thus overestimated TST and SE. Also, it failed to discriminate between non-rapid eye movement sleep stages and did not detect the rapid eye movement sleep stage. Conclusions: These findings indicate that BST is not a valid device to monitor sleep. Consumers should be careful in interpreting the conclusions on sleep quality and efficiency provided by the device.

  • 437.
    Tuominen, Jarno
    et al.
    Department of Psychology, University of Turku, Finland / Turku Brain and Mind Center, University of Turku, Finland.
    Stenberg, Tuula
    Department of Psychology, University of Turku, Finland.
    Revonsuo, Antti
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Psychology, University of Turku, Finland / Turku Brain and Mind Center, University of Turku, Finland.
    Valli, Katja
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Psychology, University of Turku, Finland / Turku Brain and Mind Center, University of Turku, Finland.
    Social contents in dreams: An empirical test of the Social Simulation Theory2019In: Consciousness and Cognition, ISSN 1053-8100, E-ISSN 1090-2376, Vol. 69, p. 133-145Article in journal (Refereed)
    Abstract [en]

    Social Simulation Theory (SST) considers the function of dreaming to be the simulation of social events. The Sociality Bias and the Strengthening hypotheses of SST were tested. Social Content Scale (SCS) was developed to quantify social events. Additionally, we attempted to replicate a previous finding (McNamara et al., 2005, Psychological Science) of REM dreams as predisposed to aggressive, and NREM dreams to prosocial interactions. Further, we investigated the frequency and quality of interactions in late vs early REM and NREM dreams. Data consisted of wake, REM and NREM home dream reports (N = 232, 116, 116, respectively) from 15 students. Dreams overrepresented social events compared to wake reports, supporting the Sociality Bias hypothesis. However, the Strengthening Hypothesis was not supported. We weren't able to replicate the McNamara et al. finding, and no time of night effect was found. While SST gained partial support, further research on social contents in dreams is required. © 2019 Elsevier Inc.

  • 438.
    Ulfenborg, Benjamin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Bioinformatics tools for discovery and evaluation of biomarkers: Applications in clinical assessment of cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancer is a disease characterized by abnormal proliferation of cells in the body and ranks as the second leading cause of death worldwide. In order to improve cancer patient care, a major focus of cancer research is to discover biomarkers. A biomarker is a biological molecule found in tissues or body fluids and can be used to predict or assess disease states. The aim of this thesis is to develop bioinformatics tools for discovery and evaluation of novel biomarkers from high-throughput datasets.

    MicroRNAs (miRNAs) are short non-coding RNAs that function as negative regulators of gene expression. Dysregulation of miRNAs in cancer is frequently reported, making them interesting as biomarker candidates. GenoScan was developed for genome-wide discovery of miRNA-coding genes, as a first step in the identification of novel mi-RNA biomarkers.

    High-throughput technologies such as microarrays allow researchers to measure the expression of thousands of genes or miRNAs simultaneously. The Decision Trunk Classifier (DTC) algorithm has been developed to screen datasets from these experiments for biomarker candidates. When applied to a miRNA expression dataset for endometrial cancer (EC) samples vs. controls, a two-marker model with 98 % accuracy was generated. These miRNAs (hsa-miR-183-5p and hsa-miRPlus-C1070) are promising as biomarkers for EC screening.

    The miREC database was developed to store gene and miRNA data from curated expression profiling studies of EC, as well as gene-miRNA regulatory connections. Using gene-miRNA interaction networks from miREC, the roles of miRNAs in cancer hallmark acquisition can be clarified. To further support exploratory analysis of expression data, DTC was extended with partial least squares regression models. The resulting PLS-DTC algorithm can be used to gain deeper insights into the perturbation of biological processes and pathways.

  • 439.
    Ulfenborg, Benjamin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Vertical and horizontal integration of multi-omics data with miodin2019In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 20, no 649Article in journal (Refereed)
    Abstract [en]

    Background: Studies on multiple modalities of omics data such as transcriptomics, genomics and proteomics are growing in popularity, since they allow us to investigate complex mechanisms across molecular layers. It is widely recognized that integrative omics analysis holds the promise to unlock novel and actionable biological insights into health and disease. Integration of multi-omics data remains challenging, however, and requires combination of several software tools and extensive technical expertise to account for the properties of heterogeneous data.

    Results: This paper presents the miodin R package, which provides a streamlined workflow-based syntax for multi-omics data analysis. The package allows users to perform analysis of omics data either across experiments on the same samples (vertical integration), or across studies on the same variables (horizontal integration). Workflows have been designed to promote transparent data analysis and reduce the technical expertise required to perform low-level data import and processing.

