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  • 1.
    Abdollahi Sani, Negar
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Robertsson, Mats
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Cooper, Philip
    De La Rue Plc, Overton, Hampshire, UK .
    Wang, Xin
    Acreo AB, Norrköping, Sweden.
    Svensson, Magnus
    Acreo AB, Norrköping, Sweden.
    Andersson Ersman, Peter
    Acreo AB, Norrköping, Sweden.
    Norberg, Petronella
    Acreo AB, Norrköping, Sweden.
    Nilsson, Marie
    Acreo AB, Norrköping, Sweden.
    Nilsson, David
    Acreo AB, Norrköping, Sweden.
    Liu, Xianjie
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, The Institute of Technology.
    Hesselbom, Hjalmar
    Hesselbom Innovation and Development HB, Huddinge, Sweden .
    Akesso, Laurent
    De La Rue Plc, Overton, Hampshire, UK .
    Fahlman, Mats
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, The Institute of Technology.
    Crispin, Xavier
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Engquist, Isak
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology. Acreo AB, Norrköping, Sweden.
    Gustafsson, Goran
    Acreo AB, Norrköping, Sweden.
    All-printed diode operating at 1.6 GHz2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 33, p. 11943-11948Article in journal (Refereed)
    Abstract [en]

    Printed electronics are considered for wireless electronic tags and sensors within the future Internet-of-things (IoT) concept. As a consequence of the low charge carrier mobility of present printable organic and inorganic semiconductors, the operational frequency of printed rectifiers is not high enough to enable direct communication and powering between mobile phones and printed e-tags. Here, we report an all-printed diode operating up to 1.6 GHz. The device, based on two stacked layers of Si and NbSi2 particles, is manufactured on a flexible substrate at low temperature and in ambient atmosphere. The high charge carrier mobility of the Si microparticles allows device operation to occur in the charge injection-limited regime. The asymmetry of the oxide layers in the resulting device stack leads to rectification of tunneling current. Printed diodes were combined with antennas and electrochromic displays to form an all-printed e-tag. The harvested signal from a Global System for Mobile Communications mobile phone was used to update the display. Our findings demonstrate a new communication pathway for printed electronics within IoT applications.

  • 2.
    Andersson, A.
    et al.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Olofsson, T.
    Department of Hematology, Lund University Hospital, SE-221 85 Lund, Sweden.
    Lindgren, D.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Nilsson, B.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Ritz, C.
    Department of Complex System Division, Theoretical Physics, Lund University, S-221 00 Lund, Sweden.
    Eden, P.
    Department of Complex System Division, Theoretical Physics, Lund University, S-221 00 Lund, Sweden.
    Lassen, C.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Rade, J.
    Center for Mathematical Sciences, Lund University, S-221 00 Lund, Sweden.
    Fontes, M.
    Center for Mathematical Sciences, Lund University, S-221 00 Lund, Sweden.
    Morse, H.
    Department of Pediatrics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Heldrup, J.
    Department of Pediatrics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Mitelman, F.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Hoglund, M.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Johansson, B.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Fioretos, T.
    Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden.
    Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 52, p. 19069-19074Article in journal (Refereed)
    Abstract [en]

    Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1. IGH@/MYC. ETV6(TEL)/RUNX1(AML1). 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies. © 2005 by The National Academy of Sciences of the USA.

  • 3.
    Andersson, David A.
    et al.
    Royal Institute of Technology.
    Simak, Sergey
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics .
    Skorodumova, Natalia V.
    Uppsala University.
    Abrikosov, Igor
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics .
    Johansson, Börje
    Uppsala University.
    Optimization of ionic conductivity in doped ceria2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, p. 3518-3521Article in journal (Refereed)
  • 4.
    Arnqvist, Göran
    et al.
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Edvardsson, Martin
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Friberg, Urban
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Nilsson, Tina
    Department of Ecology and Environmental Science, Animal Ecology, University of Umeå, Umeå, Sweden.
    Sexual conflict promotes speciation in insects.2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 19, p. 10460-10464Article in journal (Refereed)
    Abstract [en]

    Speciation rates among extant lineages of organisms vary extensively, but our understanding of the causes of this variation and, therefore, the processes of speciation is still remarkably incomplete. Both theoretical and empirical studies have indicated that sexual selection is important in speciation, but earlier discussions have focused almost exclusively on the potential role of female mate choice. Recent findings of postmating reproductive conflicts of interest between the sexes suggest a quite different route to speciation. Such conflicts may lead to perpetual antagonistic coevolution between males and females and may thus generate rapid evolutionary divergence of traits involved in reproduction. Here, we assess this hypothesis by contrasting pairs of related groups of insect species differing in the opportunity for postmating sexual conflict. Groups where females mate with many males exhibited speciation rates four times as high as in related groups where females mate only once. Our results not only highlight the general importance of postmating sexual selection in speciation, but also support the recent suggestion that sexual conflict is a key engine of speciation.

