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  • 1.
    Lundberg, Peter
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Radio Physics. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Radiation Physics.
    Ekblad, Alf
    Nilsson, Mats
    13C NMR spectroscopy studies of forest soil microbial activity: Glucose uptake and fatty acid biosynthesis2001In: Soil Biology and Biochemistry, ISSN 0038-0717, Vol. 33, no 4-5, 621-632 p.Article in journal (Refereed)
    Abstract [en]

    The intimate association of soil microorganisms with the soil matrix complicates analysis of their metabolism, since thorough separation of intact cells from the matrix is very difficult using standard protocols. Thus, in the study reported here, in situ glucose decomposition and metabolism in humus from a coniferous forest soil was monitored and evaluated using 'solution state' 13C NMR, which can be used in a non-invasive manner. [U-13C] glucose was added at a concentration of 1.73 mmol C g-1 dry organic matter, which is known to allow maximal substrate induced respiration (SIR), and the microbial metabolism of the added C was followed over a period of 28 days. The data showed that ~50% of the added glucose was consumed within three days, coinciding with the appearance of label in CH3, -CH2- and -CH = CH-groups, and in glycerol-carbons, suggesting that olefinic triacylglycerols were being formed, probably located in oil droplets. During days two to three, around 40% of the consumed glucose C was allocated into solid state components, about 40% was respired and about 20% was found as triglycerols. The triacylglycerol signal reached a maximum after 13 days, but subsequently declined by 60%, as the triacylglycerols were apparently consumed, by day 28 of the incubation. Our results indicate there was an initial formation of structural microbial C (solid state carbon) followed by formation of storage lipid C, which subsequently decreased, probably because it was used to provide the organisms with energy when the external energy source (i.e. the glucose) was depleted. The formation of unsaturated triacylglycerols, typical storage metabolites of eucaryotes, suggests that fungi were the most active organisms in the glucose degradation. ⌐ 2001 Elsevier Science Ltd.

  • 2.
    Jansson , Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    17Beta-hydroxysteroid dehydrogenase enzymes and breast cancer2009In: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, ISSN 0960-0760 , Vol. 114, no 1-2, 64-67 p.Article in journal (Refereed)
    Abstract [en]

    Sex steroids play an important role in the development and differentiation in several tissues. Biologically active hormones that are locally converted in endocrine organs in the tissue where they exert their effects without release into extracellular space is a field of endocrinology that has been called intracrinology. In pre-menopausal women the ovary is the main source of estrogens, but in post-menopausal women the estrogen production as main site of synthesis moves to peripheral tissues and almost all of the sex steroids are synthesised from precursors of adrenal origin. In breast cancer 60-80% of the tumors express high levels of oestrogen receptor (ER) alpha which gives estrogen a proliferative effect. Breast tumors tend to have a higher intratumoral estrogen concentration than normal breast tissue and plasma, and in situ synthesis and the metabolism of estrogens is believed to be of great importance for the development and progression of the disease. The activity of estrogen metabolizing enzymes in breast are mainly aromatase, estrone sulfatases and 17HSD enzymes. 17HSD1 and 17HSD2 are the family members known to be of main importance in breast cancer. High expression of 17HSD1 has been associated to poor prognosis in breast cancer and late relapse among patients with ER-positive tumors. One of the mechanisms behind high 17HSD1 expression is gene amplification. Low or absent expression of 17HSD2 is associated to decreased survival in ER-positive breast cancer. 17HSD14 is one of the latest discovered 17HSD enzymes, transfection of 17HSD14 in human breast cancer cells significantly decreased the levels of estradiol in the culture medium. Low expression of 17HSD14 mRNA expression in breast cancer was correlated to decreased survival.

    The understanding of intratumoral synthesis of sex steroids in breast cancer is crucial to understand the disease both in pre- and post-menopausal women. Further studies are desirable to state the direct role of these enzymes in breast cancer and which patients that may benefit from new therapeutic strategies targeting 17HSD enzymes. The new inhibitors targeting 17HSD1 have shown promising results in preclinical studies to have clinical potential in the future.

  • 3.
    Jansson, Agneta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Cohen, Maja
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Sivik, Tove
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 23, 11471-11477 p.Article in journal (Refereed)
    Abstract [en]

    Estrogens have an important role in the progression of breast cancer. The 17β-hydroxysteroid dehydrogenase (17HSD) family has been identified to be of significance in hormone-dependent tissues. 17HSD1 and 17HSD2 are the main 17HSD enzymes involved in breast cancer investigated this far, but it is possible that other hormone-regulating enzymes have a similar role. 17HSD5 and 17HSD12 are associated with sex steroid metabolism, and 17HSD14 is a newly discovered enzyme that may be involved in the estrogen balance. The mRNA expression of 17HSD5, 17HSD12, and 17HSD14 were analyzed in 131 breast cancer specimens by semiquantitative real-time PCR. The results were compared with recurrence-free survival and breast cancer-specific survival of the patients. The breast cancer cell lines MCF7, SKBR3, and ZR75-1 were transiently transfected with 17HSD14 to investigate any possible effect on estradiol levels. We found that high 17HSD5 was related to significantly higher risk of late relapse in estrogen receptor (ER)-positive patients remaining recurrence-free later than 5 years after diagnosis (P = 0.02). No relation to 17HSD12 expression was found, indicating that 17HSD12 is of minor importance in breast cancer. Patients with ER-positive tumors with high expression levels of 17HSD14 showed a significantly better prognosis about recurrence-free survival (P = 0.008) as well as breast cancer-specific survival (P = 0.01), confirmed by multivariate analysis (P = 0.04). Transfection of 17HSD14 in the human breast cancer cells MCF7 and SKBR3 significantly decreased the levels of estradiol, presenting an effect of high expression levels of the enzyme. ©2006 American Association for Cancer Research.

  • 4.
    Sivik, Tove
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Medical Genetics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Fornander, Tommy
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Skoog, Lambert
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer2012In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 7, e40568- p.Article in journal (Refereed)
    Abstract [en]

    Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

    Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

    Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

    Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

  • 5.
    Auer, Cornelia
    et al.
    Zuse Institute Berlin, Berlin, Germany.
    Nair, Jaya
    IIIT – Bangalore, Electronics City, Hosur Road, Bangalore, India.
    Zobel, Valentin
    Zuse Institue Berlin, Berlin, Germany.
    Hotz, Ingrid
    Zuse Institue Berlin, Berlin, Germany.
    2D Tensor Field Segmentation2011In: Dagstuhl Follow-Ups, E-ISSN 1868-8977, Vol. 2, 17-35 p.Article in journal (Refereed)
    Abstract [en]

    We present a topology-based segmentation as means for visualizing 2D symmetric tensor fields. The segmentation uses directional as well as eigenvalue characteristics of the underlying field to delineate cells of similar (or dissimilar) behavior in the tensor field. A special feature of the resulting cells is that their shape expresses the tensor behavior inside the cells and thus also can be considered as a kind of glyph representation. This allows a qualitative comprehension of important structures of the field. The resulting higher-level abstraction of the field provides valuable analysis. The extraction of the integral topological skeleton using both major and minor eigenvector fields serves as a structural pre-segmentation and renders all directional structures in the field. The resulting curvilinear cells are bounded by tensorlines and already delineate regions of equivalent eigenvector behavior. This pre-segmentation is further adaptively refined to achieve a segmentation reflecting regions of similar eigenvalue and eigenvector characteristics. Cell refinement involves both subdivision and merging of cells achieving a predetermined resolution, accuracy and uniformity of the segmentation. The buildingblocks of the approach can be intuitively customized to meet the demands or different applications. Application to tensor fields from numerical stress simulations demonstrates the effectiveness of our method.

  • 6.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Ivanova, S.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Tracey, K.J.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin2003In: Biochemical Journal, ISSN 0264-6021, Vol. 371, no 2, 429-436 p.Article in journal (Refereed)
    Abstract [en]

    Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.

  • 7.
    Yu, Zhengquan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    3-Aminopropanal is a lysosomotropic aldehyde that causes oxidative stress and apoptosis by rupturing lysosomes2003In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 111, no 6, 643-652 p.Article in journal (Refereed)
    Abstract [en]

    During cerebral ischemia and following trauma, potent cytotoxic polyamine-derived aminoaldehydes form, diffuse, and damage adjacent tissues not directly subjected to the initial insult. One such aldehyde is 3-aminopropanal (3-AP). The mechanisms by which such a small aldehydic compound is excessively cytotoxic have been unclear until recently when we showed that 3-AP, having the structure of a weak lysosomotropic base, concentrates within the acidic vacuolar compartment and causes lysosomal rupture that, in turn, induces caspase activation and apoptotic cell death. Here, using cultured J774 cells and 3-AP as a way to selectively burst lysosomes, we show that moderate lysosomal rupture induces a transient wave of oxidative stress. The start of this oxidative stress period is concomitant with a short period of enhanced mitochondrial membrane potential that later fades and is replaced by a decreased potential before the oxidative stress diminishes. The result of the study suggests that oxidative stress, which has often been described during apoptosis induced by agonists other than oxidative stress per se, may be a consequence of lysosomal rupture with direct and/or indirect effects on mitochondrial respiration and electron transport causing a period of passing enhanced formation of reactive oxygen species.

