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  • 1.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping. Helsingborg Hospital, Helsingborg.
    Duchén, Karel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Nilsson, Lennart J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    The Placental Immune Milieu is Characterized by a Th2- and Anti-Inflammatory Transcription Profile, Regardless of Maternal Allergy, and Associates with Neonatal Immunity2015In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 73, no 5, 445-459 p.Article in journal (Refereed)
    Abstract [en]

    PROBLEM: How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear.

    METHOD OF STUDY: Expression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non-allergic women and their offspring.

    RESULTS: Placental gene expression was dominated by a Th2-/anti-inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = -0.88, P < 0.001) and IL-5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2-associated CCL22 in CBMC preceded allergy development.

    CONCLUSIONS: Gene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not associated with an enhanced Th2 immunity in placenta or PBMC, while a marked prenatal Th2 skewing, shown as increased CCL22 mRNA expression, might contribute to postnatal allergy development.

  • 2.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Duchén, Karel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Gene expression in placenta, peripheral and cord blood mononuclear cells from allergic and non-allergic women2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: The influence of maternal allergy on the development of immune responses and allergy in the offspring is not understood.

    Objective: To investigate (i) if maternal allergy influences the gene expression locally in placenta, systemically in peripheral blood mononuclear cells (PBMC) and fetally in cord blood mononuclear cells (CBMC), (ii) if the gene expression in the placenta and PBMC influences the gene expression in CBMC and (iii) how the gene expression at birth relates to allergy development during  childhood.

    Methods: A real-time PCR array was used to quantify forty immune regulatory genes in placenta, PBMC (gestational week 39) and in CBMC from 7 allergic and 12 non-allergic women and their offspring. Furthermore, quantitative real-time PCR was used to measure mRNA expression of Tbx21, GATA-3, Foxp3, RORC and CCL22 in CBMC, selected based on present PCR array results and previous protein findings in cord blood, in 13 children who developed and 11 children who did not develop allergy during childhood.

    Results: The gene expression profile in the placenta revealed a T-helper (Th) 2-/anti-inflammatory environment as compared with gene expression systemically, in PBMC. Maternal allergy was associated with increased expression of p35 in PBMC and CBMC and p40 in placenta. Placental p35 expression correlated with fetal Tbx21 expression (Rho=-0.88, p<0.001) and maternal IL-5 expression in PBMC with fetal Galectin-1 (Rho=0.91, p<0.001) expression. Allergy development in the children was preceded by high mRNA expression of the Th2-associated chemokine CCL22 at birth.

    Conclusion and clinical relevance: Gene expression locally and systemically during pregnancy influenced the offspring’s gene expression at birth, indicating an interplay between maternal and fetal immunity. Children developing allergy during childhood had an increased expression of the Th2-associated chemokine CCL22 at birth, indicating a Th2 skewing before disease onset. Maternal allergy was not associated with a Th2-dominance in placenta, PBMC or CBMC.

  • 3.
    Abrouk, Michael
    et al.
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Balcarkova, Barbora
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Simkova, Hana
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Kominkova, Eva
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Martis, Mihaela-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Institute for Bioinformatics and Systems Biology, Helmholtz Center Munich, Neuherberg, Germany.
    Jakobson, Irena
    Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 19086, Estonia.
    Timofejeva, Ljudmilla
    Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 19086, Estonia.
    Rey, Elodie
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Vrana, Jan
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Kilian, Andrzej
    Diversity Arrays Technology Pty Ltd, Yarralumla, ACT2600, Australia.
    Järve, Kadri
    Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 19086, Estonia.
    Dolezel, Jaroslav
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    Valarik, Miroslav
    Institute of Experimental Botany, Centre of the Region Hana for Biotechnological and Agricultural Research, Olomouc, Czech Republic.
    The in silico identification and characterization of a bread wheat/Triticum militinae introgression line: Characterization of alien introgression in wheat2017In: Plant Biotechnology Journal, ISSN 1467-7644, E-ISSN 1467-7652, Vol. 15, no 2, 249-256 p.Article in journal (Refereed)
    Abstract [en]

    The capacity of the bread wheat (Triticum aestivum) genome to tolerate introgression from related genomes can be exploited for wheat improvement. A resistance to powdery mildew expressed by a derivative of the cross bread wheat cv. Tähti ⨯ T. militinae (Tm) is known to be due to the incorporation of a Tm segment into the long arm of chromosome 4A. Here, a newly developed in silico method termed RICh (rearrangement identification and characterization) has been applied to characterize the introgression. A virtual gene order, assembled using the GenomeZipper approach, was obtained for the native copy of chromosome 4A; it incorporated 570 4A DArTseq markers to produce a zipper comprising 2,132 loci. A comparison between the native and introgressed forms of the 4AL chromosome arm showed that the introgressed region is located at the distal part of the arm. The Tm segment, derived from chromosome 7G, harbors 131 homoeologs out of the 357 genes present on the corresponding region of Chinese Spring 4AL. The estimated number of Tm genes transferred along with the disease resistance gene was 169. Characterizing the introgression's position, gene content and internal gene order should facilitate not only gene isolation, but may also be informative with respect to chromatin structure and behavior studies.

  • 4.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons2014In: Current pharmaceutical design, ISSN 1381-6128, Vol. 20, no 15, 2458-2468 p.Article in journal (Refereed)
    Abstract [en]

    The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

  • 5.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Geriatric Medicine in Norrköping.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Domert, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease2014In: Molecular and Cellular Neuroscience, ISSN 0890-8508, E-ISSN 1095-9327, Vol. 58, 29-39 p.Article in journal (Refereed)
    Abstract [en]

    Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

  • 6.
    Ahn, Jae-Il
    et al.
    Ottawa Hospital, Canada .
    Kuffova, Lucia
    University of Aberdeen, Scotland .
    Merrett, Kimberley
    Ottawa Hospital, Canada .
    Mitra, Debbie
    Ottawa Hospital, Canada .
    Forrester, John V.
    University of Aberdeen, Scotland .
    Li, Fengfu
    Ottawa Hospital, Canada .
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Ottawa Hospital, Canada .
    Crosslinked collagen hydrogels as corneal implants: Effects of sterically bulky vs. non-bulky carbodiimides as crosslinkers2013In: Acta Biomaterialia, ISSN 1742-7061, Vol. 9, no 8, 7796-7805 p.Article in journal (Refereed)
    Abstract [en]

    We have previously shown that recombinant human collagen can be crosslinked with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) to fabricate transparent hydrogels possessing the shape and dimensions of the human cornea. These corneal implants have been tested in a Phase I human clinical study. Although these hydrogels successfully promoted corneal tissue and nerve regeneration, the gelling kinetics were difficult to control during the manufacture of the implants. An alternative carbodiimide capable of producing hydrogels of similar characteristics as EDC in terms of strength and biocompatibility, but with a longer gelation time would be a desirable alternative. Here, we compared the crosslinking kinetics and properties of hydrogels crosslinked with a sterically bulky carbodiimide, N-Cyclohexyl-N-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMC), with that of EDC. CMC crosslinking was possible at ambient temperature whereas the EDC reaction was too rapid to control and had to be carried out at low temperatures. The highest tensile strength obtained using optimized formulations were equivalent, although CMC crosslinked hydrogels were found to be stiffer. The collagenase resistance of CMC crosslinked hydrogels was superior to that of EDC crosslinked hydrogels while biocompatibility was similar. We are also able to substitute porcine collagen with recombinant human collagen and show that the in vivo performance of both resulting hydrogels as full-thickness corneal implants is comparable in a mouse model of an orthotopic corneal graft. In conclusion, CMC is a viable alternative to EDC as a crosslinker for collagen-based biomaterials for use as corneal implants, and potentially for use in other tissue engineering applications.

  • 7.
    Aili Fagerholm, Siri
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Insulin signaling in primary adipocytes in insulin sensitive and insulin resistant states2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Increasing numbers of people world-wide develops the disease type 2 diabetes. Development of type 2 diabetes is characterized by a shift from an insulin sensitive state to an insulin resistant state in peripheral insulin responding organs, which originates from the development of insulin resistance in the adipose tissue. Insulin resistance in combination with reduced pancreatic insulin secretion lead to overt type 2 diabetes.

    In this thesis, the insulin signaling network in primary adipocytes was analyzed. Key proteins and mechanisms were studied to gain deeper knowledge of signaling both in the insulin sensitive state and in the insulin resistant state produced by rapid weight gain as well as in type 2 diabetes.

    The surface of the adipocyte is dotted with invaginations in the cell membrane called caveolae that act as important metabolic and signaling platforms in adipocytes, and also harbor the insulin receptor. In paper I we show that insulin stimulation of primary adipocytes results in a rapid phosphorylation of the insulin receptor and caveolin-1, and that internalization of the proteins is mediated by endocytosis of caveolae.

    Weight gain due to overfeeding and obesity has been associated with the development of insulin resistance in insulin sensitive tissues such as the adipose tissue. In paper II we show that short-term overfeeding for one month of lean subjects results in an insulin resistant state. At the end of the study, the subjects had developed a mild systemic insulin resistance. Moreover, in isolated subcutaneous adipocytes we found several alterations of the insulin signaling pathway that mimicked alterations found in isolated subcutaneous adipocytes from subjects with type 2 diabetes.

    In paper III we present a first dynamic mathematical model of the insulin signaling network in human adipocytes that are based on experimental data acquired in a consistent fashion. The model takes account of insulin signaling in both the healthy, insulin sensitive state and in the insulin resistant state of type 2 diabetes. We show that attenuated mTORC1-mediated positive feedback to control of phosphorylation of IRS1 at Ser307 is an essential component of the insulin resistant state of type 2 diabetes. A future application of the model is the identification and evaluation of drug targets for the treatment of insulin resistance and type 2 diabetes.

    In paper IV we examine the protein kinase that catalyzes the insulin stimulated mTORC1- mediated feedback to IRS1. We find that the phosphorylation of IRS1 at Ser307 is not likely to be catalyzed by the kinases S6K1, mTOR or PKB. However, a catalyzing protein kinase for the in vitro phosphorylation of IRS1 at Ser307 was found to be associated with the complex mTORC1.

    In conclusion, this thesis provide new insights and characterize mechanisms of the intrinsically complex insulin signaling network of primary adipocytes, both in insulin sensitive and insulin resistant states.