    Conclusions: The miodin package is implemented in R and is freely available for use and extension under the GPL-3 license. Package source, reference documentation and user manual are available at https://gitlab.com/algoromics/miodin.

  • 440.
    Ulfenborg, Benjamin
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Jurcevic, Sanja
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Lindelöf, Angelica
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Klinga-Levan, Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Olsson, Björn
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    miREC: a database of miRNAs involved in the development of endometrial cancer2015In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 8, no 1, article id 104Article in journal (Refereed)
    Abstract [en]

    Background

    Endometrial cancer (EC) is the most frequently diagnosed gynecological malignancy and the fourth most common cancer diagnosis overall among women. As with many other forms of cancer, it has been shown that certain miRNAs are differentially expressed in EC and these miRNAs are believed to play important roles as regulators of processes involved in the development of the disease. With the rapidly growing number of studies of miRNA expression in EC, there is a need to organize the data, combine the findings from experimental studies of EC with information from various miRNA databases, and make the integrated information easily accessible for the EC research community.

    Findings

    The miREC database is an organized collection of data and information about miRNAs shown to be differentially expressed in EC. The database can be used to map connections between miRNAs and their target genes in order to identify specific miRNAs that are potentially important for the development of EC. The aim of the miREC database is to integrate all available information about miRNAs and target genes involved in the development of endometrial cancer, and to provide a comprehensive, up-to-date, and easily accessible source of knowledge regarding the role of miRNAs in the development of EC. Database URL: http://www.mirecdb.orgwebcite.

    Conclusions

    Several databases have been published that store information about all miRNA targets that have been predicted or experimentally verified to date. It would be a time-consuming task to navigate between these different data sources and literature to gather information about a specific disease, such as endometrial cancer. The miREC database is a specialized data repository that, in addition to miRNA target information, keeps track of the differential expression of genes and miRNAs potentially involved in endometrial cancer development. By providing flexible search functions it becomes easy to search for EC-associated genes and miRNAs from different starting points, such as differential expression and genomic loci (based on genomic aberrations).

  • 441.
    Ulfenborg, Benjamin
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Karlsson, Alexander
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Riveiro, Maria
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Améen, Caroline
    Takara Bio Europe AB, Gothenburg, Sweden.
    Åkesson, Karolina
    Takara Bio Europe AB, Gothenburg, Sweden.
    Andersson, Christian X.
    Takara Bio Europe AB, Gothenburg, Sweden.
    Sartipy, Peter
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Cardiovascular and Metabolic Disease Global Medicines Development Unit, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    A data analysis framework for biomedical big data: Application on mesoderm differentiation of human pluripotent stem cells2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179613Article in journal (Refereed)
    Abstract [en]

    The development of high-throughput biomolecular technologies has resulted in generation of vast omics data at an unprecedented rate. This is transforming biomedical research into a big data discipline, where the main challenges relate to the analysis and interpretation of data into new biological knowledge. The aim of this study was to develop a framework for biomedical big data analytics, and apply it for analyzing transcriptomics time series data from early differentiation of human pluripotent stem cells towards the mesoderm and cardiac lineages. To this end, transcriptome profiling by microarray was performed on differentiating human pluripotent stem cells sampled at eleven consecutive days. The gene expression data was analyzed using the five-stage analysis framework proposed in this study, including data preparation, exploratory data analysis, confirmatory analysis, biological knowledge discovery, and visualization of the results. Clustering analysis revealed several distinct expression profiles during differentiation. Genes with an early transient response were strongly related to embryonic-and mesendoderm development, for example CER1 and NODAL. Pluripotency genes, such as NANOG and SOX2, exhibited substantial downregulation shortly after onset of differentiation. Rapid induction of genes related to metal ion response, cardiac tissue development, and muscle contraction were observed around day five and six. Several transcription factors were identified as potential regulators of these processes, e.g. POU1F1, TCF4 and TBP for muscle contraction genes. Pathway analysis revealed temporal activity of several signaling pathways, for example the inhibition of WNT signaling on day 2 and its reactivation on day 4. This study provides a comprehensive characterization of biological events and key regulators of the early differentiation of human pluripotent stem cells towards the mesoderm and cardiac lineages. The proposed analysis framework can be used to structure data analysis in future research, both in stem cell differentiation, and more generally, in biomedical big data analytics.