  • 5.
    Bach, Anders
    et al.
    University of Copenhagen.
    Clausen, Bettina H
    University of South Denmark.
    Moller, Magda
    University of Copenhagen.
    Vestergaard, Bente
    University of Copenhagen.
    Chi, Celestine N
    Uppsala University.
    Round, Adam
    European Molecular Biol Lab.
    Sorensen, Pernille L
    University of Copenhagen.
    Nissen, Klaus B
    University of Copenhagen.
    Kastrup, Jette S
    University of Copenhagen.
    Gajhede, Michael
    University of Copenhagen.
    Jemth, Per
    Uppsala University.
    Kristensen, Anders S
    University of Copenhagen.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Lambertsen, Kate L
    University of South Denmark.
    Stromgaard, Kristian
    University of Copenhagen.
    A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 9, p. 3317-3322Article in journal (Refereed)
    Abstract [en]

    Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.

  • 6.
    Baker, Maggie
    et al.
    NIAAA, USA.
    Lindell, Stephen G.
    NIAAA, USA.
    Driscoll, Carlos A.
    NIAAA, USA.
    Zhou, Zhifeng
    NIAAA, USA.
    Yuan, Qiaoping
    NIAAA, USA.
    Schwandt, Melanie L.
    NIAAA, USA.
    Miller-Crews, Isaac
    NIAAA, USA.
    Simpson, Elizabeth A.
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Paukner, Annika
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Francesco Ferrari, Pier
    University of Claude Bernard Lyon, France.
    Kumar Sindhu, Ravi
    NIAAA, MD 20852 USA.
    Razaqyar, Muslima
    NIAAA, USA.
    Sommer, Wolfgang H.
    Heidelberg University, Germany; Heidelberg University, Germany.
    Lopez, Juan F.
    University of Michigan, MI 48109 USA.
    Thompson, Robert C.
    University of Michigan, MI 48109 USA.
    Goldman, David
    NIAAA, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Dee Higley, J.
    Brigham Young University, UT 84602 USA.
    Suomi, Stephen J.
    Eunice Shriver Kennedy National Institute Child Health and Huma, MD 20837 USA.
    Barr, Christina S.
    NIAAA, USA.
    Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 44, p. 11769-11774Article in journal (Refereed)
    Abstract [en]

    Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to deter mine whether a gain-of-function nonsynonymous OXTR SNP inter acted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavior al differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.

  • 7.
    Barro-Soria, Rene
    et al.
    University of Miami, FL 33136 USA.
    Ramentol, Rosamary
    University of Miami, FL 33136 USA.
    Liin, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Perez, Marta E.
    University of Miami, FL 33136 USA.
    Kass, Robert S.
    Columbia University, NY 10032 USA.
    Larsson, H. Peter
    University of Miami, FL 33136 USA.
    KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 35, p. E7367-E7376Article in journal (Refereed)
    Abstract [en]

    KCNE beta-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-to-gate coupling.

  • 8. Berkenstam, Anders
    et al.
    Kristensen, Jens
    Mellström, Karin
    Carlsson, Bo
    Malm, Johan
    Rehnmark, Stefan
    Garg, Neeraj
    Andersson, Carl Magnus
    Rudling, Mats
    Sjöberg, Folke
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Burn Unit . Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Angelin, Bo
    Baxter, John D.
    The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 2, p. 663-667Article in journal (Refereed)
    Abstract [en]

    Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115, (3-[[3,5-dibromo-4- [4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis. © 2007 by The National Academy of Sciences of the USA.

  • 9.
    Bilbao, Ainhoa
    et al.
    Central Institute of Mental Health, Mannheim.
    Rodriguez Parkitna, Jan
    German Cancer Research Center, Heidelberg.
    Engblom, David
    German Cancer Research Center, Heidelberg.
    Perreau-Lenz, Stephanie
    Central Institute of Mental Health, Mannheim.
    Sanchis-Segura, Carles
    Central Institute of Mental Health, Mannheim.
    Schneider, Miriam
    Central Institute of Mental Health, Mannheim.
    Konopka, Witold
    German Cancer Research Center, Heidelberg.
    Westphal, Magdalena
    German Cancer Research Center, Heidelberg.
    Breen, Gerome
    King's College London.
    Desrivieres, Sylvane
    King's College London.
    Klugmann, Matthias
    University of Mainz.
    Guindalini, Camila
    Universidade Federal de São Paulo.
    Vallada, Homero
    Universidade de São Paulo.
    Laranjeira, Ronaldo
    Universidade Federal de São Paulo.
    Rodriguez de Fonseca, Fernando
    Hospital Carlos Haya.
    Schumann, Gunter
    King's College London.
    Schuetz, Guenther
    Central Institute of Mental Health, Mannheim.
    Spanagel, Rainer
    Central Institute of Mental Health, J5, 68159 Mannheim.
    Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 45, p. 17549-17554Article in journal (Refereed)
    Abstract [en]