    List of papers
    1. Rapid insulin-dependent endocytosis of the insulin receptor by caveolae in primary adipocytes
    Open this publication in new window or tab >>Rapid insulin-dependent endocytosis of the insulin receptor by caveolae in primary adipocytes
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    2009 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 6, e5985- p.Article in journal (Refereed) Published
    Abstract [en]

    Background: The insulin receptor is localized in caveolae and is dependent on caveolae or cholesterol for signaling in adipocytes. When stimulated with insulin, the receptor is internalized. Methodology/Principal Findings: We examined primary rat adipocytes by subcellular fractionation to examine if the insulin receptor was internalized in a caveolae-mediated process. Insulin induced a rapid, t1/2 less than3 min, endocytosis of the insulin receptor in parallel with receptor tyrosine autophosphorylation. Concomitantly, caveolin-1 was phosphorylated at tyrosine(14) and endocytosed. Vanadate increased the phosphorylation of caveolin-1 without affecting insulin receptor phosphorylation or endocytosis. Immunocapture of endosomal vesicles with antibodies against the insulin receptor co-captured caveolin-1 and immunocapture with antibodies against tyrosine(14)-phosphorylated caveolin-1 co-captured the insulin receptor, demonstrating that the insulin receptor was endocytosed together with tyrosine(14)-phosphorylated caveolin-1. By immunogold electron microscopy the insulin receptor and caveolin-1 were colocalized in endosome vesicles that resembled caveosomes. Clathrin was not endocytosed with the insulin receptor and the inhibitor of clathrin-coated pit-mediated endocytosis, chlorpromazine, did not inhibit internalization of the insulin receptor, while transferrin receptor internalization was inhibited. Conclusion: It is concluded that in response to insulin stimulation the autophosphorylated insulin receptor in primary adipocytes is rapidly endocytosed in a caveolae-mediated process, involving tyrosine phosphorylation of caveolin-1.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-21319 (URN)10.1371/journal.pone.0005985 (DOI)
    Note
    Original Publication: Siri Fagerholm, Unn Örtegren Kugelberg, M. Karlsson, I. Ruishalme and Peter Strålfors, Rapid insulin-dependent endocytosis of the insulin receptor by caveolae in primary adipocytes, 2009, PLoS ONE, (4), 6, e5985. http://dx.doi.org/10.1371/journal.pone.0005985 Available from: 2009-09-30 Created: 2009-09-30 Last updated: 2013-07-08
    2. Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects
    Open this publication in new window or tab >>Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects
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    2009 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, Vol. 15, no 7-8, 228-234 p.Article in journal (Refereed) Published
    Abstract [en]

    Insulin resistance and type 2 diabetes (T2D) are closely linked to obesity. Numerous prospective studies have reported on weight gain, insulin resistance, and insulin signaling in experimental animals, but not in humans. We examined insulin signaling in adipocytes from lean volunteers, before and at the end of a 4-wk period of consuming a fast-food, high-calorie diet that led to weight gain. We also examined adipocytes from patients with T2D. During the high-calorie diet, subjects gained 10% body weight and 19% total body fat, but stayed lean (body mass index = 24.3 kg/m2) and developed moderate systemic insulin resistance. Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. Unlike the T2D subjects, in subjects on the high-calorie diet, likely owing to the ongoing weight-gain, phosphorylation of MAP-kinases ERK1/2 became hyperresponsive to insulin. To our knowledge this study is the first to investigate insulin signaling during overeating in humans, and it demonstrates that T2D effects on intracellular insulin signaling already occur after 4 wks of a high-calorie diet and that the effects in humans differ from those in laboratory animals.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20893 (URN)10.2119/molmed.2009.00037 (DOI)000276043800004 ()
    Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2013-09-10
    3. Insulin Signaling in Type 2 Diabetes: Experimental and Modeling Analyses Reveal Mechanisms of Insulin Resistance in Human Adipocytes
    Open this publication in new window or tab >>Insulin Signaling in Type 2 Diabetes: Experimental and Modeling Analyses Reveal Mechanisms of Insulin Resistance in Human Adipocytes
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    2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 14, 9867-9880 p.Article in journal (Refereed) Published
    Abstract [en]

    Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems-level mechanistic understanding of insulin resistance in humans. We developed a dynamic mathematical model of insulin signaling – normally and in diabetes – based on quantitative steady-state and dynamic time-course data on signaling intermediaries in human mature adipocytes. At the core of insulin resistance is attenuation of a positive feedback from mammalian target of rapamycin in complex with raptor (mTORC1) to the insulin receptor substrate-1 (IRS1), which explains reduced sensitivity and signal strength throughout the signaling network. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-84999 (URN)10.1074/jbc.M112.432062 (DOI)000317114000027 ()
    Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2014-02-24Bibliographically approved
    4. Phosphorylation of IRS1 at Serine 307 in Response to Insulin in Human Adipocytes Is Not Likely to be Catalyzed by p70 Ribosomal S6 Kinase
    Open this publication in new window or tab >>Phosphorylation of IRS1 at Serine 307 in Response to Insulin in Human Adipocytes Is Not Likely to be Catalyzed by p70 Ribosomal S6 Kinase
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    2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 4Article in journal (Refereed) Published
    Abstract [en]

    The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. This in turn directly affects downstream signaling and is in human adipocytes implicated in the pathogenesis of insulin resistance and type 2 diabetes. The phosphorylation is inhibited by rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR) in complex with raptor (mTORC1). The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1.

    Place, publisher, year, edition, pages
    Public Library of Science, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-93257 (URN)10.1371/journal.pone.0059725 (DOI)000317717300032 ()
    Note

    Funding Agencies|Swedish Diabetes Fund||Novo Nordic Foundation||University of Linkoping||Swedish Research Council||

    Available from: 2013-05-28 Created: 2013-05-28 Last updated: 2013-07-08
  • 8.
    Akanda, Nesar
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Tofighi, Roshan
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Brask, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Tamm, Christoffer
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ceccatelli, Sandra
    Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden .
    Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells2008In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 7, no 20, 3225-3234 p.Article in journal (Refereed)
    Abstract [en]

    microRNAs (miRNAs) are small non-coding RNAs that regulate a large variety of cellular processes including differentiation, apoptosis and proliferation. Several miRNAs display defective expression patterns in human tumors with the consequent alteration of target oncogene or tumor suppressor genes. Many of these miRNAs modulate the major proliferation pathways through direct interaction with critical regulators such as RAS, PI3K/PTEN or ABL, as well as members of the retinoblastoma pathway, Cyclin-CDK complexes or cell cycle inhibitors of the INK4 or Cip/Kip families. A complex interplay between miRNAs and MYC or E2F family members also exists to modulate cell cycle-dependent transcription during normal or tumoral proliferation. The ability of miRNAs to modulate these proliferation pathways may have relevant implications not only in physiological or developmental processes but also in tumor progression or cancer therapy.

  • 9.
    Alarcon, E I
    et al.
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Vulesevic, B
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Argawal, A
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Ross, A
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Bejjani, P
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Podrebarac, J
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Ravichandran, Ranjithkumar
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Phopase, Jaywant
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Suuronen, E J
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Coloured cornea replacements with anti-infective properties: expanding the safe use of silver nanoparticles in regenerative medicine.2016In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 8, no 12, 6484-6489 p.Article in journal (Refereed)
    Abstract [en]

    Despite the broad anti-microbial and anti-inflammatory properties of silver nanoparticles (AgNPs), their use in bioengineered corneal replacements or bandage contact lenses has been hindered due to their intense yellow coloration. In this communication, we report the development of a new strategy to pre-stabilize and incorporate AgNPs with different colours into collagen matrices for fabrication of corneal implants and lenses, and assessed their in vitro and in vivo activity.

  • 10.
    Alarcon, Emilio I.
    et al.
    University of Ottawa, Canada; University of Ottawa, Canada; University of Ottawa, Canada.
    Udekwu, Klas I.
    Karolinska Institute, Sweden.
    Noel, Christopher W.
    University of Ottawa, Canada; .
    Gagnon, Luke B. -P.
    University of Ottawa, Canada.
    Taylor, Patrick K.
    University of Ottawa, Canada.
    Vulesevic, Branka
    University of Ottawa, Canada.
    Simpson, Madeline J.
    University of Ottawa, Canada.
    Gkotzis, Spyridon
    Karolinska Institute, Sweden.
    Islam, Mohammed Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Lee, Chyan-Jang
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Richter-Dahlfors, Agneta
    Karolinska Institute, Sweden.
    Mah, Thien-Fah
    University of Ottawa, Canada.
    Suuronen, Erik J.
    University of Ottawa, Canada.
    Scaiano, Juan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Ottawa, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Safety and efficacy of composite collagen-silver nanoparticle hydrogels as tissue engineering scaffolds2015In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 7, no 44, 18789-18798 p.Article in journal (Refereed)
    Abstract [en]

    The increasing number of multidrug resistant bacteria has revitalized interest in seeking alternative sources for controlling bacterial infection. Silver nanoparticles (AgNPs), are amongst the most promising candidates due to their wide microbial spectrum of action. In this work, we report on the safety and efficacy of the incorporation of collagen coated AgNPs into collagen hydrogels for tissue engineering. The resulting hybrid materials at [AgNPs] less than0.4 mu M retained the mechanical properties and biocompatibility for primary human skin fibroblasts and keratinocytes of collagen hydrogels; they also displayed remarkable anti-infective properties against S. aureus, S. epidermidis, E. coli and P. aeruginosa at considerably lower concentrations than silver nitrate. Further, subcutaneous implants of materials containing 0.2 mu M AgNPs in mice showed a reduction in the levels of IL-6 and other inflammation markers (CCL24, sTNFR-2, and TIMP1). Finally, an analysis of silver contents in implanted mice showed that silver accumulation primarily occurred within the tissue surrounding the implant.

  • 11.
    Alehagen, Urban
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Johansson, Peter
    Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Björnstedt, Mikael
    Division of Pathology F42, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Post, Claes
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Aaseth, Jan
    Research Department, Innlandet Hospital Trust and Hedmark University College, Norway.
    Relatively high mortality risk in elderly Swedish subjects with low selenium status2016In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 70, no 1, 91-96 p.Article in journal (Refereed)
    Abstract [en]

    Background/Objectives: 

    The daily dietary intake of selenium (Se), an essential trace element, is still low in Sweden in spite of decades of nutritional information campaigns and the effect of this on the public health is presently not well known. The objective of this study was to determine the serum Se levels in an elderly Swedish population and to analyze whether a low Se status had any influence on mortality.

    Subjects/Methods: 

    Six-hundred sixty-eight (n=668) elderly participants were invited from a municipality and evaluated in an observational study. Individuals were followed for 6.8 years and Se levels were re-evaluated in 98 individuals after 48 months. Clinical examination of all individuals included functional classification, echocardiography, electrocardiogram and serum Se measurement. All mortality was registered and endpoints of mortality were assessed by Kaplan–Meier plots, and Cox proportional hazard ratios adjusted for potential confounding factors were calculated.

    Results: 

    The mean serum Se level of the study population (n=668) was 67.1 μg/l, corresponding to relatively low Se intake. After adjustment for male gender, smoking, ischemic heart disease, diabetes, chronic obstructive pulmonary disease and impaired heart function, persons with serum Se in the lowest quartile had 43% (95% confidence interval (CI): 1.02–2.00) and 56% (95% CI: 1.03–2.36) increased risk for all-cause and cardiovascular mortality, respectively. The result was not driven by inflammatory effects on Se concentration in serum.

    Conclusion: 

    The mean serum Se concentration in an elderly Swedish population was 67.1 μg/l, which is below the physiological saturation level for several selenoprotein enzymes. This result may suggest the value of modest Se supplementation in order to improve the health of the Swedish population.

  • 12.
    Alexandre, Campos
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Apraiz, Itzaso
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    da Fonseca, Rute R
    The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Shotgun analysis of the marine mussel Mytilus edulis hemolymph proteome and mapping the innate immunity elements.2015In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 15, no 23-24, 4021-4029 p.Article in journal (Refereed)
    Abstract [en]

    The marine mussel innate immunity provides protection to pathogen invasion and inflammation.In this regard, the mussel hemolymph takes a main role in the animal innate response.Despite the importance of this body fluid in determining the physiological condition of theanimal, little is known about the molecular mechanisms underlying the cellular and humoralresponses. In this work, we have applied aMS (nano-LC-MS/MS) strategy integrating genomicand transcriptomic data with the aim to: (i) identify the main protein functional groups thatcharacterize hemolymph and (ii) to map the elements of innate immunity in the marine musselMytilus edulis hemolymph proteome. After sample analysis and first protein identificationbased onMS/MS data comparison, proteins with unknown functions were annotated with blastusing public database (nrNCBI) information. Overall 595 hemolymph proteins were identifiedwith high confidence and annotated. These proteins encompass primary cellular metabolicprocesses: energy production and metabolism of biomolecules, as well as processes related tooxidative stress defence, xenobiotic detoxification, drug metabolism, and immune response.A group of proteins was identified with putative immune effector, receptor, and signalingfunctions in M. edulis. Data are available via ProteomeXchange with identifier PXD001951(http://proteomecentral.proteomexchange.org/dataset/PXD001951).