  • 8.
    Cahill, N
    et al.
    Uppsala University, Sweden.
    Bergh, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kanduri, M
    Uppsala University, Sweden.
    Göransson-Kultima, H
    Uppsala University, Sweden.
    Mansouri, L
    Uppsala University, Sweden.
    Isaksson, A
    Sahlgrenska University Hospital, Sweden.
    Ryan, F
    Institute of Technology, Dublin, Ireland.
    Smedby, K E
    Karolinska Institutet, Stockholm, Sweden.
    Juliusson, G
    Institute of Technology, Dublin, Ireland.
    Sundström, C
    Uppsala University, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rosenquist, R
    Uppsala University, Sweden.
    450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments2013In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 1, 150-158 p.Article in journal (Refereed)
    Abstract [en]

    In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K-arrays, we provide the most comprehensive DNA methylation study of CLL to date, analysing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (e.g. CLLU1, LPL, ZAP70, NOTCH1), epigenetic regulator (e.g. HDAC9, HDAC4, DNMT3B), B-cell signaling (e.g. IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.Leukemia accepted article preview online, 27 August 2012; doi:10.1038/leu.2012.245.

  • 9. Sastry, M
    et al.
    Gustafsson, Håkan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Radiation Physics.
    Lund, Anders
    Linköping University, Department of Physics, Chemistry and Biology.
    Lund, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Radiation Physics. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Radiation Physics.
    51V(n,β)52Cr reaction for neutron dosimetry: Development and assessment of a spectrophotometric method for determination of Cr in vanadium at sub ppm level2004In: Spectrochimica Acta Part A - Molecular and Biomolecular Spectroscopy, ISSN 1386-1425, Vol. 60, no 10, 2363-2367 p.Article in journal (Refereed)
    Abstract [en]

    With a view to monitoring the changes in coloration caused by the nuclear reaction 51V(n,β)52Cr in solution of vanadyl sulphate and using it for neutron dosimetry, electronic absorption spectra of vanadyl sulphate solutions were investigated at different concentrations of chromate impurity in micromolar range. It was observed that the presence of chromate enhances the absorptivity over a wide wavelength range serving essentially as a colouring agent for vanadium matrix, presumably due to charge transfer process. The absorbance at 380nm varied linearly over a wide concentration range. The limit of detection of chromate obtained is shown to be adequate for detecting neutron-induced chemical transmutation of vanadium to chromium under standard reactor conditions, when used with long path length cells. It was observed that the absorbance does not change on electron irradiation, suggesting that radiolytic effects due to beta decay, if any, do not interfere in the measurement of neutron-induced changes. In addition to its potential for neutron dosimetry, this is the first report of a simple and direct method of estimation of Cr in vanadium matrix at sub ppm level.

  • 10.
    Nestor, Colm
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Hägg Nilsson, Cathrine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Mattson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Wang, Hui
    MD Anderson Cancer Centre, TX 77030 USA.
    Rundquist, Olof
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Meehan, Richard R.
    University of Edinburgh, Scotland.
    Klocke, Bernward
    Genomatix Software GmbH, Germany.
    Seifert, Martin
    Genomatix Software GmbH, Germany.
    Hauck, Stefanie M.
    German Research Centre Environm Health GmbH, Germany.
    Laumen, Helmut
    Technical University of Munich, Germany; Technical University of Munich, Germany; Helmholtz Zentrum Munchen, Germany; Technical University of Munich, Germany; Technical University of Munich, Germany.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 2, 559-570 p.Article in journal (Refereed)
    Abstract [en]

    5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment.

  • 11. Robert, T.
    et al.
    Marinova, M.
    Juillaguet, S.
    Henry, Anne
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, The Institute of Technology.
    Polychroniadis, E.K.
    Camassel, J.
    6H-type zigzag faults in low-doped 4H-SiC epitaxial layers.2010In: Mat. Sci. Forum, Vols. 645-648, 2010, 347-350 p.Conference paper (Refereed)
    Abstract [en]

    A new type of 6H zigzag faults has been identified from high resolution transmission electron microscopy (HRTEM) measurements performed on low-doped 4H-SiC homoepitaxial layer grown on off-axis substrates in a hot-wall CVD reactor. They are made of half unit cells of 6H with corresponding low temperature photoluminescence (LTPL) response ranging from about 3 eV to 2.5 eV at liquid helium temperature.

  • 12.
    Li, Wei
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Johnson, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Xi-Ming
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    7beta-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destabilization2009In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 43, no 11, 1072-1079 p.Article in journal (Refereed)
    Abstract [en]

    Peripheral natural killer (NK) cells are reduced in patients with coronary artery disease and highly susceptible to apoptosis induced by oxidized lipids including 7beta-hydroxycholesterol (7betaOH) in vitro. The present study aimed to further explore the mechanisms behind 7betaOH-mediated cytotoxicity to human NK cells. Human NK cells were purified and treated with 7betaOH in different concentrations and times. Cell death, lysosomal and mitochondrial permeabilization and reactive oxygen species (ROS) production were then analysed. The 7betaOH induced time and dose dependent apoptosis and necrosis in human NK cells, which was preceded by loss of lysosomal integrity and enhanced ROS production. At later time points, the mitochondrial membrane permeability in 7betaOH-treated cells was significantly increased. The findings indicate that 7betaOH induces human NK cell death through early lysosomal permeabilization and consequent oxidative stress. The data further suggest that 7betaOH may induce immune disturbances in clinical settings such as atherosclerosis.

  • 13.
    Li, Wei
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Johnson, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Xi-Ming
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    7ß-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destabilization2009In: Free radical research, ISSN 1071-5762, Vol. 43, no 11, 1072-1079 p.Article in journal (Refereed)
    Abstract [en]

    Peripheral natural killer (NK) cells are reduced in patients with coronary artery disease and highly susceptible to apoptosis induced by oxidized lipids including 7beta-hydroxycholesterol (7betaOH) in vitro. The present study aimed to further explore the mechanisms behind 7betaOH-mediated cytotoxicity to human NK cells. Human NK cells were purified and treated with 7betaOH in different concentrations and times. Cell death, lysosomal and mitochondrial permeabilization and reactive oxygen species (ROS) production were then analysed. The 7betaOH induced time and dose dependent apoptosis and necrosis in human NK cells, which was preceded by loss of lysosomal integrity and enhanced ROS production. At later time points, the mitochondrial membrane permeability in 7betaOH-treated cells was significantly increased. The findings indicate that 7betaOH induces human NK cell death through early lysosomal permeabilization and consequent oxidative stress. The data further suggest that 7betaOH may induce immune disturbances in clinical settings such as atherosclerosis.

  • 14.
    Du, Chun
    et al.
    Chinese Academy of Science.
    Li, Cuihong
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Li, Weiwei
    Chinese Academy of Science.
    Chen, Xiong
    Chinese Academy of Science.
    Bo, Zhishan
    Beijing Normal University.
    Veit, Clemens
    Fraunhofer Institute for Solar Energy Systems ISE.
    Ma, Zaifei
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Wuerfel, Uli
    Fraunhofer Institute for Solar Energy Systems ISE.
    Zhu, Hongfei
    Chinese Academy of Science.
    Hu, Wenping
    Chinese Academy of Science.
    Zhang, Fengling
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    9-Alkylidene-9H-Fluorene-Containing Polymer for High-Efficiency Polymer Solar Cells2011In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 44, no 19, 7617-7624 p.Article in journal (Refereed)
    Abstract [en]

    A novel donor-acceptor copolymer containing 9-alkylidene-9H-fluorene unit in the main chain, poly[9-(1-hexylheptylidene)-2,7-fluorene-alt-5, 5-(4,7-di-2-thienyl-5,6-dialkoxy-2,1,3-benzothiadiazole)] (PAFDTBT), has been synthesized and evaluated in bulk heterojunction polymer solar cells (BHJ PSCs). The polymer possesses a low band gap of 1.84 eV, a low-lying HOMO energy level (5.32 eV), and excellent solubility in common organic solvents. PSCs based on PAFDTBT and (6,6)-phenyl-C(71)-butyric add methyl ester (PC(71)BM) demonstrate a power conversion efficiency (PCE) of 6.2% with a high fill factor (FF) of 0.70, which indicates that 9-alkylidene-9H-fluorene can be a very useful building block for constructing narrow band gap conjugated polymers for high-efficiency BHJ PSCs.