    The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.

  • 10.
    Brautigam, Lars
    et al.
    Karolinska Institute, Sweden .
    Dahl Ejby Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden .
    Poschmann, Gereon
    University of Dusseldorf, Germany .
    Nystrom, Staffan
    Karolinska Institute, Sweden .
    Bannenberg, Sarah
    Karolinska Institute, Sweden .
    Dreij, Kristian
    Karolinska Institute, Sweden .
    Lepka, Klaudia
    University of Dusseldorf, Germany .
    Prozorovski, Timour
    University of Dusseldorf, Germany .
    Montano, Sergio J
    Karolinska Institute, Sweden .
    Aktas, Orhan
    University of Dusseldorf, Germany .
    Uhlen, Per
    Karolinska Institute, Sweden .
    Stuehler, Kai
    University of Dusseldorf, Germany .
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden .
    Holmgren, Arne
    Karolinska Institute, Sweden .
    Berndt, Carsten
    Karolinska Institute, Sweden .
    Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 12013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 50, p. 20057-20062Article in journal (Refereed)
    Abstract [en]

    Embryonic development depends on complex and precisely orchestrated signaling pathways including specific reduction/oxidation cascades. Oxidoreductases of the thioredoxin family are key players conveying redox signals through reversible posttranslational modifications of protein thiols. The importance of this protein family during embryogenesis has recently been exemplified for glutaredoxin 2, a vertebrate-specific glutathione-disulfide oxidoreductase with a critical role for embryonic brain development. Here, we discovered an essential function of glutaredoxin 2 during vascular development. Confocal microscopy and time-lapse studies based on two-photon microscopy revealed that morpholino-based knockdown of glutaredoxin 2 in zebrafish, a model organism to study vertebrate embryogenesis, resulted in a delayed and disordered blood vessel network. We were able to show that formation of a functional vascular system requires glutaredoxin 2-dependent reversible S-glutathionylation of the NAD(+)-dependent protein deacetylase sirtuin 1. Using mass spectrometry, we identified a cysteine residue in the conserved catalytic region of sirtuin 1 as target for glutaredoxin 2-specific deglutathionylation. Thereby, glutaredoxin 2-mediated redox regulation controls enzymatic activity of sirtuin 1, a mechanism we found to be conserved between zebrafish and humans. These results link S-glutathionylation to vertebrate development and successful embryonic angiogenesis.

  • 11.
    Brioni, JD
    et al.
    Abbott Laboratories.
    Moreland, RB
    Abbott Laboratories.
    Cowart, M
    Abbott Laboratories.
    Hsieh, GC
    Abbott Laboratories.
    Stewart, AO
    Abbott Laboratories.
    Hedlund, Petter
    Lund University Hospital.
    Donnelly-Roberts, DL
    Abbott Laboratories.
    Nakane, M
    Abbott Laboratories.
    Lynch, JJ
    Abbott Laboratories.
    Kolasa, T
    Abbott Laboratories.
    Polakowski, JS
    Abbott Laboratories.
    Osinski, MA
    Abbott Laboratories.
    Marsh, K
    Abbott Laboratories.
    Andersson, KE
    Lund University Hospital.
    Sullivan, JP
    Abbott Laboratories.
    Activation of dopamine D-4 receptors by ABT-724 induces penile erection in rats2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 17, p. 6758-6763Article in journal (Refereed)
    Abstract [en]

    Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D(4) receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D(4) receptor agonist that activates human dopamine D(4) receptors with an EC(50) of 12.4 nM and 61% efficacy, with no effect on dopamine D(1), D(2), D(3), or D(5) receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction.