  • 13.
    Alkaissi, Hammoudi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ekstrand, Jimmy
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Jawad, Aksa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Nielsen, Jesper Bo
    University of Southern Denmark, Denmark.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice2016In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, no 7, 920-926 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A. SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.

    OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations.

    METHODS: A. SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.

    RESULTS: Renal Hg concentrations differed significantly between A. SW and B10. S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A. SW strain than in the B10. S strain.

    CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion.

  • 14.
    Alkhori, Liza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mechanisms of sensory neuron diversification during development and in the adult Drosophila: How to make a difference2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nervous system contains a vast number of neurons and displays a great diversity in cell types and classes. Even though this has been known for a long time, the exact mechanism of cell specification is still poorly understood. How does a cell know what type of neuron to which it should be specified? It is important to understand cellular specification, not only for our general understanding of biological processes, but also to allow us to develop treatments for patients with destructive diseases, such as Alzheimer’s, Parkinson, cancer or stroke. To address how neuronal specification and thereby diversification is evolved, we have chosen to study a complex but defined set of neurons, the Drosophila olfactory system. Olfactory sensory neurons (OSNs) detect an enormous variety of small volatile molecules with extremely high specificity and sensitivity. The adult Drosophila olfactory system contains 34 OSN classes each defined by their expression of a specific odorant receptor (OR). In both insects and vertebrates, each OSN expresses only one OR. In mouse there are approximately 1200 and in Drosophila 60 different OR genes. Despite the range of mechanisms known to determine cell identity and that the olfactory system is remarkably conserved across the phyla, it is still unclear how an OSN chooses to express a particular OR from a large genomic repertoire. In this thesis, the specification and diversification of the final steps establishing an OSN identity is addressed. We find seven transcription factors that are continuously required in different combinations for the expression of all ORs. The TFs can in different gene context both activate and repress OR expression, making the regulation more economical and indicating that repression is crucial for correct gene expression. We further identified a repressor complex that is able to segregate OR expression between OSN classes and propose a mechanism on how one single co-repressor can specify a large number of neuron classes.Exploring the OSN we found the developmental Hh signalling pathway is expressed in the postmitotic neuron. We show several fundamental similarities between the canonical Drosophila Hh pathway and the cilia mediated Hh transduction in component function. Further investigation revealed a function of cilia mediated Hh signalling in sensory neuron modulator. The results generated here will create a greater in vivo understanding of how postmitotic processes generate neurons with different fates and contribute to the maintaining of neuron function.

    List of papers
    1. Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
    Open this publication in new window or tab >>Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
    Show others...
    2012 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 10, no 3, e1001280- p.Article in journal (Refereed) Published
    Abstract [en]

    The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system.

    Place, publisher, year, edition, pages
    Public Library of Science, 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-76960 (URN)10.1371/journal.pbio.1001280 (DOI)000302239700004 ()
    Note
    Funding Agencies|Marie Curie Actions (European Commission)||Swedish Research Council||Swedish Strategic Research Foundation||Boehringer Ingelheim GmbH||DFG||Schram-Foundation||Available from: 2012-04-27 Created: 2012-04-27 Last updated: 2015-09-02
    2. The corepressor Atrophin specifies odorant receptor expression in Drosophila
    Open this publication in new window or tab >>The corepressor Atrophin specifies odorant receptor expression in Drosophila
    2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 3, 1355-1364 p.Article in journal (Refereed) Published
    Abstract [en]

    In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.

    Place, publisher, year, edition, pages
    Federation of American Societies for Experimental Biology, 2014
    Keyword
    HDAC, Notch, epigenetic, neuronal differentiation, olfactory system
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-104702 (URN)10.1096/fj.13-240325 (DOI)000335324800027 ()24334704 (PubMedID)
    Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2015-03-18Bibliographically approved
    3. Cilia-Mediated Hedgehog Signaling in Drosophila
    Open this publication in new window or tab >>Cilia-Mediated Hedgehog Signaling in Drosophila
    2014 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 7, no 3, 672-680 p.Article in journal (Refereed) Published
    Abstract [en]

    Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-107115 (URN)10.1016/j.celrep.2014.03.052 (DOI)000335560900009 ()
    Note

    At the time for thesis presentation publication was in status: Manuscript

    Available from: 2014-06-05 Created: 2014-06-05 Last updated: 2016-12-28Bibliographically approved
    4. Hh signalling regulates odorant receptor cilia localization in Drosophila
    Open this publication in new window or tab >>Hh signalling regulates odorant receptor cilia localization in Drosophila
    Show others...
    2014 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development. Here, we show that in adult OSNs the Hh pathway regulate 􀁒dorant receptor transport to cilia and put forward a novel non-developmental function of the pathway as a neuromodulator. We demonstrate that the level of Hh signal modulate the OSNs response to odors. We show that knock down of Hh and Smoothened (Smo), a transmembrane protein that transduce the signal, are required for receptor transport. We further show that the coreceptor, Orco, has an Hh independent transport path and that knock down of Smo segregate OR and Orco to different vesicular compartments. Last, we show that the odor response to the second receptor type in Drosophila olfaction, the ionotropic receptors (IRs), also require Hh signalling. Thus, Hh signalling is a general regulator of the odorant response that fulfils the criteria of being a potential player in Drosophila odorant adaptation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-104705 (URN)
    Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2014-02-24Bibliographically approved
  • 15.
    Alkhori, Liza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Sanchez, Gonzalo M.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian W.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kuzhandaivel, Anujaianthi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, The Institute of Technology.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hh signalling regulates odorant receptor cilia localization in Drosophila2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development. Here, we show that in adult OSNs the Hh pathway regulate 􀁒dorant receptor transport to cilia and put forward a novel non-developmental function of the pathway as a neuromodulator. We demonstrate that the level of Hh signal modulate the OSNs response to odors. We show that knock down of Hh and Smoothened (Smo), a transmembrane protein that transduce the signal, are required for receptor transport. We further show that the coreceptor, Orco, has an Hh independent transport path and that knock down of Smo segregate OR and Orco to different vesicular compartments. Last, we show that the odor response to the second receptor type in Drosophila olfaction, the ionotropic receptors (IRs), also require Hh signalling. Thus, Hh signalling is a general regulator of the odorant response that fulfils the criteria of being a potential player in Drosophila odorant adaptation.

  • 16.
    Alkhori, Liza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    The corepressor Atrophin specifies odorant receptor expression in Drosophila2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 3, 1355-1364 p.Article in journal (Refereed)
    Abstract [en]

    In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.

  • 17.
    Almeida, A. M.
    et al.
    CVZ Centre Vet and Zootecnia, Portugal; CIISA Centre Interdisciplinar Invest Sanidade Anim, Portugal; UNL, Portugal; IBET Institute Biol Expt and Tecnol, Portugal.
    Bassols, A.
    University of Autonoma Barcelona, Spain.
    Bendixen, E.
    Aarhus University, Denmark.
    Bhide, M.
    University of Vet Medical and Pharm, Slovakia.
    Ceciliani, F.
    University of Milan, Italy.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. University of Basque Country, Spain.
    Eckersall, P. D.
    University of Glasgow, Scotland.
    Hollung, K.
    Nofima AS, Norway.
    Lisacek, F.
    Swiss Institute Bioinformat, Switzerland.
    Mazzucchelli, G.
    University of Liege, Belgium.
    McLaughlin, M.
    University of Glasgow, Scotland.
    Miller, I.
    University of Vet Med, Austria.
    Nally, J. E.
    ARS, IA 50010 USA.
    Plowman, J.
    AgResearch, New Zealand.
    Renaut, J.
    Centre Rech Public Gabriel Lippmann, Luxembourg.
    Rodrigues, P.
    University of Algarve, Portugal.
    Roncada, P.
    University of Milan, Italy.
    Staric, J.
    University of Ljubljana, Slovenia.
    Turk, R.
    University of Zagreb, Croatia.
    Animal board invited review: advances in proteomics for animal and food sciences2015In: Animal, ISSN 1751-7311, E-ISSN 1751-732X, Vol. 9, no 1Article, review/survey (Refereed)
    Abstract [en]

    Animal production and health (APH) is an important sector in the world economy, representing a large proportion of the budget of all member states in the European Union and in other continents. APH is a highly competitive sector with a strong emphasis on innovation and, albeit with country to country variations, on scientific research. Proteomics (the study of all proteins present in a given tissue or fluid - i.e. the proteome) has an enormous potential when applied to APH. Nevertheless, for a variety of reasons and in contrast to disciplines such as plant sciences or human biomedicine, such potential is only now being tapped. To counter such limited usage, 6 years ago we created a consortium dedicated to the applications of Proteomics to APH, specifically in the form of a Cooperation in Science and Technology (COST) Action, termed FA1002 - Proteomics in Farm Animals: www.cost-faproteomics.org. In 4 years, the consortium quickly enlarged to a total of 31 countries in Europe, as well as Israel, Argentina, Australia and New Zealand. This article has a triple purpose. First, we aim to provide clear examples on the applications and benefits of the use of proteomics in all aspects related to APH. Second, we provide insights and possibilities on the new trends and objectives for APH proteomics applications and technologies for the years to come. Finally, we provide an overview and balance of the major activities and accomplishments of the COST Action on Farm Animal Proteomics. These include activities such as the organization of seminars, workshops and major scientific conferences, organization of summer schools, financing Short-Term Scientific Missions (STSMs) and the generation of scientific literature. Overall, the Action has attained all of the proposed objectives and has made considerable difference by putting proteomics on the global map for animal and veterinary researchers in general and by contributing significantly to reduce the East-West and North-South gaps existing in the European farm animal research. Future activities of significance in the field of scientific research, involving members of the action, as well as others, will likely be established in the future.

  • 18.
    Amandusson, Asa
    et al.
    Uppsala University, Sweden .
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Estrogenic influences in pain processing2013In: Frontiers in neuroendocrinology (Print), ISSN 0091-3022, E-ISSN 1095-6808, Vol. 34, no 4, 329-349 p.Article, review/survey (Refereed)
    Abstract [en]

    Gonadal hormones not only play a pivotal role in reproductive behavior and sexual differentiation, they also contribute to thermoregulation, feeding, memory, neuronal survival, and the perception of somatosensory stimuli. Numerous studies on both animals and human subjects have also demonstrated the potential effects of gonadal hormones, such as estrogens, on pain transmission. These effects most likely involve multiple neuroanatomical circuits as well as diverse neurochemical systems and they therefore need to be evaluated specifically to determine the localization and intrinsic characteristics of the neurons engaged. The aim of this review is to summarize the morphological as well as biochemical evidence in support for gonadal hormone modulation of nociceptive processing, with particular focus on estrogens and spinal cord mechanisms.

  • 19.
    Anders Eriksson, Mats
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden; Gothenburg University, Sweden.
    Lieden, Agne
    Karolinska Institute, Sweden; Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Westerlund, Joakim
    Stockholm University, Sweden.
    Bremer, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Division of Clinical Genetics, University Hospital, Link.
    Wincent, Josephine
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Sahlin, Ellika
    Karolinska Institute, Sweden; Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Gillberg, Christopher
    Gothenburg University, Sweden.
    Fernell, Elisabeth
    Gothenburg University, Sweden.
    Anderlid, Britt-Marie
    Karolinska Institute, Sweden; Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Rare copy number variants are common in young children with autism spectrum disorder2015In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no 6, 610-618 p.Article in journal (Refereed)
    Abstract [en]

    AimSeveral studies have suggested that rare copy number variants (CNVs) are an important genetic contributor to autism spectrum disorders. The aims of the study were to use chromosomal microarray to investigate the presence of rare copy number variants in a population-based cohort of well-characterised young children with autism spectrum disorders and to relate the genetic results to neurodevelopmental profiles and medical conditions. MethodsWe performed chromosomal microarray on samples from 162 children who had been referred to the Stockholm Autism Centre for Young Children in Sweden after being diagnosed with autism spectrum disorder between 20 and 54months of age. ResultsPathogenic aberrations were detected in 8.6% of the children and variants of uncertain significance were present in another 8.6%. CNVs were more frequent in children with congenital malformations or dysmorphic features as well as in the subgroup with intellectual disability. ConclusionOur results support the use of chromosomal microarray methods for the first tier genetic analysis of autism spectrum disorder. However, it is likely in the near future that chromosomal microarray methods will probably be replaced by whole-exome and whole-genome sequencing technologies in clinical genetic testing.