  • 15.
    Zuse, Ann
    et al.
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany; Manitoba Institute of Cell Biology, CancerCare Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, Canada.
    Prinz, Helge
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
    Müller, Klaus
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
    Schmidt, Peter
    Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany.
    Günther, Eckhard G.
    Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany.
    Schweizer, Frank
    Department of Chemistry, Univ. Manitoba, Winnipeg, Canada.
    Prehn, Jochen H.M.
    Department of Physiology and RCSI Research Institute, St. Stephen's Green, Dublin, Ireland.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    9-benzylidene-naphtho[2,3-b]thiophen-4-ones and benzylidene-9(10H)-anthracenones as novel tubulin interacting agents with high apoptosis-inducing activity2007In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 575, no 1-3, 34-45 p.Article in journal (Refereed)
    Abstract [en]

    Tubulin-binding 9-benzylidene-naphtho[2,3-b]thiophen-4-ones 1a and 1b and benzylidene-9(10H)-anthracenone 2 were evaluated for their ability to induce cell death. We examined the effect of the molecules on cell cycle progression, organization of microtubule networks, and apoptosis induction. As determined by flow cytometry, cancer cells were predominantly arrested in metaphase with 4N DNA before cell death occurred. By using indirect immunofluorescence techniques we visualized microtubule depolymerization recognizable by short microtubule fragments scattered around the nucleus. The incubation with 1a and 2 resulted in chromatin condensation, nuclear fragmentation, and cell shrinkage, which are, among others, typical features of apoptotic cell death. Furthermore, time- and dose-dependent induction of apoptosis in SH-SY5Y cells was detected via cleavage of Ac-DEVD-AMC, a fluorigenic substrate for caspase-3. We observed a lower apoptotic activity in neuroblastoma cells overexpressing Bcl-xL, suggesting activation of the mitochondrial apoptosis pathway. Western blot analysis demonstrated that caspase-3, an apoptosis mediator, was activated in a time-dependent manner after exposure of SH-SY5Y cells to drugs 1a and 2. Taken together, the agents investigated in the present study display strong apoptosis-inducing activity and therefore show promise for the development of novel chemotherapeutics.

  • 16.
    Bhide, Ameya
    et al.
    Linköping University, Department of Electrical Engineering, Integrated Circuits and Systems. Linköping University, Faculty of Science & Engineering.
    Alvandpour, Atila
    Linköping University, Department of Electrical Engineering, Integrated Circuits and Systems. Linköping University, Faculty of Science & Engineering.
    A 11-GS/s 1.1-GHz Bandwidth Interleaved ΔΣ DAC for 60-GHz Radio in 65-nm CMOS2015In: IEEE Journal of Solid-State Circuits, ISSN 0018-9200, E-ISSN 1558-173X, Vol. 50, no 10, 2306-2310 p.Article in journal (Refereed)
    Abstract [en]

    This work presents an 11 GS/s 1.1 GHz bandwidth interleaved ΔΣ DAC in 65 nm CMOS for the 60 GHz radio baseband. The high sample rate is achieved by using a two-channel interleaved MASH 1–1 architecture with a 4 bit output resulting in a predominantly digital DAC with only 15 analog current cells. Two-channel interleaving allows the use of a single clock for the logic and the multiplexing which requires each channel to operate at half sampling rate of 5.5 GHz. To enable this, a look-ahead technique is proposed that decouples the two channels within the integrator feedback path thereby improving the speed as compared to conventional loop-unrolling. Measurement results show that the ΔΣ DAC achieves a 53 dB SFDR, -49 dBc IM3 and 39 dB SNDR within a 1.1 GHz bandwidth while consuming 117 mW from 1 V digital/1.2 V analog supplies. Furthermore, the proposed ΔΣ DAC can satisfy the spectral mask of the IEEE 802.11ad WiGig standard with a second order reconstruction filter.

  • 17.
    Herbertsson, Helena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Kühme, Tobias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Hammarström, Sven
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    A 12(S)-HETE receptor in Lewis lung carcinoma cells.1999In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 447, 193-198 p.Article in journal (Other academic)
  • 18.
    Kurahashi, Yuko
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Herbertsson, Helena
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderström, Mats
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Rosenfeld, Michael G
    University of California, San Diego, La Jolla, CA, USA.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    A 12(S)-hydroxyeicosatetraenoic acid receptor interacts with steroid receptor coactivator-12000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 11, 5779-5783 p.Article in journal (Refereed)
    Abstract [en]

    Lewis lung carcinoma cells contain specific high-affinity binding sites for the eicosanoid 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid [12(S)-HETE]. These binding sites have a cytosolic/nuclear localization and contain the heat shock proteins hsp70 and hsp90 as components of a high molecular weight cytosolic binding complex. The ligand binding subunit of this complex is a protein with an apparent molecular mass of ÿ50 kDa as judged by gel permeation chromatography. In this report, we present data showing that the 50-kDa 12(S)-HETE binding protein interacts as a homodimer with steroid receptor coactivator-1 (SRC-1) in the presence of 12(S)-HETE. Two putative interaction domains were mapped. One of these (amino acids 701-781) was within the nuclear receptor interaction domain in SRC-1 required for binding of various steroid and thyroid hormone receptors. It contains the most C-terminal of the three copies of LXXLL motif present in the nuclear receptor interaction domain. The second interaction domain was present in the N-terminal part of SRC-1 (amino acids 1-221). This region has two LXXLL motifs, one does not bind and the other binds only weakly to steroid and thyroid hormone receptors. Glutathione S-transferase (GST) pulldown experiments and far Western analyses demonstrated that the N-terminal region of SRC-1 (amino acids 1-212) alone does not bind the 50-kDa 12(S)-HETE binding protein, whereas GST/?SRC-11-1138 ligand-dependently pulled down a protein of ÿ50 kDa in size. Our results suggest that the 50-kDa 12(S)-HETE binding protein is a receptor that may signal through interaction with a nuclear receptor coactivator protein.

  • 19.
    Braian, Clara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Svensson, Mattias
    Karolinska Institute, Sweden.
    Brighenti, Susanna
    Karolinska Institute, Sweden.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Parasa, Venkata R.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection2015In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 104, 1-9 p., e53084Article in journal (Refereed)
    Abstract [en]

    Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us understand the disease mechanisms and advance the discoveries of new treatment options. In vitro cell cultures of monolayers or co-cultures lack the three-dimensional (3D) environment and tissue responses. Herein, we describe an innovative in vitro model of a human lung tissue, which holds promise to be an effective tool for studying the complex events that occur during infection with Mycobacterium tuberculosis (M. tuberculosis). The 3D tissue model consists of tissue-specific epithelial cells and fibroblasts, which are cultured in a matrix of collagen on top of a porous membrane. Upon air exposure, the epithelial cells stratify and secrete mucus at the apical side. By introducing human primary macrophages infected with M. tuberculosis to the tissue model, we have shown that immune cells migrate into the infected-tissue and form early stages of TB granuloma. These structures recapitulate the distinct feature of human TB, the granuloma, which is fundamentally different or not commonly observed in widely used experimental animal models. This organotypic culture method enables the 3D visualization and robust quantitative analysis that provides pivotal information on spatial and temporal features of host cell-pathogen interactions. Taken together, the lung tissue model provides a physiologically relevant tissue micro-environment for studies on TB. Thus, the lung tissue model has potential implications for both basic mechanistic and applied studies. Importantly, the model allows addition or manipulation of individual cell types, which thereby widens its use for modelling a variety of infectious diseases that affect the lungs.

  • 20.
    Aifa, Sami
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Aydin, J
    Nordvall, G
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Svensson, Samuel
    Hermanson, O
    A basic peptide within the juxtamembrane region is required for EGF receptor dimerization2005In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 302, no 1, 108-114 p.Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is fundamental for normal cell growth and organ development, but has also been implicated in various pathologies, notably tumors of epithelial origin. We have previously shown that the initial 13 amino acids (P13) within the intracellular juxtamembrane region (R645-R657) are involved in the interaction with calmodulin, thus indicating an important role for this region in EGFR function. Here we show that P13 is required for proper dimerization of the receptor. We expressed either the intracellular domain of EGFR (TKJM) or the intracellular domain lacking P13 (ΔTKJM) in COS-7 cells that express endogenous EGFR. Only TKJM was immunoprecipitated with an antibody directed against the extracellular part of EGFR, and only TKJM was tyrosine phosphorylated by endogenous EGFR. Using SK-N-MC cells, which do not express endogenous EGFR, that were stably transfected with either wild-type EGFR or recombinant full-length EGFR lacking P13 demonstrated that P13 is required for appropriate receptor dimerization. Furthermore, mutant EGFR lacking P13 failed to be autophosphorylated. P13 is rich in basic amino acids and in silico modeling of the EGFR in conjunction with our results suggests a novel role for the juxtamembrane domain (JM) of EGFR in mediating intracellular dimerization and thus receptor kinase activation and function. © 2004 Elsevier Inc. All rights reserved.