  • 442.
    Ulfenborg, Benjamin
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Klinga-Levan, Karin
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Olsson, Björn
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Classification of tumor samples from expression data using decision trunks2013In: Cancer Informatics, ISSN 1176-9351, E-ISSN 1176-9351, Vol. 12, p. 53-66Article in journal (Refereed)
    Abstract [en]

    We present a novel machine learning approach for the classification of cancer samples using expression data. We refer to the method as "decision trunks," since it is loosely based on decision trees, but contains several modifications designed to achieve an algorithm that: (1) produces smaller and more easily interpretable classifiers than decision trees; (2) is more robust in varying application scenarios; and (3) achieves higher classification accuracy. The decision trunk algorithm has been implemented and tested on 26 classification tasks, covering a wide range of cancer forms, experimental methods, and classification scenarios. This comprehensive evaluation indicates that the proposed algorithm performs at least as well as the current state of the art algorithms in terms of accuracy, while producing classifiers that include on average only 2-3 markers. We suggest that the resulting decision trunks have clear advantages over other classifiers due to their transparency, interpretability, and their correspondence with human decision-making and clinical testing practices. © the author(s), publisher and licensee Libertas Academica Ltd.

  • 443.
    Ulfenborg, Benjamin
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Klinga-Levan, Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Olsson, Björn
    University of Skövde, School of Bioscience. University of Skövde, The Informatics Research Centre.
    Genome-wide discovery of miRNAs using ensembles of machine learning algorithms and logistic regression2015In: International Journal of Data Mining and Bioinformatics, ISSN 1748-5681, Vol. 13, no 4, p. 338-359Article in journal (Refereed)
    Abstract [en]

    In silico prediction of novel miRNAs from genomic sequences remains a challenging problem. This study presents a genome-wide miRNA discovery software package called GenoScan and evaluates two hairpin classification methods. These methods, one ensemble-based and one using logistic regression were benchmarked along with 15 published methods. In addition, the sequence-folding step is addressed by investigating the impact of secondary structure prediction methods and the choice of input sequence length on prediction performance. Both the accuracy of secondary structure predictions and the miRNA prediction are evaluated. In the benchmark of hairpin classification methods, the regression model achieved highest classification accuracy. Of the structure prediction methods evaluated, ContextFold achieved the highest agreement between predicted and experimentally determined structures. However, both the choice of secondary structure prediction method and input sequence length had limited impact on hairpin classification performance.

  • 444.
    Ulfenborg, Benjamin
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Klinga-Levan, Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Olsson, Björn
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    GenoScan: Genomic Scanner for Putative miRNA Precursors2014In: Bioinformatics Research and Applications: 10th International Symposium, ISBRA 2014, Zhangjiajie, China, June 28-30, 2014. Proceedings / [ed] Mitra Basu, Yi Pan, Jianxin Wang, Springer, 2014, p. 266-277Conference paper (Refereed)
    Abstract [en]

    The significance of miRNAs has been clarified over the last decade as thousands of these small non-coding RNAs have been found in a wide variety of species. By binding to specific target mRNAs, miRNAs act as negative regulators of gene expression in many different biological processes. Computational approaches for discovery of miRNAs in genomes usually take the form of an algorithm that scans sequences for miRNA-characteristic hairpins, followed by classification of those hairpins as miRNAs or nonmiRNAs. In this study, two new approaches to genome-scale miRNA discovery are presented and evaluated. These methods, one ensemble-based and one using logistic regression, have been designed to detect miRNA candidates without relying on conservation or transcriptome data, and to achieve high-confidence predictions in reasonable computational time. GenoScan achieves high accuracy with a good balance between sensitivity and specificity. In a benchmark evaluation including 15 previously published methods, the regression-based approach in GenoScan achieved the highest classification accuracy.

  • 445.
    Ulvestad, Maria
    et al.
    AstraZeneca, Sweden / Cellectis AB, Sweden / University of Oslo, Norway.
    Nordell, Pär
    AstraZeneca, Sweden.
    Asplund, Annika
    Cellectis AB, Sweden.
    Rehnström, Marie
    Cellectis AB, Sweden.
    Jacobsson, Susanna
    Cellectis AB, Sweden.
    Holmgren, Gustav
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Sweden / Sahlgrenska University Hospital, Sweden.
    Davidson, Lindsay
    University of Dundee, Scotland.
    Brolén, Gabriella
    AstraZeneca, Sweden.
    Edsbagge, Josefina
    Cellectis AB, Sweden.
    Björquist, Petter
    Cellectis AB, Sweden.
    Küppers-Munther, Barbara
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Sweden.
    Andersson, Tommy B.
    AstraZeneca, Sweden / Karolinska Institute, Sweden.
    Drug metabolizing enzyme and transporter protein profiles of hepatocytes derived from human embryonic and induced pluripotent stem cells2013In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 86, no 5, p. 691-702Article in journal (Refereed)
    Abstract [en]