  • 20.
    Andersson, Per
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Jan-Erik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Internal Medicine, County Council of Jönköping, Jönköping.
    Landberg, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Festin, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Norrköping, Sweden.
    Consequences of high-sensitivity troponin T testing applied in a primary care population with chest pain compared with a commercially available point-of-care troponin T analysis: an observational prospective study2015In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 8, no 1, 1-9 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:There is a demand for a highly sensitive and specific point-of care test to detect acute myocardial infarction (AMI). It is unclear if a high-sensitivity troponin assay will have enough discriminative power to become a decision support in primary care. The aim of this study was to evaluate a high-sensitivity troponin T assay performed in three primary health care centres in southeast Sweden and to compare the outcome with a point-of-care troponin T test.METHODS:This study included 115 patients who consulted their general practitioner for chest pain, dyspnoea on exertion, unexplained weakness and/or fatigue in the last 7days. Troponin T was analysed by a point-of-care test and a high-sensitivity method together with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and creatinine. All patients were checked for AMI or unstable angina (UA) within 30days of study enrolment. Univariate and multivariate logistic regression was carried out to examine possible connections between troponin T[greater than or equal to]15ng/L, clinical variables and laboratory findings at baseline. In addition, 21 patients with troponin T[greater than or equal to]15ng/L and no signs of AMI or UA were followed up for 2-3years.RESULTS:Three patients were diagnosed with AMI and three with UA. At the [greater than or equal to]15ng/L cut-off, the troponin T method had 100% sensitivity, 75% specificity for AMI and a positive predictive value of 10%. The troponin T point-of-care test missed one case of AMI and the detection limit was 50ng/L. Troponin T[greater than or equal to]15ng/L was correlated to age [greater than or equal to]65years (odds ratio (OR), 10.9 95% CI 2.28-51.8) and NT-proBNP in accordance with heart failure (OR 8.62 95% CI 1.61-46.1). Fourteen of the 21 patients, without signs of AMI or UA at baseline, still had increased troponin T at follow-up after 2-3years.CONCLUSIONS:A high-sensitivity troponin T assay could become useful in primary care as a point-of-care test for patients <65years. For patients older than 65-70years, a higher decision limit than [greater than or equal to]15ng/L should be considered and used in conjunction with clinical parameters and possibly with NT-proBNP.

  • 21.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Wäster, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lysosomal exocytosis and caspase-8-mediated apoptosis in UVA-irradiated keratinocytes2013In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 126, no 24, 5578-5584 p.Article in journal (Refereed)
    Abstract [en]

    Ultraviolet (UV) irradiation is a major environmental carcinogen involved in the development of skin cancer. To elucidate the initial signaling during UV-induced damage in human keratinocytes, we investigated lysosomal exocytosis and apoptosis induction. UVA, but not UVB, induced plasma membrane damage, which was repaired by Ca2+-dependent lysosomal exocytosis. The lysosomal exocytosis resulted in extracellular release of cathepsin D and acid sphingomyelinase (aSMase). Two hours after UVA irradiation, we detected activation of caspase-8, which was reduced by addition of anti-aSMAse. Furthermore, caspase-8 activation and apoptosis was reduced by prevention of endocytosis and by the use of cathepsin inhibitors. We conclude that lysosomal exocytosis is part of the keratinocyte response to UVA and is followed by cathepsin-dependent activation of caspase-8. The findings have implications for the understanding of UV-induced skin damage and emphasize that UVA and UVB initiate apoptosis through different signaling pathways in keratinocytes.

  • 22.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Wäster, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    The lysosome: from waste bag to potential therapeutic target2013In: Journal of Molecular Cell Biology, ISSN 1674-2788, E-ISSN 1759-4685, Vol. 5, no 4, 214-226 p.Article, review/survey (Refereed)
    Abstract [en]

    Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior. They are central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. In contrast to the rather simplified view of lysosomes as waste bags, nowadays lysosomes are recognized as advanced organelles involved in many cellular processes and are considered crucial regulators of cell homeostasis. The function of lysosomes is critically dependent on soluble lysosomal hydrolases (e.g. cathepsins) as well as lysosomal membrane proteins (e.g. lysosome-associated membrane proteins). This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death. Regulation of lysosomal biogenesis and function via the transcription factor EB (TFEB) will also be discussed. In addition, lysosomal contribution to diseases, including lysosomal storage disorders, neurodegenerative disorders, cancer, and cardiovascular diseases, is presented.

  • 23.
    Armstrong, Andrea
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mattsson, Niklas
    Sahlgrens University Hospital, Sweden University of Calif San Francisco, CA 94143 USA .
    Appelqvist, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Bob
    Sahlgrens University Hospital, Sweden .
    Svensson, Samuel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. AlzeCure Fdn.
    Blennow, Kaj
    Sahlgrens University Hospital, Sweden .
    Zetterberg, Henrik
    Sahlgrens University Hospital, Sweden UCL Institute Neurol, England .
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease2014In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, no 1, 150-160 p.Article in journal (Refereed)
    Abstract [en]

    The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

  • 24.
    Asif, Muhammad
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology. COMSATS institute of Information Technology, Lahore, Pakistan.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Willander, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Electrochemical Biosensors Based on ZnO Nanostructures to Measure Intracellular Metal Ions and Glucose2011In: Journal of Analytical & Bioanalytical Techniques, ISSN 2155-9872, Vol. S7, no 003, 1-9 p.Article in journal (Refereed)
    Abstract [en]

    Zinc oxide (ZnO) nanostructures have attracted much interest for intracellular electrochemical measurements because of its large surface area, and its biocompatible properties. To design intracellular biosensors for metal ions and glucose, we grew ZnO nanorods on the tip of borosilicate glass capillaries (0.7μm in diameter) and characterized the nano-scale structure with field-emission scanning electron microscopy and high-resolution transmission electron microscopy. The ZnO nanorods were functionalized accordingly for intracellular free metal ions or glucose measurements. Selectivity was achieved by using a metal-ion selective plastic membrane or glucose oxidase enzyme for glucose measurements. These functionalized ZnO nanorods showed high sensitivity and good biocompatibility for intracellular environments. Human adipocytes and frog oocytes were used for determinations of intracellular free metal ions and glucose concentrations. In this review, we discuss the simple and direct approach for intracellular measurements using ZnO nanostructure-based potentiometric biosensors for clinical and non-clinical applications. The performance of ZnO nanostructure-based intracellular sensor can be improved through engineering of morphology, effective surface area, functionality, and adsorption/desorption capability. This study paves the way to find applications in biomedicine by using this simple and miniaturized biosensing device

  • 25.
    Asklund, Thomas
    et al.
    Department of Radiation Sciences and Oncology, Umeå University, Sweden .
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Bergqvist, Michael
    Department of Radiology, Oncology and Radiation Sciences, Uppsala University Hospital, Sweden; Department of Radiation Sciences, Umeå University, Sweden .
    Björ, Ove
    Department of Radiation Sciences and Oncology, Umeå University, Sweden .
    Henriksson, Roger
    Department of Radiation Sciences and Oncology, Umeå University, Sweden: Regional Cancer Centre Stockholm, Gotland, Sweden .
    Brain tumors in Sweden: Data from a population-based registry 1999-2012.2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226XArticle in journal (Refereed)
    Abstract [en]

    Background. The Swedish brain tumor registry has, since it was launched in 1999, provided significant amounts of data on histopathological diagnoses and on important aspects of surgical and medical management of these patients. The purpose is mainly quality control, but also as a resource for research. Methods. Three Swedish healthcare regions, constituting 40% of the Swedish population, have had an almost complete registration. The following parameters are registered: diagnosis according to SNOMED/WHO classification, symptoms, performance status, pre- and postoperative radiology, tumor size and localization, extent of surgery and occurrence of postoperative complications, postoperative treatment, such as radiotherapy and/or chemotherapy, other treatments, complications and toxicity, occurrence of reoperation/s, participation in clinical trials, multidisciplinary conferences and availability of a contact nurse. Results. Surgical radicality has been essentially constant, whereas the use of early (within 72 hours) postoperative CT and MRI has increased, especially for high-grade glioma, which is a reflection of quality of surgery. Survival of patients with high-grade glioma has increased, especially in the age group 60-69. Patients aged 18-39 years had a five-year survival of 40%. Waiting times for the pathological report has been slightly prolonged. Geographical differences do exist for some of the variables. Conclusion. Population-based registration is valuable for assessment of clinical management, which could have impact on patient care. As a result of short survival and/or the propensity to affect cognitive functions this patient group has considerable difficulties to make their voices heard in society. We therefore believe that a report like the present one can contribute to the spread of knowledge and increase the awareness for this patient group among caregivers and policy makers.

  • 26.
    Atkins, Alison Lynn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Helms, M L
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    O'Toole, L A
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    Belknap, J K
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing.2001In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 157, no 1, 96-104 p.Article in journal (Refereed)
    Abstract [en]

    RATIONALE: At high doses, methamphetamine produces repetitive stereotypic behaviors, and the degree to which this occurs is heritable.

    OBJECTIVES: Mice of a B6D2F2 genetic background were selectively bred for four generations for high (HMA) and low (LMA) numbers of stereotyped chewing episodes measured for 1 min at 33 min post-injection following 10 mg/kg methamphetamine (changed to 7 mg/kg for the high line and 15 mg/kg for the low line in the third selected generation to avoid ceiling and floor effects, respectively). We sought to determine whether stereotypic behaviors other than number of repetitive chewing episodes were altered by the selective breeding process.

    METHODS: HMA and LMA mice of the third and fourth selected generations were tested for chewing stereotypy, for a number of other stereotypic behaviors previously observed in rodents, and for several other non-stereotypic responses to methamphetamine. Testing in the third selected generation was conducted by observing behaviors on videotape following 7 mg/kg methamphetamine. In the fourth selected generation, mice were also tested in automated activity monitors following 10 mg/kg methamphetamine and in climbing chimneys following 16 mg/kg methamphetamine. Dose-response curves with doses of 1, 2, 3.5, 7, 10, and 15 mg/kg methamphetamine were constructed for the most commonly observed behaviors.

    RESULTS: LMA mice, which exhibited low stereotyped chewing, exhibited high stereotyped circling and climbing, and the reverse was true for these behaviors for HMA mice. For most of the other behaviors measured, there were drug effects but no differences between selected lines.

    CONCLUSIONS: These results suggest that these three stereotyped behaviors, chewing, circling, and climbing, at least partly share the same mechanisms, and therefore are influenced by at least some of the same genes, since animals selectively bred for low methamphetamine-induced stereotyped chewing exhibited high amounts of circling and climbing when given methamphetamine. This also suggests that the other stereotypic behaviors that we measured do not occur by the same genetically determined mechanisms as stereotypic chewing.