  • 21.
    Dravida, Subhadra
    et al.
    University of Ottawa Eye Institute, Ottawa, ON, Canada.
    Gaddipati, Subhash
    Sudhakar and Sreekant Ravi Stem Cell Laboratory, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa, ON, Canada and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
    Merrett, Kim
    University of Ottawa Eye Institute, Ottawa, ON, Canada.
    Lakshmi Madhira, Soundarya
    Sudhakar and Sreekant Ravi Stem Cell Laboratory, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    Sangwan, Virender S.
    Cornea and Anterior Segment Services, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    Vemuganti, Geeta K.
    Sudhakar and Sreekant Ravi Stem Cell Laboratory and Ophthalmic Pathology Services, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    A biomimetic scaffold for culturing limbal stem cells: a promising alternative for clinical transplantation2008In: JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, ISSN 1932-6254, Vol. 2, no 5, 263-271 p.Article in journal (Refereed)
    Abstract [en]

    Limbal tissues can be cultured on various types of scaffolds to create a sheet of limbal-corneal epithelium for research as well as clinical transplantation. An optically clear, biocompatible, biomimetic scaffold would be an ideal replacement graft for transplanting limbal stem cells. in this study, we evaluated the physical and culture characteristics of the recombinant human cross-linked collagen scaffold (RHC-III scaffold) and compared it with denuded human amniotic membrane (HAM). Optical/mechanical properties and microbial susceptibility were measured for the scaffolds. With the approval of the institutional review board, 2 mm. fresh human limbal tissues were cultured on 2.5 x 2.5 cm(2) scaffolds in a medium containing autologous serum in a feeder cell-free submerged system. The cultured cell systems were characterized by morphology and immunohistochemistry for putative stem cells and differentiated cell markers. The refractive index (RI) and tensile strength of the RHC-III scaffold were comparable to human cornea, with delayed in vitro degradation compared to HAM. RHC-III scaffolds were 10-fold less susceptible to microbial growth. Cultures were initiated on day 1, expanded to form a monolayer by day 3 and covered the entire growth surface in 10 days. Stratified epithelium on the scaffolds was visualized by transmission electron microscopy. The cultured cells showed p63 and ABCG2 positivity in the basal layer and were immunoreactive for cytokeratin K3 and K12 in the suprabasal layers. RHC-III scaffold supports and retains the growth and stemness of limbal stem cells, in addition to resembling human cornea; thus, it could be a good replacement scaffold for growing cells for clinical transplantation.

  • 22.
    Fagerholm, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil S
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Merrett, Kimberley
    University of Ottawa Eye Institute.
    Jackson, W Bruce
    University of Ottawa Eye Institute.
    Munger, Rejean
    University of Ottawa Eye Institute.
    Liu, Yuwen
    CooperVision Inc, Pleasanton, USA .
    Polarek, James W
    FibroGen Inc, San Francisco.
    Söderqvist, Monica
    Synsam Opticians, Linköping.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study2010In: Science translational medicine, ISSN 1946-6234, Vol. 2, no 46, 46-61 p.Article in journal (Refereed)
    Abstract [en]

    Corneas from human donors are used to replace damaged tissue and treat corneal blindness, but there is a severe worldwide shortage of donor corneas. We conducted a phase 1 clinical study in which biosynthetic mimics of corneal extracellular matrix were implanted to replace the pathologic anterior cornea of 10 patients who had significant vision loss, with the aim of facilitating endogenous tissue regeneration without the use of human donor tissue. The biosynthetic implants remained stably integrated and avascular for 24 months after surgery, without the need for long-term use of the steroid immunosuppression that is required for traditional allotransplantation. Corneal reepithelialization occurred in all patients, although a delay in epithelial closure as a result of the overlying retaining sutures led to early, localized implant thinning and fibrosis in some patients. The tear film was restored, and stromal cells were recruited into the implant in all patients. Nerve regeneration was also observed and touch sensitivity was restored, both to an equal or to a greater degree than is seen with human donor tissue. Vision at 24 months improved from preoperative values in six patients. With further optimization, biosynthetic corneal implants could offer a safe and effective alternative to the implantation of human tissue to help address the current donor cornea shortage.

  • 23.
    Landtblom, Anne-Marie
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Lindvall, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Neurology . Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Ledin, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Berlin, Gösta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    A case report of plasmapheresis treatment in a patient with paraneoplastic cerebellar degeneration and high anti-Yo antibody titers2008In: Therapeutic Apheresis and Dialysis, ISSN 1744-9979, Vol. 12, no 1, 82-85 p.Article in journal (Refereed)
    Abstract [en]

    A patient with paraneoplastic cerebellar degeneration due to anti-Purkinje cell antibodies (anti-Yo) arising from ovarian carcinoma with metastases was treated with three plasmapheresis (PP) series (a total of 22 PP treatments) over one year and was monitored by repeated otoneurological testing, balance tests and clinical investigations. Blood samples for antibody titers were checked on several occasions. Initially there was a weak clinical response and significantly improved test results regarding the caloric response, as well as a possible effect on visual suppression of the vestibulo-ocular reflex after caloric ear irrigation. After the first series of PP treatment, new metastases were found. A half year later there was a progressive course with increasing general symptoms. Serology tests showed continuously high titers of anti-Yo antibody, although somewhat lower after PP. We thus report a minor and short-lived effect of PP, possibly inhibited by the natural course of metastatic disease. © 2008 International Society for Apheresis.

  • 24.
    La Fleur, Linnea
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of ENT - Head and Neck Surgery UHL.
    A CD44(high)/EGFR(low) Subpopulation within Head and Neck Cancer Cell Lines Shows an Epithelial-Mesenchymal Transition Phenotype and Resistance to Treatment2012In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 9Article in journal (Refereed)
    Abstract [en]

    Mortality in head and neck squamous cell carcinoma (HNSCC) is high due to emergence of therapy resistance which results in local and regional recurrences that may have their origin in resistant cancer stem cells (CSCs) or cells with an epithelial-mesenchymal transition (EMT) phenotype. In the present study, we investigate the possibility of using the cell surface expression of CD44 and epidermal growth factor receptor (EGFR), both of which have been used as stem cell markers, to identify subpopulations within HNSCC cell lines that differ with respect to phenotype and treatment sensitivity. Three subpopulations, consisting of CD44(high)/EGFR(low), CD44(high)/EGFR(high) and CD44(low) cells, respectively, were collected by fluorescence-activated cell sorting. The CD44(high)/EGFR(low) population showed a spindle-shaped EMT-like morphology, while the CD44(low) population was dominated by cobblestone-shaped cells. The CD44(high)/EGFR(low) population was enriched with cells in G0/G1 and showed a relatively low proliferation rate and a high plating efficiency. Using a real time PCR array, 27 genes, of which 14 were related to an EMT phenotype and two with stemness, were found to be differentially expressed in CD44(high)/EGFR(low) cells in comparison to CD44(low) cells. Moreover, CD44(high)/EGFR(low) cells showed a low sensitivity to radiation, cisplatin, cetuximab and gefitinib, and a high sensitivity to dasatinib relative to its CD44(high)/EGFR(high) and CD44(low) counterparts. In conclusion, our results show that the combination of CD44 (high) and EGFR (low) cell surface expression can be used to identify a treatment resistant subpopulation with an EMT phenotype in HNSCC cell lines.

  • 25.
    Ulfendahl, Mats
    et al.
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Hu, Zhengqing
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Duan, Maoli
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Wei, Dongguang
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    A cell therapy approach to substitute neural elements in the inner ear2007In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 92, no 1-2, 75-79 p.Article in journal (Refereed)
    Abstract [en]

    Three different donor tissues were tested for their capacity to survive, integrate and differentiate in the adult inner ear. Surviving embryonic dorsal root ganglion cells were found within the spiral ganglion neuron region and along the auditory nerve fibers. In the presence of exogenous nerve growth factor (NGF), the dorsal root ganglion cells formed extensive growth of neurites that seemed to contact the host neurons. Adult neural stem cells survived relative poorly in the inner car whereas embryonic stem cells showed a somewhat greater capacity for survival and integration. Overall, the survival rate of implanted tissue was quite low in the cochlea. It is concluded that an inner ear cell therapy approach based on the implantation of exogenous cells will require that important survival factors are identified and supplied. In addition, it is possible that the physical properties of the cochlea, e.g., fluid-filled compartments and very limited space for cell proliferation, are unfavorable, at least in the normal cochlea.

  • 26.
    Fritzsche, Michael
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Fredriksson, Magnus
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Carlsson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    A cell-based sensor system for toxicity testing using multiwavelength fluorescence spectroscopy2009In: ANALYTICAL BIOCHEMISTRY, ISSN 0003-2697, Vol. 387, no 2, 271-275 p.Article in journal (Refereed)
    Abstract [en]

    A novel cell-based fluorometric sensor system for toxicity monitoring is described, which uses functional spontaneously contracting cardiomyocytes (HL-1 cell line) as the biological recognition element. Based on these highly specialized cells, it has the potential of providing a sensitive and relevant analytical in vitro toxicity testing method. The system was configured by propagating the surface-attaching HL-1 cardiomyocytes in the wells of a 96-well microtiter plate and connecting the plate via an optical fiber to a fluorescence spectrometer capable of excitation-emission matrix scanning. The fluorescence data were analyzed using a conventional spectral analysis software program. The performance of the system for detection of general cytotoxicity to the cells was evaluated using three well-known drugs: verapamil, quinidine, and acetaminophen. The dose-response curves were assessed and the EC50 values were determined (0.10 +/- 0.007, 0.23 +/- 0.025, and 12.32 +/- 2.40 mM, respectively). Comparison with in vitro and in vivo reference data for the drugs showed good correlations, suggesting that this cell-based sensor system Could be a useful tool in pharmacological in vitro drug testing.