    Human embryonic and induced pluripotent stem cell-derived hepatocytes (hESC-Hep and hiPSC-Hep) have the potential to provide relevant human in vitro model systems for toxicity testing and drug discovery studies. In this study, the expression and function of important drug metabolizing cytochrome P450 (CYP) enzymes and transporter proteins in hESC-Hep and hiPSC-Hep were compared to cryopreserved human primary hepatocytes (hphep) and HepG2 cells. Overall, CYP activities in hESC-Hep and hiPSC-Hep were much lower than in hphep cultured for 4 h, but CYP1A and 3A activities were comparable to levels in hphep cultured for 48 h (CYP1A: 35% and 26% of 48 h hphep, respectively; CYP3A: 80% and 440% of 48 h hphep, respectively). Importantly, in hESC-Hep and hiPSC-Hep, CYP activities were stable or increasing for at least one week in culture which was in contrast to the rapid loss of CYP activities in cultured hphep between 4 and 48 h after plating. With regard to transporters, in hESC-Hep and hiPSC-Hep, pronounced NTCP activity (17% and 29% of 4 h hphep, respectively) and moderate BSEP activity (6% and 8% of 4 h hphep, respectively) were observed. Analyses of mRNA expression and immunocytochemistry supported the observed CYP and transporter activities and showed expression of additional CYPs and transporters. In conclusion, the stable expression and function of CYPs and transporters in hESC-Hep and hiPSC-Hep for at least one week opens up the possibility to reproducibly perform long term and extensive studies, e.g. chronic toxicity testing, in a stem cell-derived hepatic system. (C) 2013 Elsevier Inc. All rights reserved.

  • 446.
    Uvnäs-Moberg, Kerstin
    et al.
    The Swedish University of Agricultural Sciences, Skara.
    Handlin, Linda
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Petersson, Maria
    Karolinska Institutet.
    Promises and pitfalls of hormone research in human-animal interaction2011In: How Animals Affect Us: Examining the Influence of Human-Animal Interaction on Child Development and Human Health / [ed] Peggy McCardle, Sandra McCune, James A. Griffin, Valerie Maholmes, American Psychological Association (APA), 2011, 1Chapter in book (Other academic)
  • 447.
    Vallabhu, Rishu
    et al.
    University of Skövde.
    Falck, Eva
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Lindlöf, Angelica
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    A systems biology view of the spliceosome component Phf5a in relation to estrogen and cancer2014In: Journal of Computer Science and Systems Biology, ISSN 0974-7230, Vol. 7, no 6, p. 193-202Article in journal (Refereed)
    Abstract [en]

    Cancer is a broad term for a wide spectrum of diseases and which involves the alteration in expression levels of several hundreds of genes. As such, the study of the disease from a systems biology point of view becomes rational, as the properties of a system as a whole may be very different from the properties of its individual components. However, understanding a network at the systems level not only requires knowledge about the components of the network, but also the interactions between them.

    Here, a systems biology view of the rat PHD finger protein 5A (Phf5a) gene was attempted; a gene previously identified as aberrantly expressed in estrogen dependent endometrial adenocarcinoma tumors from both rat and human. Phf5 ais a highly conserved cysteine rich (C4HC3) zinc finger and such proteins predominantly have a role in chromatin mediated transcriptional regulation. Moreover, PHF5A is a component of the macromolecular complex spliceosome that takes part in pre-mRNA splicing and spliceosome component coding genes have previously been shown to be implicated in various cancer types and suggested to potentially be novel antitumor drugs.

    To derive a systems biology view, in this study, a weighted gene network was inferred from a list of genes having correlated expression profiles to Phf5a as nodes, and common transcription factors and microRNAs regulating these genes together with annotation about biological process ontology term(s) and pathway(s) as edge weights. In the inferred network a higher weight indicates more annotation shared between two genes and, hence, the network facilitates the identification of closely interacting genes with Phf5a. The results show that highly weighted edges connect Phf5a to other spliceosome components, but also to genes involved in the metabolism of proteins, proteasome and DNA replication, repair and recombination. The results also link Phf5a to the Myc/Rb/E2F pathway, one of the central pathways associated with cancer. The proposed method for inferring a weighted gene network can easily be applied to other genes and diseases. 