  • 27.
    Atkins, Alison Lynn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Mashhoon, Yasmin
    Department of Psychology, Boston University, Boston, MA 02215, United States.
    Kantak, Kathleen M
    Department of Psychology, Boston University, Boston, MA 02215, United States.
    Hippocampal regulation of contextual cue-induced reinstatement of cocaine-seeking behavior.2008In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 90, no 3, 481-491 p.Article in journal (Refereed)
    Abstract [en]

    Associations between cocaine and cues facilitate development and maintenance of addiction. We hypothesized that the ventral hippocampus is important for acquisition of these associations. Rats were trained to self-administer cocaine, with or without pre-exposure to distinct sets of cocaine- and saline-paired contextual cues. Next, rats were conditioned for 3 days with the distinct sets of contextual cues paired with cocaine and saline along with distinct discrete cues. Vehicle or lidocaine was infused into the ventral hippocampus prior to conditioning sessions. Following extinction, reinstatement of cocaine-seeking behavior was examined following exposure to contextual cues, discrete cues, or their combination. Inactivation of the ventral hippocampus during conditioning blocked acquisition of the association between cocaine and cocaine-paired contextual cues in that only lidocaine-treated rats with short-term cue exposure failed to reinstate responding in the presence of cocaine-paired contextual cues. Lidocaine also prevented rats in both cue exposure groups from discriminating between cocaine- and saline-paired contextual cues during reinstatement tests. Reinstatement induced by cocaine-paired discrete cues or by contextual and discrete cues together was not impaired for either cue exposure condition. The hippocampus is important for acquisition of the association between cocaine and context and in maintaining discrimination between cocaine-relevant and -irrelevant contextual cues.

  • 28.
    Atkins, Alison Lynn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rustay, N R
    Portland Alcohol Research Center, United States, Department of Veterans Affairs, Portland,United States .
    Crabbe, J C
    Portland Alcohol Research Center, United States, Department of Veterans Affairs, Portland,United States .
    Anxiety and sensitivity to ethanol and pentobarbital in alcohol withdrawal seizure-prone and withdrawal seizure-resistant mice.2000In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 24, no 12, 1743-1749 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice were selectively bred for high and low handling-induced convulsions, respectively, after chronic ethanol treatment. Withdrawal severity is one factor that may contribute to the development of alcoholism and/or substance abuse, and anxiety is another. We sought to explore whether these factors are genetically related.

    METHODS: WSP and WSR mice of two replicate pairs of selected lines were tested for anxiety-related behaviors on the canopy stretched-attend-posture apparatus 20 min after intraperitoneal injection of ethanol (2 g/kg, 20% v/v), pentobarbital (20 mg/kg), or an equivalent volume of saline. Dependent measures of anxiety included number of stretched attend postures (SAP) and time spent in the exposed area of the apparatus. Number of line crossings, which measures overall activity, was also scored.

    RESULTS: WSP mice given saline exhibited more SAP than WSR mice given saline, which indicated greater baseline anxiety. Ethanol and pentobarbital both reduced SAP and increased time spent in the exposed area of the apparatus, which indicated that both drugs exerted an anxiolytic effect. Despite baseline differences in SAP between selected lines, both anxiolytic drugs reduced SAP to similar levels in WSP and WSR mice.

    CONCLUSIONS: These results support the hypothesis that WSP mice are more sensitive than WSR mice to the anxiety-reducing effects of ethanol and pentobarbital. Some genes that influence this difference are likely to be the same as those that influence ethanol withdrawal severity. Thus, higher basal anxiety and greater genetic sensitivity to anxiolytic drug effects may relate to a greater genetic predisposition to the development of severe alcohol withdrawal signs.

  • 29.
    Aziz, Abdul Maruf Asif
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brothers, Shaun
    University of Miami Health System, University of Miami, Miami, USA.
    Sartor, Gregory
    University of Miami Health System, University of Miami, Miami, USA.
    Holm, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Wahlestedt, Claes
    University of Miami Health System, University of Miami, Miami, USA.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 19-20, 3553-3563 p.Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

    OBJECTIVES: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

    RESULTS: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

    CONCLUSION: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

  • 30.
    Azzouzi, Sawsen
    et al.
    University of Sousse, Tunisia.
    Patra, Hirak Kumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ben Ali, Mounir
    University of Sousse, Tunisia.
    Nooredeen Abbas, Mohammed
    National Research Centre, Egypt.
    Dridi, Cherif
    Centre Research Microelect and Nanotechnol CRMN Sousse, Tunisia.
    Errachid, Abdelhamid
    University of Lyon 1, France.
    Turner, Anthony
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Citrate-selective electrochemical mu-sensor for early stage detection of prostate cancer2016In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 228, 335-346 p.Article in journal (Refereed)
    Abstract [en]

    The extremely specialised anatomical function of citrate inside the prostate, make it one of the preferred biomarkers for early stage detection of prostate cancer. However, current detection methods are seriously limited due to the very low citrate concentrations that need to be measured in order to follow disease progression. In the present work, we report a novel citrate-selective-sensor based on iron (III) phthalocyanine chloride-C-monoamido-Poly-n-Butyl Acrylate (Fe(III)MAPcC1 P n BA) modified gold -electrodes for the electrochemical determination and estimation of the pathophysiological range of citrate. The newly synthesised ionophore has been structurally characterised using Fourier transform infrared (FTIR) and UV-vis spectroscopy. Contact angle measurements and atomic force microscopy (AFM) have been used to investigate the adhesion and morphological properties of the membrane. The developed citrate-selective-electrodes had a Nernstian sensitivity of-19.34 +/- 0.83 mV/decade with a detection limit of about 9 x 10-6M and a linear range from 4 x 10(-5)M to 10(-1) M, which covered the pathologically important clinical range. Electrochemical impedance spectroscopy (EIS) showed very high sensitivity with a lower Limit of detection 1.7 x 10(-9) M and linear detection range (10(-8)-10(-1) M), which is very important not only for the early-stage diagnosis and screening procedures, but also in mapping the stage of the cancer too. (C) 2016 Elsevier B.V. All rights reserved.

  • 31.
    Bagger-Sjoback, Dan
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Stromback, Karin
    Academic Hospital, Sweden.
    Hakizimana, Pierre
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    Plue, Jan
    Stockholm University, Sweden.
    Larsson, Christina
    Karolinska University Hospital, Sweden.
    Hultcrantz, Malou
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Papatziamos, Georgios
    Karolinska University Hospital, Sweden.
    Smeds, Henrik
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Danckwardt-Lilliestrom, Niklas
    Academic Hospital, Sweden.
    Hellstrom, Sten
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Johansson, Ann
    Karolinska University Hospital, Sweden.
    Tideholm, Bo
    Karolinska University Hospital, Sweden.
    Fridberger, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery2015In: PLoS ONE, ISSN 1932-6203, Vol. 10, no 3, e0115657- p.Article in journal (Refereed)
    Abstract [en]

    Background Otosclerosis is a disorder that impairs middle ear function, leading to conductive hearing loss. Surgical treatment results in large improvement of hearing at low sound frequencies, but high-frequency hearing often suffers. A likely reason for this is that inner ear sensory cells are damaged by surgical trauma and loud sounds generated during the operation. Animal studies have shown that antioxidants such as N-Acetylcysteine can protect the inner ear from noise, surgical trauma, and some ototoxic substances, but it is not known if this works in humans. This trial was performed to determine whether antioxidants improve surgical results at high frequencies. Methods We performed a randomized, double-blind and placebo-controlled parallel group clinical trial at three Swedish university clinics. Using block-stratified randomization, 156 adult patients undergoing stapedotomy were assigned to intravenous N-Acetylcysteine (150 mg/kg body weight) or matching placebo (1:1 ratio), starting one hour before surgery. The primary outcome was the hearing threshold at 6 and 8 kHz; secondary outcomes included the severity of tinnitus and vertigo. Findings One year after surgery, high-frequency hearing had improved 2.7 +/- 3.8 dB in the placebo group (67 patients analysed) and 2.4 +/- 3.7 dB in the treated group (72 patients; means +/- 95% confidence interval, p = 0.54; linear mixed model). Surgery improved tinnitus, but there was no significant intergroup difference. Post-operative balance disturbance was common but improved during the first year, without significant difference between groups. Four patients receiving N-Acetylcysteine experienced mild side effects such as nausea and vomiting. Conclusions N-Acetylcysteine has no effect on hearing thresholds, tinnitus, or balance disturbance after stapedotomy.

  • 32.
    Bagger-Sjoback, Dan
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stromback, Karin
    Uppsala University, Sweden.
    Hultcrantz, Malou
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Papatziamos, Georgios
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Smeds, Henrik
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Danckwardt-Lilliestrom, Niklas
    Uppsala University, Sweden.
    Tideholm, Bo
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Johansson, Ann
    Karolinska University Hospital, Sweden.
    Hellstrom, Sten
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Hakizimana, Pierre
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fridberger, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    High-frequency hearing, tinnitus, and patient satisfaction with stapedotomy: A randomized prospective study2015In: Scientific Reports, ISSN 2045-2322, Vol. 5, no 13341Article in journal (Refereed)
    Abstract [en]

    Otosclerosis is a common disorder that leads to conductive hearing loss. Most patients with otosclerosis also have tinnitus, and surgical treatment is known to improve hearing as well as tinnitus. Some patients however experience worsening of tinnitus after the operation, but there are no known factors that allow surgeons to predict who will be at risk. In this prospective observational study on 133 patients undergoing stapedotomy, we show that postoperative air conduction thresholds at very high stimulus frequencies predict improvement of tinnitus, as assessed with proportional odds logistic regression models. Young patients were significantly more likely to experience reduction of tinnitus and patients whose tinnitus became better were also more satisfied with the outcome of the operation. These findings have practical importance for patients and their surgeons. Young patients can be advised that surgery is likely to be beneficial for their tinnitus, but a less positive message should be conveyed to older patients.

  • 33.
    Bagheri, Maryam
    et al.
    Ilam University of Medical Science, Iran .
    Rezakhani, Arjang
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Turkina, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Roghani, Mehrdad
    Shahed University, Iran .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Amyloid Beta1-40-Induced Astrogliosis and the Effect of Genistein Treatment in Rat: A Three-Dimensional Confocal Morphometric and Proteomic Study2013In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed)
    Abstract [en]

    Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy and proliferation of astrocytes. Here, we performed 3D confocal microscopy to evaluate the morphological response of reactive astrocytes positive for glial fibrillary acidic protein (GFAP) in rats, to the presence of Aβ1–40 in the rat brain before and after treatment with genistein. In 50 astrocytes per animal, we measured the volume and surface area for the nucleus, cell body, the entire cell, the tissue covered by single astrocytes and quantified the number and length of branches, the density of the astrocytes and the intensity of GFAP immunoreactivity. Injecting Aβ1–40 into the brain of rats caused astrogliosis indicated by increased values for all measured parameters. Mass spectrometric analysis of hippocampal tissue in Aβ1–40-injected brain showed decreased amounts of tubulins, enolases and myelin basic protein, and increased amounts of dihydropyrimidinase-related protein 2. In Aβ1–40-injected rats pretreated with genistein, GFAP intensity was decreased to the sham-operated group level, and Aβ1–40-induced astrogliosis was significantly ameliorated.

  • 34.
    Bagheri, Maryam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rezakhani, Arjang
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Roghani, Mehrdad
    Neurophysiology Research Center, Shahed University, Iran.
    Joghataei, Mohammad T.
    Iran University of Medical Science, Iran.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Protocol for Three-dimensional Confocal Morphometric Analysis of Astrocytes2015In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 106, e53113- p.Article in journal (Refereed)
    Abstract [en]

    As glial cells in the brain, astrocytes have diverse functional roles in the central nervous system. In the presence of harmful stimuli, astrocytes modify their functional and structural properties, a condition called reactive astrogliosis. Here, a protocol for assessment of the morphological properties of astrocytes is presented. This protocol includes quantification of 12 different parameters i.e. the surface area and volume of the tissue covered by an astrocyte (astrocyte territory), the entire astrocyte including branches, cell body, and nucleus, as well as total length and number of branches, the intensity of fluorescence immunoreactivity of antibodies used for astrocyte detection, and astrocyte density (number/1,000 mu m(2)). For this purpose three-dimensional (3D) confocal microscopic images were created, and 3D image analysis software such as Volocity 6.3 was used for measurements. Rat brain tissue exposed to amyloid beta(1-40) (A beta(1-40)) with or without a therapeutic intervention was used to present the method. This protocol can also be used for 3D morphometric analysis of other cells from either in vivo or in vitro conditions.