  • 27.
    Wetterö, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Pettersson, Sofia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Holmgren Peterson, Kajsa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    A cellular imaging CDIO project for 2nd semester students in engineering biology2006In: World Transactions on Engineering and Technology Education, ISSN 1446-2257, Vol. 5, no 2, 279-282 p.Article in journal (Refereed)
    Abstract [en]

    The demand for exact engineering within the life sciences is growing and the Engineering Biology programme at Linköping University, Linköping, Sweden, prepares students for a career at this interface. Conceive – Design – Implement – Operate (CDIO) was recently pioneered in an introductory project course. Groups of six to seven students apply a LIPS scalable project model from traditional engineering educational environments on, for example, a cellular imaging task in a hospital setting, prior to taking courses in cell biology/optics. Besides facilitating the implementation of CDIO in higher courses, students gain early career insight and enhance their communication skills. A customer (senior teacher) needs to visualise structures in cells, and the student group is contracted to deliver an applied and optimised method to meet specified requirements. The customer reviews deliverables before the tollgates and communicates with the student project leader. Other students are responsible for documentation and subsystems. The project is allocated laboratory facilities and hardware, and two fictitious subcontractors supply samples and consumables. Extra teachers perform supervision and methodological consultation. In summary, CDIO is indeed applicable and rewarding in cellular imaging, yet is also challenging.

  • 28.
    Doillon, CJ
    et al.
    CHUL Research Center, Laval University, Quebec City, Quebec, Canada.
    Watsky, MA
    Department of Physiology, University of Tennessee, Health Science Center, Memphis, TN, USA.
    Hakim, M
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    Wang, J
    Department of Physiology, University of Tennessee, Health Science Center, Memphis, TN, USA.
    Munger, R
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    Laycock, N
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    Osborne, R
    The Procter and Gamble Company, Miami Valley Laboratories, Cincinnati, OH, USA.
    Griffith, M
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    A collagen-based scaffold for a tissue engineered human cornea: Physical and physiological properties2003In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 26, no 8, 764-773 p.Article in journal (Refereed)
    Abstract [en]

    Stabilized collagen-glycosaminoglycan scaffolds for tissue engineered human corneas were characterized. Hydrated matrices were constructed by blending type I collagen with chondroitin sulphates (CS), with glutaraldehyde crosslinking. A corneal keratocyte cell line was added to the scaffolds with or without corneal epithelial and endothelial cells. Constructs were grown with or without ascorbic acid. Wound-healing was evaluated in chemical-treated constructs. Native, noncrosslinked gels were soft with limited longevity. Crosslinking strengthened the matrix yet permitted cell growth. CS addition increased transparency. Keratocytes grown within the matrix had higher frequencies of K+ channel expression than keratocytes grown on plastic. Ascorbic acid increased uncrosslinked matrix degradation in the presence of keratocytes, while it enhanced keratocyte growth and endogenous collagen synthesis in crosslinked matrices. Wounded constructs showed recovery from exposure to chemical irritants. In conclusion, this study demonstrates that our engineered, stabilized matrix is well-suited to function as an in vitro corneal stroma.

  • 29.
    Deng, C
    et al.
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Zhang, PC
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Vulesevic, B
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Kuraitis, D
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Li, FF
    Univ Ottawa, Inst Eye, Ottawa, ON K1Y 4W7 Canada.
    Yang, AF
    Agr & Agri Food Canada, Ottawa, ON Canada.
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON K1Y 4W7 Canada.
    Ruel, M
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Suuronen, EJ
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    A Collagen-Chitosan Hydrogel for Endothelial Differentiation and Angiogenesis2010In: TISSUE ENGINEERING PART A, ISSN 1937-3341, Vol. 16, no 10, 3099-3109 p.Article in journal (Refereed)
    Abstract [en]

     Cell therapy for the treatment of cardiovascular disease has been hindered by low cell engraftment, poor survival, and inadequate phenotype and function. In this study, we added chitosan to a previously developed injectable collagen matrix, with the aim of improving its properties for cell therapy and neovascularization. Different ratios of collagen and chitosan were mixed and chemically crosslinked to produce hydrogels. Swell and degradation assays showed that chitosan improved the stability of the collagen hydrogel. In culture, endothelial cells formed significantly more vascular-like structures on collagen-chitosan than collagen-only matrix. While the differentiation of circulating progenitor cells to CD31(+) cells was equal on all matrices, vascular endothelial-cadherin expression was increased on the collagen-chitosan matrix, suggesting greater maturation of the endothelial cells. In addition, the collagen-chitosan matrix supported a significantly greater number of CD133(+) progenitor cells than the collagen-only matrix. In vivo, subcutaneously implanted collagen-chitosan matrices stimulated greater vascular growth and recruited more von Willebrand factor (vWF(+)) and CXCR4(+) endothelial/angiogenic cells than the collagen-only matrix. These results indicate that the addition of chitosan can improve the physical properties of collagen matrices, and enhance their ability to support endothelial cells and angiogenesis for use in cardiovascular tissue engineering applications.

  • 30.
    Tran, Dat T
    et al.
    School of Information Sciences and Engineering University of CanberraC ACT 2601 AUSTRALIA.
    Pham, Tuan D
    Bioinformatics Applications Research Centre School of Information Technology James Cook University Townsville, Australia.
    A combined Markov and noise clustering modeling method for cell phase classification2006In: WSEAS Transactions on Biology and Biomedicine, ISSN 1109-9518, E-ISSN 2224-2902, Vol. 3, no 3, 161-166 p.Article in journal (Refereed)
    Abstract [en]

    This paper proposes a classification method of cell nuclei in different mitotic phases using a combined Markov and noise clustering modeling technique. The method was tested with the data set containing 379519 cells in 892 cell sequences for 5 phases extracted from real image sequences recorded at every fifteen minutes with a time-lapse fluorescence microscopy. Experimental results showed that the proposed method performed better than the k-means modeling method.

  • 31.
    Sjöqvist, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
    González-Cano, Rafael C.
    University of Málaga, Spain.
    López Navarette, Juan T.
    University of Málaga, Spain.
    Casado, Juan
    University of Málaga, Spain.
    Ruiz Delgado, M. Carmen
    University of Málaga, Spain.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
    Norman, Patrick
    Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
    A combined MD/QM and experimental exploration of conformational richness in branched oligothiophenes2014In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 16, no 45, 24841-24852 p.Article in journal (Refereed)
    Abstract [en]

    Infrared (IR) absorption and vibrational Raman spectra of a family of branched oligothiophenes have been determined experimentally as well as theoretically. The molecular spectra have been compared to those of the linear analogues, with identification made of spectral features due to structural properties that are valued in organic solar cell applications. The theoretical spectra have been obtained through a newly developed method in which individual conformer spectra, calculated at the time-dependent DFT level in this work, are weighted by statistics extracted from classical molecular dynamics trajectories. The agreement with experiment for the resulting averaged spectra is at least as good as, and often better than, what is observed for Boltzmann-weighted spectra. As the weights are available before the costly step of spectrum calculation, the method has the additional advantage of enabling efficient approximations. For simulating the molecular dynamics of the studied α,β-linked thiophenes and 2-methylthiophenes, high quality parameters have been derived for the CHARMM force field. Furthermore, the temperature dependence of the IR and Raman spectra have been investigated, both experimentally and theoretically.