  • 448.
    Valli, Katja
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Dreams2016In: The SAGE Encyclopedia of Theory in Psychology / [ed] Harold L. Miller, Thousand Oaks: Sage Publications, 2016Chapter in book (Other academic)
  • 449.
    Valli, Katja
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Centre for Cognitive Neuroscience, Turku Brain and Mind Center, Department of Psychology, University of Turku, Turku, Finland.
    Frauscher, Birgit
    Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
    Peltomaa, Taina
    Centre for Cognitive Neuroscience, Turku Brain and Mind Center, Department of Psychology, University of Turku, Turku, Finland.
    Gschliesser, Viola
    Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
    Revonsuo, Antti
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Centre for Cognitive Neuroscience, Turku Brain and Mind Center, Department of Psychology, University of Turku, Turku, Finland.
    Högl, Birgit
    Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
    Dreaming furiously?: A sleep laboratory study on the dream content of people with Parkinson's disease and with or without rapid eye movement sleep behavior disorder2015In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 16, no 3, p. 419-427Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) has been related to altered, action-filled, vivid, and aggressive dream content, but research comparing the possible differences in dreams of Parkinson's disease (PD) patients with and without RBD is scarce. The dream content of PD patients with and without RBD was analyzed with specific focus on action-filledness, vividness, emotional valence, and threats.

    METHODS: A total of 69 REM and NREM dream reports were collected in the sleep laboratory, 37 from nine PD patients with RBD and 32 from six PD patients without RBD. A content analysis of (1) action-filledness (actions and environmental events); (2) vividness (emotions and cognitive activity); (3) intensity of actions, events and emotions; (4) emotional valence, and (5) threatening events was performed on the transcripts.

    RESULTS: Altogether 563 dream elements expressing action-filledness and vividness were found. There were no significant between-group differences in the number or distribution of elements reflecting action-filledness or vividness, emotional valence or threats. In within-group analyses, PD patients with RBD had significantly more negative compared to positive dreams (p = 0.012) and compared to PD patients without RBD, a tendency to have more intense actions in their dreams (p = 0.066).

    CONCLUSIONS: Based on the results of this study, there are no major between-group differences in the action-filledness, vividness, or threat content of dreams of PD patients with and without RBD. However, within-group analyses revealed that dreams were more often negatively than positively toned in PD patients with RBD.

  • 450.
    Verma, Deepti
    et al.
    Linköping University.
    Eriksson, Per
    Linköping University.
    Sahdo, Berolla
    Örebro University.
    Persson, Alexander
    Linköping University.
    Ejdebäck, Mikael
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Särndahl, Eva
    Örebro University.
    Söderkvist, Peter
    Linköping University.
    Two Adult Siblings with Atypical Cryopyrin Associated Periodic Syndrome (CAPS) due to a Novel M299V Mutation in the NLRP3 Gene.2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 7, p. 2138-2143Article in journal (Refereed)
    Abstract [en]

    Objective: The NALP3 inflammasome is a multiprotein complex that triggers caspase 1–mediated interleukin-1β (IL-1β) release. Mutations in the gene encoding NALP3 (NLRP3) underlie the cryopyrin-associated periodic syndrome (CAPS). The aim of this study was to report a novel NLRP3 mutation in 2 siblings of Swedish descent in whom symptoms first presented in adulthood.

    Methods: Mutation analysis of NLRP3 was performed on DNA from patients with CAPS and 100 control subjects. For assessment of caspase 1 and IL-1β, blood was collected from patients and age- and sex-matched healthy control subjects. Genetic constructs containing mutant or wild-type NLRP3 were transduced into THP-1 cells, followed by assessment of IL-1β levels in cell supernatant.

    Results: Both siblings carried a novel M299V mutation in NLRP3, which was not present in the control population. The samples obtained from the patients displayed increased caspase 1 activity and elevated IL-1β levels at basal conditions as compared with healthy control subjects. THP-1 cells expressing mutated M299V revealed almost 10-fold higher IL-1β production compared with the wild-type construct.

    Conclusion: M299V is an activating mutation in NLRP3 resulting in elevated spontaneous caspase 1 activity and IL-1β levels. The classic CAPS phenotype was lacking in these adult siblings. Whereas one sibling displayed a milder phenotype that has so far responded satisfactorily to oral nonsteroidal antiinflammatory drugs in combination with low-dose corticosteroids, the inflammatory symptoms in the sibling with the more severe case responded well to IL-1β blockade. Understanding the pathogenic mechanism underlying such disorders can be helpful for the physician. Our study reinforces the importance of genetic testing and laboratory investigations in combination with careful phenotypic evaluation for the diagnosis of such patients.

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