  • 35.
    Bauer, Eva
    et al.
    Technical University of Munich, Germany.
    Schmutzer, Thomas
    Leibniz Institute Plant Genet and Crop Plant Research IPK Gat, Germany.
    Barilar, Ivan
    University of Hohenheim, Germany.
    Mascher, Martin
    Leibniz Institute Plant Genet and Crop Plant Research IPK Gat, Germany.
    Gundlach, Heidrun
    Helmholtz Zentrum Munchen, Germany.
    Martis, Mihaela-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Helmholtz Zentrum Munchen, Germany.
    Twardziok, Sven O.
    Helmholtz Zentrum Munchen, Germany.
    Hackauf, Bernd
    Julius Kuhn Institute, Germany.
    Gordillo, Andres
    KWS LOCHOW GMBH, Germany.
    Wilde, Peer
    KWS LOCHOW GMBH, Germany.
    Schmidt, Malthe
    KWS LOCHOW GMBH, Germany.
    Korzun, Viktor
    KWS LOCHOW GMBH, Germany.
    Mayer, Klaus F. X.
    Helmholtz Zentrum Munchen, Germany.
    Schmid, Karl
    University of Hohenheim, Germany.
    Schoen, Chris-Carolin
    Technical University of Munich, Germany.
    Scholz, Uwe
    Leibniz Institute Plant Genet and Crop Plant Research IPK Gat, Germany.
    Towards a whole-genome sequence for rye (Secale cereale L.)2017In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 89, no 5, 853-869 p.Article in journal (Refereed)
    Abstract [en]

    We report on a whole-genome draft sequence of rye (Secale cereale L.). Rye is a diploid Triticeae species closely related to wheat and barley, and an important crop for food and feed in Central and Eastern Europe. Through whole-genome shotgun sequencing of the 7.9-Gbp genome of the winter rye inbred line Lo7 we obtained a de novo assembly represented by 1.29 million scaffolds covering a total length of 2.8 Gbp. Our reference sequence represents nearly the entire low-copy portion of the rye genome. This genome assembly was used to predict 27 784 rye gene models based on homology to sequenced grass genomes. Through resequencing of 10 rye inbred lines and one accession of the wild relative S. vavilovii, we discovered more than 90 million single nucleotide variants and short insertions/deletions in the rye genome. From these variants, we developed the high-density Rye600k genotyping array with 600 843 markers, which enabled anchoring the sequence contigs along a high-density genetic map and establishing a synteny-based virtual gene order. Genotyping data were used to characterize the diversity of rye breeding pools and genetic resources, and to obtain a genome-wide map of selection signals differentiating the divergent gene pools. This rye whole-genome sequence closes a gap in Triticeae genome research, and will be highly valuable for comparative genomics, functional studies and genome-based breeding in rye.

  • 36.
    Bausch, Birke
    et al.
    Albert Ludwigs University, Germany.
    Schiavi, Francesca
    Ist Ricovero and Cura Carattere Science, Italy.
    Ni, Ying
    Cleveland Clin, OH 44106 USA.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Patocs, Attila
    Semmelweis University, Hungary; Semmelweis University, Hungary.
    Ngeow, Joanne
    National Cancer Centre Singapore, Singapore; Nanyang Technology University, Singapore.
    Wellner, Ulrich
    University of Lubeck, Germany.
    Malinoc, Angelica
    Albert Ludwigs University, Germany.
    Taschin, Elisa
    Ist Ricovero and Cura Carattere Science, Italy.
    Barbon, Giovanni
    Ist Ricovero and Cura Carattere Science, Italy.
    Lanza, Virginia
    Ist Ricovero and Cura Carattere Science, Italy.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stenman, Adam
    Karolinska Institute, Sweden.
    Larsson, Catharina
    Karolinska Institute, Sweden.
    Svahn, Fredrika
    Karolinska Institute, Sweden.
    Chen, Jin-Lian
    Cleveland Clin, OH 44106 USA.
    Marquard, Jessica
    Cleveland Clin, OH 44106 USA.
    Fraenkel, Merav
    Hadassah Hebrew University, Israel.
    Walter, Martin A.
    University Hospital, Switzerland.
    Peczkowska, Mariola
    Institute Cardiol, Poland.
    Prejbisz, Aleksander
    Institute Cardiol, Poland.
    Jarzab, Barbara
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Hasse-Lazar, Kornelia
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Petersenn, Stephan
    Centre Endocrine Tumors, Germany.
    Moeller, Lars C.
    University of Duisburg Essen, Germany.
    Meyer, Almuth
    HELIOS Klin, Germany.
    Reisch, Nicole
    Ludwigs Maximilians University of Munich, Germany.
    Trupka, Arnold
    City Hospital, Germany.
    Brase, Christoph
    University of Erlangen Nurnberg, Germany.
    Galiano, Matthias
    University Hospital Erlangen, Germany.
    Preuss, Simon F.
    University of Cologne, Germany.
    Kwok, Pingling
    University of Regensburg, Germany.
    Lendvai, Nikoletta
    Semmelweis University, Hungary.
    Berisha, Gani
    Albert Ludwigs University, Germany.
    Makay, Ozer
    Ege University, Turkey.
    Boedeker, Carsten C.
    HELIOS Hanseklinikum Stralsund, Germany.
    Weryha, Georges
    University of Nancy, France.
    Racz, Karoly
    Semmelweis University, Hungary.
    Januszewicz, Andrzej
    Institute Cardiol, Poland.
    Walz, Martin K.
    Kliniken Essen Mitte, Germany; Kliniken Essen Mitte, Germany.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Opocher, Giuseppe
    Ist Ricovero and Cura Carattere Science, Italy.
    Eng, Charis
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs University, Germany.
    Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention2017In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 3, no 9, 1204-1212 p.Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P amp;lt; .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

  • 37.
    Bayat, N.
    et al.
    Stockholm University, Sweden.
    Lopes, Viviana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Sanchez-Dominguez, M.
    Centre Invest Mat Avanzados CIMAV SC, Mexico.
    Lakshmanan, R.
    Royal Institute Technology KTH, Sweden.
    Rajarao, G. K.
    Royal Institute Technology KTH, Sweden.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Basque Country Medical Sch, Spain.
    Assessment of functionalized iron oxide nanoparticles in vitro: introduction to integrated nanoimpact index2015In: ENVIRONMENTAL SCIENCE-NANO, ISSN 2051-8153, Vol. 2, no 4, 380-394 p.Article in journal (Refereed)
    Abstract [en]

    Functionalization of super paramagnetic iron oxide NPs (SPIONs) with different coatings renders them with unique physicochemical properties that allow them to be used in a broad range of applications such as drug targeting and water purification. However, it is required to fill the gap between the promises of any new functionalized SPIONs and the effects of these coatings on the NPs safety. Nanotoxicology is offering diverse strategies to assess the effect of exposure to SPIONs in a case-by-case manner but an integrated nanoimpact scale has not been developed yet. We have implemented the classical integrated biological response (IBR) into an integrated nanoimpact index (INI) as an early warning scale of nano-impact based on a combination of toxicological end points such as cell proliferation, oxidative stress, apoptosis and genotoxicity. Here, the effect of SPIONs functionalized with tri-sodium citrate (TSC), polyethylenimine (PEI), aminopropyl-triethoxysilane (APTES) and Chitosan (chitosan) were assessed on human keratinocytes and endothelial cells. Our results show that endothelial cells were more sensitive to exposure than keratinocytes and the initial cell culture density modulated the toxicity. PEI-SPIONs had the strongest effects in both cell types while TSC-SPIONS were the most biocompatible. This study emphasizes not only the importance of surface coatings but also the cell type and the initial cell density on the selection of toxicity assays. The INI developed here could offer an initial rationale to choose either modifying SPIONs properties to reduce its nanoimpact or performing a complete risk assessment to define the risk boundaries.

  • 38.
    Bayat, Narges
    et al.
    Stockholm University, Sweden.
    Lopes, Viviana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schoelermann, Julia
    University of Bergen, Norway.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Stockholm University, Sweden; University of Basque Country, Spain.
    Vascular toxicity of ultra-small TiO2 nanoparticles and single walled carbon nanotubes in vitro and in vivo2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 63Article in journal (Refereed)
    Abstract [en]

    Ultra-small nanoparticles (USNPs) at 1-3 nm are a subset of nanoparticles (NPs) that exhibit intermediate physicochemical properties between molecular dispersions and larger NPs. Despite interest in their utilization in applications such as theranostics, limited data about their toxicity exist. Here the effect of TiO2-USNPs on endothelial cells in vitro, and zebrafish embryos in vivo, was studied and compared to larger TiO2-NPs (30 nm) and to single walled carbon nanotubes (SWCNTs). In vitro exposure showed that TiO2-USNPs were neither cytotoxic, nor had oxidative ability, nevertheless were genotoxic. In vivo experiment in early developing zebrafish embryos in water at high concentrations of TiO2-USNPs caused mortality possibly by acidifying the water and caused malformations in the form of pericardial edema when injected. Myo1C involved in glomerular development of zebrafish embryos was upregulated in embryos exposed to TiO2-USNPs. They also exhibited anti-angiogenic effects both in vitro and in vivo plus decreased nitric oxide concentration. The larger TiO2-NPs were genotoxic but not cytotoxic. SWCNTs were cytotoxic in vitro and had the highest oxidative ability. Neither of these NPs had significant effects in vivo. To our knowledge this is the first study evaluating the effects of TiO2-USNPs on vascular toxicity in vitro and in vivo and this strategy could unravel USNPs potential applications. (C) 2015 Elsevier Ltd. All rights reserved.

  • 39.
    Bayat, Narges
    et al.
    Stockholm University, Sweden .
    Rajapakse, Katarina
    University of Ljubljana, Slovenia .
    Marinsek-Logar, Romana
    University of Ljubljana, Slovenia .
    Drobne, Damjana
    University of Ljubljana, Slovenia Centre Excellence Adv Mat and Technology Future CONAMASTE, Slovenia Centre Excellence Nanosci and Nanotechnol CO Nanoctr, Slovenia .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    The effects of engineered nanoparticles on the cellular structure and growth of Saccharomyces cerevisiae2014In: Nanotoxicology, ISSN 1743-5390, Vol. 8, no 4, 363-373 p.Article in journal (Refereed)
    Abstract [en]

    In order to study the effects of nanoparticles (NPs) with different physicochemical properties on cellular viability and structure, Saccharomyces cerevisiae were exposed to different concentrations of TiO2-NPs (1-3 nm), ZnO-NPs (less than100 nm), CuO-NPs (less than50 nm), their bulk forms, Ag-NPs (10 nm) and single-walled carbon nanotubes (SWCNTs). The GreenScreen assay was used to measure cyto- and genotoxicity, and transmission electron microscopy (TEM) used to assess ultrastructure. Cu-ONPs were highly cytotoxic, reducing the cell density by 80% at 9 cm(2)/ml, and inducing lipid droplet formation. Cells exposed to Ag-NPs (19 cm(2)/ml) and TiO2-NPs (147 cm(2)/ml) contained dark deposits in intracellular vacuoles, the cell wall and vesicles, and reduced cell density (40 and 30%, respectively). ZnO-NPs (8 cm(2)/ml) caused an increase in the size of intracellular vacuoles, despite not being cytotoxic. SWCNTs did not cause cytotoxicity or significant alterations in ultrastructure, despite high oxidative potential. Two genotoxicity assays, GreenScreen and the comet assay, produced different results and the authors discuss the reasons for this discrepancy. Classical assays of toxicity may not be the most suitable for studying the effects of NPs in cellular systems, and the simultaneous assessment of other measures of the state of cells, such as TEM are highly recommended.