  • 32.
    Nordigården, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Tang, Yanjuan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    A comparative study of various FLT3-ITDs in relation to function and signalingManuscript (preprint) (Other academic)
    Abstract [en]

    Internal tandem duplications (ITD) in the FMS like tyrosine kinase (FLT3) receptor are one of the most common classes of mutations in acute myeloid leukemia (AML), which presence indicates a poor prognosis. Lengths of FLT3-ITD mutations found in patients can vary from 3 up to hundreds of nucleotides and may be located either in the juxtamembrane domain or the tyrosine kinase-1 domain (TKD1). There are contradicting opinions whether the length of the ITD has an impact on the clinical situation and whether tyrosines duplicated are of any significance for oncogenic signaling. Considering the substantial differences in lengths as well as the variability of start and end points of ITDs, we have performed a study of various FLT3-ITD mutations isolated from AML-patients. The ITD region from leukemic blasts of nine AML patients were sequenced and cloned by PCR into the human wildtype FLT3 cDNA, inserted to a retroviral GFP-containing vector. The hematopoietic progenitor cell line FDC-P1 was used to elucidate the impact of the different ITDs on growth, survival, signal transduction, and resistance to the FLT3-targeting inhibitor PKC412. Interestingly, the shortest and the longest ITDs were two of the three mutations that lead to the poorest survival of cells upon cytokine-deprivation, indicating that ITD size may not influence the transforming potential of cells. Furthermore one ITD that starts and ends relatively 3´ positioned, and comprises the 5´-part of the TKD1 showed both a survival advantage in starvation experiments and a significantly higher proliferation potential in comparison to several other mutations. Two other ITDs spanning this region, but with more 5´localized starting points, displayed less sensitivity to PKC412 treatment. However, this was not associated to STAT5 activity and MCL-1 upregulation as suggested by previous report. Taken together, this study suggests that different FLT3-ITD mutations may induce distinct signaling and response towards FLT3 targeting drugs, dependent of FLT3-ITD composition and not length.

  • 33.
    Sharifimajd, Babak
    et al.
    Linköping University, Department of Management and Engineering, Mechanics. Linköping University, The Institute of Technology.
    Stålhand, Jonas
    Linköping University, Department of Management and Engineering, Mechanics. Linköping University, The Institute of Technology.
    A continuum model for excitation–contraction of smooth muscle under finite deformations2014In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 355, 1-9 p.Article in journal (Refereed)
    Abstract [en]

    The main focus in most of continuum based muscle models is the muscle contraction dynamics while other physiological processes governing muscle contraction, e.g., the cell membrane excitation and the activation, are ignored. These latter processes are essential to initiate contraction and to determine the amount of generated force, and by excluding them, the developed model cannot replicate the true behavior of the muscle in question. The aim of this study is to establish a thermodynamically and physiologically consistent framework which allows to model smooth muscle contraction by including cell membrane excitability and kinetics of myosin phosphorylation, along with dynamics of smooth muscle contraction. The model accounts for these processes through a set of coupled dissipative constitutive equations derived by applying the first principles. To show the performance of the derived model, it is evaluated for two different cases: a mechanochemical study of pig taenia coli cells where the excitation process is excluded, and a complete excitation–contraction process of rat myometrium. The results show that the model is able to replicate important aspects of the smooth muscle EC process acceptably.

  • 34.
    Ahsan, Naveed
    et al.
    Linköping University, Department of Electrical Engineering. Linköping University, The Institute of Technology.
    Ouacha, Aziz
    Linköping University, Department of Electrical Engineering, Electronic Devices. Linköping University, The Institute of Technology.
    Svensson, Christer
    Linköping University, Department of Electrical Engineering, Electronic Devices. Linköping University, The Institute of Technology.
    Samuelsson, Carl
    Swedish Defence Research Agency (FOI), P.O. Box 1165, SE-581 11 Linköping, Sweden.
    Dąbrowski, Jerzy
    Linköping University, Department of Electrical Engineering, Electronic Devices. Linköping University, The Institute of Technology.
    A Design Approach for Flexible RF Circuits Using Reconfigurable PROMFA Cells2009In: Analog Integrated Circuits and Signal Processing, ISSN 0925-1030Article in journal (Other academic)
    Abstract [en]

    This paper presents a design approach for flexible RF circuits using Programmable Microwave Function Array (PROMFA) cells. The concept is based on an array of generic cells that can be dynamically reconfigured. Therefore, the same circuit can be used for various functions e.g. amplifier, tunable filter and tunable oscillator. For proof of concept a test chip has been implemented in 90nm CMOS process. The chip measurement results indicate that a single unit cell amplifier has a typical gain of 4dB with noise figure of 2.65dB at 1.5GHz. The measured input referred 1dB compression point is -8dBm with an IIP3 of +1.1dBm at 1GHz. In a single unit cell oscillator configuration, the oscillator can achieve a wide tuning range of 600MHz to 1.8GHz. The measured phase noise is -94dBc/Hz at an offset frequency of 1MHz for the oscillation frequency of 1.2GHz. A single unit cell oscillator consumes 18mW at 1.2GHz while providing -8dBm power into 50Ω load. In a single unit cell filter configuration, the tunable band pass filter can achieve a reasonable tuning range of 600MHz to 1.2GHz with a typical power consumption of 13mW at 1GHz. A single unit cell has a total chip area of 0.091mm2 including the coupling capacitors.

  • 35.
    Johansson, Kenny
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Electrical Engineering, Electronics System.
    Gustafsson, Oscar
    Linköping University, The Institute of Technology. Linköping University, Department of Electrical Engineering, Electronics System.
    Wanhammar, Lars
    Linköping University, The Institute of Technology. Linköping University, Department of Electrical Engineering, Electronics System.
    A detailed complexity model for multiple constant multiplication and an algorithm to minimize the complexity2005In: European Conf. Circuit Theory Design,2005, Cork: IEEE , 2005, III/465- p.Conference paper (Refereed)
    Abstract [en]

    Multiple constant multiplication (MCM) has been an active research area for the last decade. Most work so far have only considered the number of additions to realize a number of constant multiplications with the same input. In this work, we consider the number of full and half adder cells required to realize those additions, and a novel complexity measure is proposed. The proposed complexity measure can be utilized for all types of constant operations based on shifts, additions and subtractions. Based on the proposed complexity measure a novel MCM algorithm is presented. Simulations show that compared with previous algorithms, the proposed MCM algorithm have a similar number of additions while the number of full adder cells are significantly reduced.

  • 36.
    Shamsudin, Nebil
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    A Device for Measurement of Capillary Refilling Time2012Independent thesis Advanced level (degree of Master (Two Years)), 80 credits / 120 HE creditsStudent thesis
    Abstract [en]

    The main objective of this project is to design, construct and validate a portable prototype of a device that is capable of performing a test to accurately measure Capillary Refilling Time (CRT), and to analyze the results with defined parameters; force, area, pressure (compression) and time. This prototype is dedicated to study and evaluate CRT readouts for different pressure values, collected from healthy subjects.The presented prototype of this study is capable of producing skin compressing and to measure the refilling time of capillaries following this compression. This prototype introduces accuracy, mechanical reproducibility and controlling options for the applied pressure and compression time. The presented prototype is non-invasive, portable and it can be used to conduct more CRT tests and other capillary refilling studies.CRT measurement is done by calculating time interval starting from the first point when the applied pressure is released; ending with the recording point at the time when the concentration of red blood cells has reached the level of its pre-occlusion values.Based on the calculated CRT values and the number of iterations of the test in CRT tables, one can observe that given the same applied pressure value, CRT values do not significantly vary when the test is repetitively conducted on the same subject and on the same site.

  • 37. Chen, Fangyi
    et al.
    Zha, Dingjun
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Choudhury, Niloy
    Jacques, Steven L
    Wang, Ruikang K
    Shi, Xiaorui
    Nuttall, Alfred L
    A differentially amplified motion in the ear for near-threshold sound detection2011In: Nature Neuroscience, ISSN 1097-6256, Vol. 14, no 6, 770-774 p.Article in journal (Refereed)
    Abstract [en]

    The ear is a remarkably sensitive pressure fluctuation detector. In guinea pigs, behavioral measurements indicate a minimum detectable sound pressure of ∼20 μPa at 16 kHz. Such faint sounds produce 0.1-nm basilar membrane displacements, a distance smaller than conformational transitions in ion channels. It seems that noise within the auditory system would swamp such tiny motions, making weak sounds imperceptible. Here we propose a new mechanism contributing to a resolution of this problem and validate it through direct measurement. We hypothesized that vibration at the apical side of hair cells is enhanced compared with that at the commonly measured basilar membrane side. Using in vivo optical coherence tomography, we demonstrated that apical-side vibrations peaked at a higher frequency, had different timing and were enhanced compared with those at the basilar membrane. These effects depend nonlinearly on the stimulus sound pressure level. The timing difference and enhancement of vibrations are important for explaining how the noise problem is circumvented.

  • 38.
    Gustafsson, Mikael
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    A distributed image-processing system for measurements of intracellular calcium in living cells1991In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 36, no 4, 199-221 p.Article in journal (Refereed)
    Abstract [en]

    During the last decade, image-processing techniques have been introduced as a valuable tool in biologically oriented research. In combination with novel fluorescent probes, these techniques permit assessment of subcellular distributions of several intracellularly important cations, such as free calcium ions and protons. Typically, systems used for image processing are located centrally around the experimental setup. This configuration has drawbacks, mainly because the laborious extraction and processing of data that generally follow an experimental session limits the access to the system for other investigators. We describe here the principles of a distributed image processing system, based on IBM-compatible personal computers (PCs), that without extra hardware can cope with all the necessary image processing involved in imaging of intracellular cations. The potential of the PC as an image processor, however, reaches beyond this specific application and many image processing tasks can be carried out successfully on a standard PC. Thus, the centrally located dedicated image processor is used only for image acquisition in the experimental situation. This in turn optimizes the utilization of expensive resources and increases efficiency. The mouse-operated software is described in detail, so that interested investigators can extract useful parts for integration into their own applications and experimental environment.