  • 40.
    Belin, Andrea Carmine
    et al.
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ran, Caroline
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Anvret, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Paddock, Silvia
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Westerlund, Marie
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Håkansson, Anna
    Department of Pharmacology, Sahlgrenska Academy at Göteborg University, Sweden.
    Nissbrandt, Hans
    Department of Pharmacology, Sahlgrenska Academy at Göteborg University, Sweden.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Dizdar, Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Ahmadi, Ahmad
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Anvret, Maria
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Willows, Thomas
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Sydow, Olof
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Galter, Dagmar
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 522, no 1, 30-5 p.Article in journal (Refereed)
    Abstract [en]

    Pesticide exposure has been suggested to increase the risk to develop Parkinson's disease (PD). The arylesterase paraoxonase 1 (PON1) is mainly expressed in the liver and hydrolyzes organophosphates such as pesticides. The polymorphism Leu54Met (rs854560) in PON1, impairing enzyme activity and leading to decreased PON1 expression levels, has been reported to be associated with Parkinson's disease (PD). PON1 is part of a cluster on chromosome 7q21.3 together with PON2 and PON3. We investigated the occurrence of four additional polymorphisms in PON1 and two in PON2 in a Swedish PD case-control material. We found a significant association (p=0.007) with a PON1 promoter polymorphism, rs854571. The minor allele was more common among controls than PD cases which suggest a protective effect. This is strengthened by the fact that rs854571 is in strong linkage disequilibrium with another PON1 promoter polymorphism, rs854572, reported to increase PON1 gene expression. Our findings support the hypothesis that PON1 is involved in the etiology of PD and that higher PON1 levels are reducing the risk for PD.

  • 41.
    Belknap, J K
    et al.
    Research Service (R&D5), Department of Veterans Affairs Medical Center, Portland Alcohol Research Center, and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon, 97201, USAUSA.
    Atkins, Alison Lynn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies.2001In: Mammalian Genome, ISSN 0938-8990, E-ISSN 1432-1777, Vol. 12, no 12, 893-899 p.Article in journal (Refereed)
    Abstract [en]

    On the basis of eight independent quantitative trait loci (QTL) studies of ethanol (alcohol) preference drinking in mice, a meta-analysis was carried out to examine the replicability of QTLs across studies and to enhance the power of QTL detection and parameter estimation. To avoid genetic heterogeneity, we analyzed only studies of mapping populations derived from the C57BL/6 (B6) and DBA/2 (D2) inbred progenitor strains. Because these studies were carried out in five different laboratories, there were substantial differences in testing procedure, data analysis, and especially in the choice of mapping population (BXD recombinant inbred strains, F2, backcross, selected lines, or congenic strains). Despite this, we found several QTLs that were sufficiently robust as to appear consistently across studies given the strengths and weaknesses of the mapping populations employed. These were on Chromosomes (Chrs) 2 (proximal to mid), 3 (mid to distal), 4 (distal), and 9 (proximal to mid). The P value for each of these QTLs, combined across all applicable studies, ranged from 10(-7) to 10(-15), with the additive effect of each QTL accounting for 3-5% of the trait variance extrapolated to an F2 population. Two other QTLs on Chrs 1 (distal) and 11 (mid) were less consistent, but still reached overall significance (P <.0001).

  • 42.
    Ben Said, Mariem
    et al.
    Centre Biotechnol Sfax, Tunisia .
    Chouchene, Ebtissem
    Institute Hedi Raies Ophtalmol Tunis, Tunisia .
    Ben Salem, Salma
    Centre Biotechnol Sfax, Tunisia .
    Daoud, Kods
    Centre Biotechnol Sfax, Tunisia .
    Largueche, Leila
    Institute Hedi Raies Ophtalmol Tunis, Tunisia .
    Bouassida, Walid
    CHUH Bourguiba Sfax, Tunisia .
    Benzina, Zeineb
    CHUH Bourguiba Sfax, Tunisia .
    Ayadi, Hammadi
    Centre Biotechnol Sfax, Tunisia .
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Matri, Leila
    Institute Hedi Raies Ophtalmol Tunis, Tunisia .
    Hmani-Aifa, Mounira
    Centre Biotechnol Sfax, Tunisia .
    Posterior microphthalmia and nanophthalmia in Tunisia caused by a founder c.1059_1066insC mutation of the PRSS56 gene2013In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 528, no 2, 288-294 p.Article in journal (Refereed)
    Abstract [en]

    Congenital microphthalmia (CMIC) is a common developmental ocular disorder characterized by a small, and sometimes malformed, eye. Posterior microphthalmia (PM) and nanophthalmia are two rare subtypes of isolated CMIC characterized by extreme hyperopia due to short axial length and elevated lens/eye volume ratio. While nanophthalmia is associated with a reduced size in both anterior and posterior segments, PM involves a normal-size anterior chamber but a small posterior segment. less thanbrgreater than less thanbrgreater thanSeveral genes encoding transcription and non-transcription regulators have been identified in different forms of CMIC. MFRP gene mutations have, for instance, been associated with nanophthalmia, and mutations in the recently identified PRSS56 gene have been linked to PM. So far, these two forms of CMIC have been associated with 9 mutations in PRSS56. Of particular interest, a c.1059_1066insC mutation has recently been reported in four Tunisian families with isolated PM and one Tunisian family with nanophthalmia. Here, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous Tunisian family (PM7) affected with PM and identified the same causative disease mutation. A total of 24 polymorphic markers spanning the PRSS56 gene in 6 families originating from different regions of Tunisia were analyzed to investigate the origin of the c.1059_1066insC mutation and to determine whether it arose in a common ancestor. A highly significant disease-associated haplotype, spanning across the 146 kb of the 2q37.1 chromosome, was conserved in those families, suggesting that c.1059_1066insC arose from a common founder. The age of the mutation in this haplotype was estimated to be around 1850 years. The identification of such founder effects may greatly simplify diagnostic genetic screening and lead to better prognostic counseling.

  • 43.
    Bendz, Maria
    et al.
    Stockholm University, Sweden .
    Skwark, Marcin
    Stockholm University, Sweden .
    Nilsson, Daniel
    Stockholm University, Sweden .
    Granholm, Viktor
    Stockholm University, Sweden .
    Cristobal, Susana
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kall, Lukas
    Royal Institute Technology KTH, Sweden .
    Elofsson, Arne
    Stockholm University, Sweden .
    Membrane protein shaving with thermolysin can be used to evaluate topology predictors2013In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 13, no 9, 1467-1480 p.Article in journal (Refereed)
    Abstract [en]

    Topology analysis of membrane proteins can be obtained by enzymatic shaving in combination with MS identification of peptides. Ideally, such analysis could provide quite detailed information about the membrane spanning regions. Here, we examine the ability of some shaving enzymes to provide large-scale analysis of membrane proteome topologies. To compare different shaving enzymes, we first analyzed the detected peptides from two over-expressed proteins. Second, we analyzed the peptides from non-over-expressed Escherichia coli membrane proteins with known structure to evaluate the shaving methods. Finally, the identified peptides were used to test the accuracy of a number of topology predictors. At the end we suggest that the usage of thermolysin, an enzyme working at the natural pH of the cell for membrane shaving, is superior because: (i) we detect a similar number of peptides and proteins using thermolysin and trypsin; (ii) thermolysin shaving can be run at a natural pH and (iii) the incubation time is quite short. (iv) Fewer detected peptides from thermolysin shaving originate from the transmembrane regions. Using thermolysin shaving we can also provide a clear separation between the best and the less accurate topology predictors, indicating that using data from shaving can provide valuable information when developing new topology predictors.

  • 44.
    Benner, Axel
    et al.
    German Cancer Research Centre, Germany.
    Mansouri, Larry
    Uppsala University, Sweden.
    Rossi, Davide
    Amedeo Avogadro University of Eastern Piedmont, Italy.
    Majid, Aneela
    University of Leicester, England.
    Willander, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Parker, Anton
    Royal Bournemouth Hospital, England.
    Bond, Gareth
    University of Oxford, England.
    Pavlova, Sarka
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Nueckel, Holger
    University of Duisburg Essen, Germany.
    Merkel, Olaf
    Paracelus Medical University, Austria.
    Ghia, Paolo
    University of Bita Salute San Raffaele, Italy.
    Montserrat, Emili
    University of Barcelona, Spain.
    Arifin Kaderi, Mohd
    Uppsala University, Sweden; Int Islamic University of Malaysia, Malaysia.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Gaidano, Gianluca
    Amedeo Avogadro University of Eastern Piedmont, Italy.
    Dyer, Martin J. S.
    University of Leicester, England.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Linderholm, Mats
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Oscier, David
    Royal Bournemouth Hospital, England.
    Tvaruzkova, Zuzana
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Pospisilova, Sarka
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Duehrsen, Ulrich
    University of Duisburg Essen, Germany.
    Greil, Richard
    Paracelus Medical University, Austria.
    Doehner, Hartmut
    University of Ulm, Germany.
    Stilgenbauer, Stephan
    University of Ulm, Germany.
    Zenz, Thorsten
    German Cancer Research Centre, Germany; University of Heidelberg Hospital, Germany.
    MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 8, 1285-1291 p.Article in journal (Refereed)
    Abstract [en]

    A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.

  • 45.
    Bergh, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Arts and Sciences.
    Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) cells rapidly die when put in culture implying that microenvironmental signals delivered by accessory cells confer CLL cells with a growth advantage. Recent findings show that CLL cells are antigen experienced and antigen binding play a critical role in the pathogenesis of the disease. The overall aim of this thesis was to study the influence of the microenvironment and antigen binding in CLL.

    In paper I, we studied the influence of the small redox-regulatory molecule thioredoxin (Trx) on CLL cell survival and proliferation. We found Trx to be highly expressed in CLL lymph nodes (LNs), secreted from stromal cells surrounding proliferating CLL cells in proliferation centers, indicating growth promoting properties. Secreted Trx was also shown to protect CLL cells from apoptosis.

    In paper II, oxidized LDL was added to subset #1 CLL cells. However, in contrast to our hypothesis, we could not observe activation and proliferation of CLL cells. Instead subset #1 CLL cells were unresponsive/anergic through the B cell receptor (BcR). This anergic state could however be overcome by “wash out” of bound antigen or addition of toll-like receptor 9 stimulation in some patients.

    Gene expression profiles differ between groups of CLL patients and in peripheral blood (PB) and LN compartment, due to different microenvironments. However, it is not known whether these differences also apply for DNA methylation. In paper III, we identified various genes that were alternatively methylated between IGHV mutated (M) and unmutated (UM) groups. For example prognostic genes, CLLU1 and LPL, genes involved in B cell signaling, IBTK, as well as numerous TGF-β and NF-κB/TNF pathway genes.

    The intensity and duration of BcR signals are fine-tuned by enhancing or inhibitory coreceptors. SHP-1 inhibits BcR-signals by dephosphorylation. In paper IV, we compared the expression and activity of SHP-1 in CLL cells from LN with matched PB samples. However, in contrast to our hypothesis, SHP-1 activity/phosphorylation status in PB and LN, did not differ significantly.

    This thesis, add another piece to the puzzle, on how the microenvironment and antigens influence CLL pathogenesis. Since great variations among individuals are seen, further studies in different groups of patients are necessary to elucidate the importance of antigen for the development of CLL.

    List of papers
    1. Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro
    Open this publication in new window or tab >>Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro
    Show others...
    2007 (English)In: Haematologica, ISSN 0390-6078, Vol. 92, no 11, 1495-1504 p.Article in journal (Refereed) Published
    Abstract [en]

    Background and Objectives: The redox-regulatory protein thioredoxin has several functions including transcriptional regulation, and antioxidant, cytokine, and chemokine activities. We have previously shown that extracellular thioredoxin protects B-cell chronic lymphocytic leukemia (CLL) cells from apoptosis in vitro. In this study we were interested to determine whether thioredoxin is produced by cells surrounding the CLL cells in the in vivo microenvironment and whether this cell-derived thioredoxin has any leukemia growth-promoting effect in vitro. Design and Methods: Lymph nodes from CLL patients (n=25) were analyzed for thioredoxin expression by immunohistology. Stromal cells purified from the lymph nodes were analyzed for thioredoxin secretion at the single cell level using an ELIspot assay. The survival effect of the stromal-derived thioredoxin was tested by co-culturing stromal- and CLL cells with and without Fab-fragments of an anti-thioredoxin antibody. Results: The results indicated that the thioredoxin production correlated with the amount of proliferating cells and was mainly localized to the proliferation centers (pseudofollicles) in the CLL lymph nodes. The leukemia cells per se showed minimal thioredoxin levels, in contrast, stromal cells strongly expressed thioredoxin. Purified primary stromal cells, which secreted extracellular thioredoxin, significantly protected the CLL cells from undergoing apoptosis in 72 h co-cultures. Interestingly, this anti-apoptotic effect could be abrogated by addition of Fab-fragments of an anti- thioredoxin antibody. Interpretation and Conclusions: In conclusion, we have shown that stromal cells in the lymph node microenvironment produce thioredoxin and that the thioredoxin production is localized to the proliferation centers of the CLL lymph nodes. In addition, thioredoxin produced by purified stromal cells rescued CLL cells from apoptosis in vitro. ©2007 Ferrata Storti Foundation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-40728 (URN)10.3324/haematol.11448 (DOI)54003 (Local ID)54003 (Archive number)54003 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-09-22
    2. Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
    Open this publication in new window or tab >>Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
    Show others...
    2014 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 11, 1722-1730 p.Article in journal (Refereed) Published
    Abstract [en]

    Chronic lymphocytic leukemia B-cells express auto/xeno-antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen, since it is more faithful to B-cell physiology than anti-IgM, for analysis of downstream B-cell receptor-signal transduction events. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen-binding induced prompt receptor-clustering, followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca2+ mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48 hours culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor-unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia indicating that these cells proliferate by other mechanisms that may override B-cell receptor-silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.

    Place, publisher, year, edition, pages
    Ferrata Storti Foundation, 2014
    Keyword
    Anergy; B-cell Receptor Signaling; Chronic Lymphocytic Leukemia; Oxidized LDL; Stereotyped subsets
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-109020 (URN)10.3324/haematol.2014.106054 (DOI)000347016300013 ()25085355 (PubMedID)
    Available from: 2014-07-28 Created: 2014-07-28 Last updated: 2017-09-22
    3. 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
    Open this publication in new window or tab >>450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
    Show others...
    2013 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 1, 150-158 p.Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80705 (URN)10.1038/leu.2012.245 (DOI)000313511400021 ()22922567 (PubMedID)
    Available from: 2012-08-29 Created: 2012-08-29 Last updated: 2017-09-22
    4. B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral blood
    Open this publication in new window or tab >>B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral blood
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Protein tyrosine phosphatase SHP-1 expression and activity is downregulated or lost in several leukemias and lymphomas due to DNA promotor hypermethylation, catalytic site mutation or oxidation, or phosphorylation at inhibitory sites, implying a negative role of SHP-1 in development of leukemias/lymphomas. In chronic lymphocytic leukemia (CLL), B cell receptor (BcR) and microenvironment signal levels are important in the pathogenesis. Considering that SHP-1 is a BcR signaling suppressor, we hypothesized that SHP-1 would be down-regulated and/or inactivated in the proliferative center lymph node (LN) cells. We analyzed PTPN6 (SHP-1) gene expression, SHP-1 protein expression and phosphorylation status in matched CD5+/CD19+ peripheral blood (PB) and LN cells from 6 CLL patients, and in comparison, BcR (anti-IgM) in vitro triggered CLL PB cells from 10 patients. Gene expression of PTPN6 was significantly higher in PB compared to LN CLL cells in 50% of the cases. SHP-1 protein expression level and phosphorylation at SHP-1Y536 and SHP-1S591 were, however, equal in PB and LN samples. SHP-1 phosphorylation at Y536 and S591, in PB CLL cells cultured ex vivo was significantly reduced upon BcR engagement in all patient samples. These results indicate that in vivo BcR signaling in CLL is paralyzed.

    Keyword
    B cell, chronic lymphocytic leukemia, SHP-1, suppressor, tyrosine phosphorylation
    National Category
    Cell and Molecular Biology Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-124575 (URN)
    Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2017-09-22Bibliographically approved
  • 46.
    Bergh, Ann-Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    El-Schich, Zahra
    Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
    Delfani, Payam
    Department of Immunotechnology, Lund Institute of Technology, Lund University, Lund, Sweden.
    Ohlsson, Lars
    Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gjörloff Wingren, Anette
    Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.
    B cell receptor signaling suppressor SHP-1 is active in CLL lymph node and peripheral bloodManuscript (preprint) (Other academic)
    Abstract [en]

    Protein tyrosine phosphatase SHP-1 expression and activity is downregulated or lost in several leukemias and lymphomas due to DNA promotor hypermethylation, catalytic site mutation or oxidation, or phosphorylation at inhibitory sites, implying a negative role of SHP-1 in development of leukemias/lymphomas. In chronic lymphocytic leukemia (CLL), B cell receptor (BcR) and microenvironment signal levels are important in the pathogenesis. Considering that SHP-1 is a BcR signaling suppressor, we hypothesized that SHP-1 would be down-regulated and/or inactivated in the proliferative center lymph node (LN) cells. We analyzed PTPN6 (SHP-1) gene expression, SHP-1 protein expression and phosphorylation status in matched CD5+/CD19+ peripheral blood (PB) and LN cells from 6 CLL patients, and in comparison, BcR (anti-IgM) in vitro triggered CLL PB cells from 10 patients. Gene expression of PTPN6 was significantly higher in PB compared to LN CLL cells in 50% of the cases. SHP-1 protein expression level and phosphorylation at SHP-1Y536 and SHP-1S591 were, however, equal in PB and LN samples. SHP-1 phosphorylation at Y536 and S591, in PB CLL cells cultured ex vivo was significantly reduced upon BcR engagement in all patient samples. These results indicate that in vivo BcR signaling in CLL is paralyzed.

  • 47.
    Bergh, Ann-Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Evaldsson, Chamilly
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Pedersen, Lone Bredo
    Rigshospitalet Copenhagen, Denmark.
    Geisler, Christian
    Rigshospitalet Copenhagen, Denmark.
    Stamatopoulos, Kostas
    G. Papanicolaou Hospital, Greece.
    Rosenquist, Richard
    Rudbeck Laboratory, Uppsala University, Sweden .
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia2014In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 11, 1722-1730 p.Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia B-cells express auto/xeno-antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen, since it is more faithful to B-cell physiology than anti-IgM, for analysis of downstream B-cell receptor-signal transduction events. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen-binding induced prompt receptor-clustering, followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca2+ mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48 hours culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor-unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia indicating that these cells proliferate by other mechanisms that may override B-cell receptor-silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.

  • 48.
    Bergkvist, Liza
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    A beta PP processing results in greater toxicity per amount of A beta(1-42) than individually expressed and secreted A beta(1-42) in Drosophila melanogaster2016In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, no 8, 1030-1039 p.Article in journal (Refereed)
    Abstract [en]

    The aggregation of the amyloid-beta (A beta) peptide into fibrillar deposits has long been considered the key neuropathological hallmark of Alzheimers disease (AD). A beta peptides are generated from proteolytic processing of the transmembrane A beta precursor protein (A beta PP) via sequential proteolysis through the beta-secretase activity of beta-site A beta PP-cleaving enzyme (BACE1) and by the intramembranous enzyme gamma-secretase. For over a decade, Drosophila melanogaster has been used as a model organism to study AD, and two different approaches have been developed to investigate the toxicity caused by AD-associated gene products in vivo. In one model, the A beta peptide is directly over-expressed fused to a signal peptide, allowing secretion of the peptide into the extracellular space. In the other model, human A beta PP is co-expressed with human BACE1, resulting in production of the A beta peptide through the processing of A beta PP by BACE1 and by endogenous fly gamma-secretase. Here, we performed a parallel study of flies that expressed the A beta(1-42) peptide alone or that co-expressed A beta PP and BACE1. Toxic effects (assessed by eye phenotype, longevity and locomotor assays) and levels of the A beta(1-42), A beta(1-40) and A beta(1-38) peptides were examined. Our data reveal that the toxic effect per amount of detected A beta(1-42) peptide was higher in the flies co-expressing A beta PP and BACE1 than in the A beta(1-42)-expressing flies, and that the co-existence of A beta(1-42) and A beta(1-40) in the flies co-expressing A beta PP and BACE1 could be of significant importance to the neurotoxic effect detected in these flies. Thus, the toxicity detected in these two fly models seems to have different modes of action and is highly dependent on how and where the peptide is generated rather than on the actual level of the A beta(1-42) peptide in the flies. This is important knowledge that needs to be taken into consideration when using Drosophila models to investigate disease mechanisms or therapeutic strategies in AD research.

  • 49.
    Bivik, Caroline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bahrampour, Shahrzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Patrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fransson, Fredrik
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Lundin, Erika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Renhorn, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells2015In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 200, no 4, 1229-1244 p.Article in journal (Refereed)
    Abstract [en]

    The expression of neuropeptides is often extremely restricted in the nervous system, making them powerful markers for addressing cell specification . In the developing Drosophila ventral nerve cord, only six cells, the Ap4 neurons, of some 10,000 neurons, express the neuropeptide FMRFamide (FMRFa). Each Ap4/FMRFa neuron is the last-born cell generated by an identifiable and well-studied progenitor cell, neuroblast 5-6 (NB5-6T). The restricted expression of FMRFa and the wealth of information regarding its gene regulation and Ap4 neuron specification makes FMRFa a valuable readout for addressing many aspects of neural development, i.e., spatial and temporal patterning cues, cell cycle control, cell specification, axon transport, and retrograde signaling. To this end, we have conducted a forward genetic screen utilizing an Ap4-specific FMRFa-eGFP transgenic reporter as our readout. A total of 9781 EMS-mutated chromosomes were screened for perturbations in FMRFa-eGFP expression, and 611 mutants were identified. Seventy-nine of the strongest mutants were mapped down to the affected gene by deficiency mapping or whole-genome sequencing. We isolated novel alleles for previously known FMRFa regulators, confirming the validity of the screen. In addition, we identified novel essential genes, including several with previously undefined functions in neural development. Our identification of genes affecting most major steps required for successful terminal differentiation of Ap4 neurons provides a comprehensive view of the genetic flow controlling the generation of highly unique neuronal cell types in the developing nervous system.

  • 50.
    Bivik, Cecilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Winge, Marten C.
    Karolinska Institute, Sweden .
    Lieden, Agne
    Karolinska Institute, Sweden .
    Bradley, Maria
    Karolinska Institute, Sweden .
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Letter: Genetic Variation in the Inflammasome and Atopic Dermatitis Susceptibility2013In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 133, no 10, 2486-2489 p.Article in journal (Other academic)
    Abstract [en]

    n/a

1234567 1 - 50 of 453
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