  • 39.
    Lukin, Kara
    et al.
    National Jewish Health.
    Fields, Scott
    National Jewish Health.
    Guerrettaz, Lisa
    National Jewish Health.
    Straign, Desiree
    National Jewish Health.
    Rodriguez, Valerie
    National Jewish Health.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Mansson, Robert
    Lund Strategic Centre for Stem Cell Biology.
    Cambier, John C.
    National Jewish Health.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hagman, James
    National Jewish Health.
    A dose-dependent role for EBF1 in repressing non-B-cell-specific genes2011In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 6, 1787-1793 p.Article in journal (Refereed)
    Abstract [en]

    In the absence of early B-cell factor 1 (EBF1), B-cell development is arrested at an uncommitted progenitor stage that exhibits increased lineage potentials. Previously, we investigated the roles of EBF1 and its DNA-binding partner Runx1 by evaluating B lymphopoiesis in single (EBF1(het) and Runx1(het)) and compound haploinsufficent (Ebf1(+/-) Runx1(+/-), ER(het)) mice. Here, we demonstrate that decreased Ebf1 gene dosage results in the inappropriate expression of NK-cell lineage-specific genes in B-cell progenitors. Moreover, prolonged expression of Ly6a/Sca-1 suggested the maintenance of a relatively undifferentiated phenotype. These effects were exacerbated by reduced expression of Runx1 and occurred despite expression of Pax5. Repression of inappropriately expressed genes was restored in most pre-B and all immature B cells of ER(het) mice. Enforced EBF1 expression repressed promiscuous transcription in pro-B cells of ER(het) mice and in Ebf1(-/-) Pax5(-/-) fetal liver cells. Together, our studies suggest that normal levels of EBF1 are critical for maintaining B-cell identity by directing repression of non-B-cell-specific genes.

  • 40.
    Xu, Jin Wei
    et al.
    Bioinformatics Research Group School of Engineering and Information Technology The University of New South Wales Canberra, ACT 2600, Australia .
    Pham, Tuan D.
    Bioinformatics Research Group School of Engineering and Information Technology The University of New South Wales Canberra, Australia .
    Zhou, Xiaobo
    The Methodist Hospital Research Institute Cornell University Houston, TX 77030, USA.
    A double thresholding method for cancer stem cell detection2011Conference paper (Refereed)
    Abstract [en]

    Image analysis of cancer cells is important for cancer diagnosis and therapy, because it recognized as the most efficient and effective way to observe its proliferation. For the purpose of adaptive and accurate cancer cell image segmentation, a double threshold segmentation method is proposed in this paper. Based on a single gray-value histogram of the RGB color space, a double threshold, the key parameters of threshold segmentation can be fixed by a fitted-curve of the RGB component histogram. As reasonable thresholds confirmed, binary segmentation dependent on two thresholds, will be put into practice and result in binary image. With the post-processing of mathematical morphology and division of whole image, the better segmentation result can be finally achieved. By the comparison with other advanced segmentation methods such as level set and active contour, the proposed double thresholding has been found as the simplest strategy with shortest processing time as well as highest accuracy. The proposed method can be effectively used in the detection and recognition of cancer stem cells in images.

  • 41.
    Peng, Zuosheng
    et al.
    Jinan University, Peoples R China.
    Xia, Yuxin
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology. Jinan University, Peoples R China.
    Gao, Feng
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering. S China University of Technology, Peoples R China.
    Xiong, Kang
    Jinan University, Peoples R China.
    Hu, Zhanhao
    S China University of Technology, Peoples R China.
    Ian James, David
    Chalmers, Sweden.
    Chen, Junwu
    S China University of Technology, Peoples R China.
    Wang, Ergang
    Chalmers, Sweden.
    Hou, Lintao
    Jinan University, Peoples R China.
    A dual ternary system for highly efficient ITO-free inverted polymer solar cells2015In: Journal of Materials Chemistry A, ISSN 2050-7488, Vol. 3, no 36, 18365-18371 p.Article in journal (Refereed)
    Abstract [en]

    In this study, it has been found that a very fine nanostructure can be realized by mixing 1-chloronaphthalene (CN) - a high-boiling solvent into a binary chlorobenzene (CB) : 1,8-diiodooctane (DIO) solvent mixture to form a ternary solvent system. An improvement in energy level alignment is also obtained by doping ICBA into a binary PTB7 : PCBM[70] blend, whereby the ternary solute system provides a new pathway for charge transfer from PTB7 to the PCBM[ 70] : ICBA alloy. This is confirmed by imaging the surface morphology of the active layer using AFM and TEM, monitoring the transient film formation process and measuring the charge transfer states with Fourier transform photocurrent spectroscopy. An encouraging PCE of 7.65% is achieved from the dual ternary system, which is the highest value ever reported for an ITO-free inverted polymer solar cell with a PEDOT:PSS layer as the top semitransparent electrode - a system which is compatible with low-cost large-area roll-to-roll manufacturing.

  • 42.
    Ma, Zaifei
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Dang, Dongfeng
    Chalmers, Sweden Xiangtan University, Peoples R China .
    Tang, Zheng
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Gedefaw, Desta
    Chalmers, Sweden .
    Bergqvist, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Zhu, Weiguo
    Xiangtan University, Peoples R China .
    Mammo, Wendimagegn
    University of Addis Ababa, Ethiopia .
    Andersson, Mats R.
    Chalmers, Sweden .
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Zhang, Fengling
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Wang, Ergang
    Chalmers, Sweden .
    A Facile Method to Enhance Photovoltaic Performance of Benzodithiophene-Isoindigo Polymers by Inserting Bithiophene Spacer2014In: ADVANCED ENERGY MATERIALS, ISSN 1614-6832, Vol. 4, no 6Article in journal (Refereed)
    Abstract [en]

    A series of conjugated polymers containing benzodithiophene as donor and isoindigo as acceptor with no, one, two and three thiophene spacer groups is synthesized and characterized. The polymer with bithiophene as a spacer has a superior efficiency of 7.31% in solar cells. This demonstrates an important design strategy to produce polymers for high-performance solar cells by inserting thiophene spacer groups.

  • 43.
    Klarbring, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering.
    A first-principles non-equilibrium molecular dynamicsstudy of oxygen diffusion in Sm-doped ceria2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Solid oxide fuel cells are considered as one of the main alternatives for future sources of clean energy. To further improve their performance, theoretical methods able to describe the diffusion process in candidate electrolyte materials at finite temperatures are needed. The method of choice for simulating systems at finite temperature is molecular dynamics. However, if the forces are calculated directly from the Schrödinger equation (first-principles molecular dynamics) the computational expense is too high to allow long enough simulations to properly capture the diffusion process in most materials.

    This thesis introduces a method to deal with this problem using an external force field to speed up the diffusion process in the simulation. The method is applied to study the diffusion of oxygen ions in Sm-doped ceria, which has showed promise in its use as an electrolyte. Good agreement with experimental data is demonstrated, indicating high potential for future applications of the method.

  • 44.
    Ramström, A Sofia
    et al.
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Fagerberg, I.
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    A flow cytometric assay for the study of dense granule storage and release in human platelets1999In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 10, no 2-3, 153-158 p.Article in journal (Refereed)
    Abstract [en]

    The clinical manifestations of platelet dense (δ) granule defects are easy bruising, as well as epistaxis and bleeding after delivery, tooth extractions and surgical procedures. The observed symptoms may be explained either by a decreased number of granules or by a defect in the uptake/release of granule contents. We have developed a method to study platelet dense granule storage and release. The uptake of the fluorescent marker, mepacrine, into the platelet dense granule was measured using flow cytometry. The platelet population was identified by the size and binding of a phycoerythrin-conjugated antibody against GPIb. Cells within the discrimination frame were analysed for green (mepacrine) fluorescence. Both resting platelets and platelets previously stimulated with collagen and the thrombin receptor agonist peptide SFLLRN was analysed for mepacrine uptake. By subtracting the value for mepacrine uptake after stimulation from the value for uptake without stimulation for each individual, the platelet dense granule release capacity could be estimated. Whole blood samples from 22 healthy individuals were analysed. Mepacrine incubation without previous stimulation gave mean fluorescence intensity (MFI) values of 83±6 (mean ± 1 SD, range 69–91). The difference in MFI between resting and stimulated platelets was 28±7 (range 17–40). Six members of a family, of whom one had a known δ-storage pool disease, were analysed. The two members (mother and son) who had prolonged bleeding times also had MFI values disparate from the normal population in this analysis. The values of one daughter with mild bleeding problems but a normal bleeding time were in the lower part of the reference interval.

  • 45.
    Canedo, P.
    et al.
    University of Porto, Portugal.
    Thorselius, M.
    Uppsala University.
    Thunberg, U.
    Uppsala University.
    Sällström, J.
    Uppsala University.
    Sundström, C.
    Uppsala University.
    Rosén, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderberg, O.
    University of Porto, Portugal.
    A Follicular Dendritic Cell Line Promotes Somatic Hypermutations in Ramos cells In Vitro2009In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 69, no 1, 70-71 p.Article in journal (Other academic)
  • 46.
    Diaz de Zerio Mendaza, Amaia
    et al.
    Chalmers, Sweden.
    Melianas, Armantas
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Nugroho, Ferry A. A.
    Chalmers, Sweden.
    Backe, Olof
    Chalmers, Sweden.
    Olsson, Eva
    Chalmers, Sweden.
    Langhammer, Christoph
    Chalmers, Sweden.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Mueller, Christian
    Chalmers, Sweden.
    A fullerene alloy based photovoltaic blend with a glass transition temperature above 200 degrees C2017In: Journal of Materials Chemistry A, ISSN 2050-7488, Vol. 5, no 8, 4156-4162 p.Article in journal (Refereed)
    Abstract [en]

    Organic solar cells with a high degree of thermal stability require bulk-heterojunction blends that feature a high glass transition, which must occur considerably above the temperatures encountered during device fabrication and operation. Here, we demonstrate for the first time a polymer : fullerene blend with a glass transition temperature above 200 degrees C, which we determine by plasmonic nanospectroscopy. We achieve this strong tendency for glass formation through the use of an alloy of neat, unsubstituted C-60 and C-70, which we combine with the fluorothieno-benzodithiophene copolymer PTB7. A stable photovoltaic performance of PTB7 : C60 : C70 ternary blends is preserved despite annealing the active layer at up to 180 degrees C, which coincides with the onset of the glass transition. Rapid deterioration of the power conversion efficiency from initially above 5% only occurs upon exceeding the glass transition temperature of 224 degrees C of the ternary blend.

  • 47.
    Angelakis, Vangelis
    et al.
    Linköping University, Department of Science and Technology, Communications and Transport Systems. Linköping University, The Institute of Technology.
    Chen, Lei
    Linköping University, Department of Science and Technology, Communications and Transport Systems. Linköping University, The Institute of Technology.
    Yuan, Di
    Linköping University, Department of Science and Technology, Communications and Transport Systems. Linköping University, The Institute of Technology.
    A Fully Decentralized and Load-Adaptive Fractional Frequency Reuse Scheme2011In: Modeling, Analysis & Simulation of Computer and Telecommunication Systems (MASCOTS), 2011 IEEE 19th International Symposium on, 2011, 425-428 p.Conference paper (Refereed)
    Abstract [en]

    A new fully decentralized dynamic fractional frequency reuse (FFR)-based scheme for cellular OFDMA networks is introduced. FFR is a technique to mitigate inter-cell interference to improve the throughput of interference-limited users on the cell edge, to the expense of the rest of the cell's users and the aggregate throughput. The proposed scheme aims to limit the FFR-incurred loss of the center users' throughput, while still providing sufficient bandwidth for the cell edge users' communication. This is done by local information sharing and distributed optimization. The resulting flexibility of frequency reuse can be especially beneficial in scenarios with non-uniform and time-varying load. The optimization task is accomplished by solving a knapsack problem in each cell, where the goal is to maximize the center throughput while maintaining acceptable degradation on the cell edge with respect to the original FFR allocation. The performance improvement resulting from the distributed and dynamic FFR scheme is demonstrated by snapshot simulations on an 81-cells network with asymmetric cell load. The proposed scheme achieves up to a 62% gain in cell-center throughput with a cost of no more than 18% at the edges when compared to the classic FFR scheme. The overall system throughput improvement ranges from 22% to 58%.

  • 48.
    Makrantoni, Vasso
    et al.
    University of Dundee, Scotland; University of Edinburgh, Scotland.
    Ciesiolka, Adam
    Newcastle University, England; Institute Bioorgan Chemistry PAN, Poland.
    Lawless, Conor
    Newcastle University, England.
    Fernius, Josefin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Edinburgh, Scotland.
    Marston, Adele
    University of Edinburgh, Scotland.
    Lydall, David
    Newcastle University, England.
    Stark, Michael J. R.
    University of Dundee, Scotland.
    A Functional Link Between Bir1 and the Saccharomyces cerevisiae Ctf19 Kinetochore Complex Revealed Through Quantitative Fitness Analysis2017In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 7, no 9, 3203-3215 p.Article in journal (Refereed)
    Abstract [en]

    The chromosomal passenger complex (CPC) is a key regulator of eukaryotic cell division, consisting of the protein kinase Aurora B/Ipl1 in association with its activator (INCENP/Sli15) and two additional proteins (Survivin/Bir1 and Borealin/Nbl1). Here, we report a genome-wide genetic interaction screen in Saccharomyces cerevisiae using the bir1-17 mutant, identifying through quantitative fitness analysis deletion mutations that act as enhancers and suppressors. Gene knockouts affecting the Ctf19 kinetochore complex were identified as the strongest enhancers of bir1-17, while mutations affecting the large ribosomal subunit or the mRNA nonsense-mediated decay pathway caused strong phenotypic suppression. Thus, cells lacking a functional Ctf19 complex become highly dependent on Bir1 function and vice versa. The negative genetic interaction profiles of bir1-17 and the cohesin mutant mcd1-1 showed considerable overlap, underlining the strong functional connection between sister chromatid cohesion and chromosome biorientation. Loss of some Ctf19 components, such as Iml3 or Chl4, impacted differentially on bir1-17 compared with mutations affecting other CPC components: despite the synthetic lethality shown by either iml3 Delta or chl4 Delta in combination with bir1-17, neither gene knockout showed any genetic interaction with either ipl1-321 or sli15-3. Our data therefore imply a specific functional connection between the Ctf19 complex and Bir1 that is not shared with Ipl1.

  • 49.
    Li, Yongxi
    et al.
    Soochow University, Peoples R China; Chinese Academic Science, Peoples R China.
    Qian, Deping
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Zhong, Lian
    Chinese Academic Science, Peoples R China; University of Chinese Academic Science, Peoples R China.
    Lin, Jiu-Dong
    Soochow University, Peoples R China.
    Jiang, Zuo-Quan
    Soochow University, Peoples R China.
    Zhang, Zhi-Guo
    Chinese Academic Science, Peoples R China; University of Chinese Academic Science, Peoples R China.
    Zhang, Zhanjun
    Chinese Academic Science, Peoples R China; University of Chinese Academic Science, Peoples R China.
    Li, Yongfang
    Soochow University, Peoples R China; Chinese Academic Science, Peoples R China.
    Liao, Liang-Sheng
    Soochow University, Peoples R China.
    Zhang, Fengling
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.
    A fused-ring based electron acceptor for efficient non-fullerene polymer solar cells with small HOMO offset2016In: NANO ENERGY, ISSN 2211-2855, Vol. 27, 430-438 p.Article in journal (Refereed)
    Abstract [en]

    A non-fullerene electron acceptor bearing a novel backbone with fused 10-heterocyclic ring (in-dacenodithiopheno-indacenodiselenophene), denoted by IDTIDSe-IC is developed for fullerene free polymer solar cells. IDTIDSe-IC exhibits a low band gap (E-g=1.52 eV) and strong absorption in the 600850 nm region. Combining with a large band gap polymer J51 (E-g=1.91 eV) as donor, broad absorption coverage from 300 nm to 800 nm is obtained due to complementary absorption of J51 and IDTIDSe-IC, which enables a high PCE of 8.02% with a V-oc of 0.91 V, a J(SC) of 15.16 mA/cm(2) and a FF of 58.0% in the corresponding PSCs. Moreover, the EQE of 50-65% is achieved in the absorption range of IDTIDSe-IC with only about 0.1 eV HOMO difference between J51 and IDTIDSe-IC. (C) 2016 Elsevier Ltd. All rights reserved.

  • 50.
    Bruhn, Sören
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Fang, Yu
    Guiyang Medical Coll, Peoples R China University of Gothenburg, Sweden .
    Barrenäs, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Konstantinell, Aelita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Kronke, Andrea
    Cenix BioScience GmbH, Germany .
    Sonnichsen, Birte
    Cenix BioScience GmbH, Germany .
    Bresnick, Anne
    Albert Einstein Coll Med, NY 10461 USA .
    Dulyaninova, Natalya
    Albert Einstein Coll Med, NY 10461 USA .
    Wang, Hui
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Zhao, Yelin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Klingelhofer, Jorg
    University of Copenhagen, Denmark .
    Ambartsumian, Noona
    University of Copenhagen, Denmark .
    Beck, Mette K.
    Technical University of Denmark, Denmark .
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Bona, Elsa
    Boras Hospital, Sweden .
    Xiang, Zou
    University of Gothenburg, Sweden .
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy2014In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 6, no 218Article in journal (Refereed)
    Abstract [en]

    The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.

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