  • 12.
    Cao, Renhai
    et al.
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Ji, Hong
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Feng, Ninghan
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Zhang, Yin
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Yang, Xiaojuan
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Andersson, Patrik
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Sun, Yuping
    Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong , People's Republic of China.
    Tritsaris, Katerina
    Department of Cellular and Molecular Medicine, Center for Healthy Aging Panum Institute, University of Copenhagen, Copenhagen, Denmark.
    Jon Hansen, Anker
    Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark and Novo Nordisk A/S Måløv, Denmark.
    Dissing, Steen
    Department of Cellular and Molecular Medicine, Center for Healthy Aging Panum Institute, University of Copenhagen, Copenhagen, Denmark.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Sweden.
    Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 39, p. 15894-15899Article in journal (Refereed)
    Abstract [en]

    Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2-induced lymphangiogenesis. Intriguingly, the VEGFR-3-mediated signaling was required for the lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. Consequently, a VEGFR-3-specific neutralizing antibody markedly inhibited FGF-2-induced lymphangiogenesis. Thus, the VEGFR-3-induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2-stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2- and VEGF-C-induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.

  • 13.
    Carlberg, Inger
    et al.
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University.
    Hansson, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kieselbach, Thomas
    Department of Medical Nutrition and Biosciences, Karolinska Institute, Huddinge, Sweden.
    Schröder, Wolfgang P.
    Department of Biochemistry, Umeå University, Umeå, Sweden .
    Andersson, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vener, Alexander V.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    A novel plant protein undergoing light-induced phosphorylation and release from the photosynthetic thylakoid membranes2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 2, p. 757-762Article in journal (Refereed)
    Abstract [en]

    The characteristics of a phosphoprotein with a relative electrophoretic mobility of 12 kDa have been unknown during two decades of studies on redox-dependent protein phosphorylation in plant photosynthetic membranes. Digestion of this protein from spinach thylakoid membranes with trypsin and subsequent tandem nanospray-quadrupole-time-of-flight mass spectrometry of the peptides revealed a protein sequence that did not correspond to any previously known protein. Sequencing of the corresponding cDNA uncovered a gene for a precursor protein with a transit peptide followed by a strongly basic mature protein with a molecular mass of 8,640 Da. Genes encoding homologous proteins were found on chromosome 3 of Arabidopsis and rice as well as in ESTs from 20 different plant species, but not from any other organisms. The protein can be released from the membrane with high salt and is also partially released in response to light-induced phosphorylation of thylakoids, in contrast to all other known thylakoid phosphoproteins, which are integral to the membrane. On the basis of its properties, this plant-specific protein is named thylakoid soluble phosphoprotein of 9 kDa (TSP9). Mass spectrometric analyses revealed the existence of non-, mono-, di-, and triphosphorylated forms of TSP9 and phosphorylation of three distinct threonine residues in the central part of the protein. The phosphorylation and release of TSP9 from the photosynthetic membrane on illumination favor participation of this basic protein in cell signaling and regulation of plant gene expression in response to changing light conditions.

  • 14.
    Castellazzi, M.
    et al.
    Ecole Normale Supérieure, Lyon, France.
    Spyrou, Giannis
    Institut Pasteur, Paris, France.
    La Vista, N.
    Ecole Normale Supérieure, Lyon, France.
    Dangy, J-P
    Ecole Normale Supérieure, Lyon, France.
    Piu, F.
    Ecole Normale Supérieure, Lyon, France.
    Yaniv, M.
    Institut Pasteur, Paris, France.
    Brun, G.
    Ecole Normale Supérieure, Lyon, France.
    Overexpression of c-jun, junB, or junD affects cell growth differently1991In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 88, no 20, p. 8890-8894Article in journal (Refereed)
    Abstract [en]

    The coding sequences of murine c-jun, junB, or junD, which code for proteins with practically identical dimerization and DNA binding properties, were introduced into a nondefective retroviral vector, and the phenotype of primary avian fibroblasts chronically infected with each of these viruses was studied. Cells expressing c-jun grew in low-serum medium and developed into colonies in agar, two properties characteristic of in vitro transformation. Cells expressing junB grew in agar, with a reduced efficiency as compared to c-jun, but did not grow in low-serum medium. Finally, no effect of junD expression on cell growth was observed. These different phenotypes suggest that these three closely related transcription factors play distinct roles during normal cell growth. Analysis of c-jun deletion mutants and of c-jun/junB and c-jun/junD chimeric genes showed that the N-terminal portion (amino acids 2-168) of the c-Jun protein that is involved in transcriptional activation is required for efficient transformation. On the contrary, cells expressing a truncated mouse c-Jun lacking this N-terminal domain grew slower than normal embryo fibroblasts. The reduced growth rate may be related to the finding that expression of the intact or the truncated mouse c-jun repressed the endogenous avian c-Jun homologue, suggesting that functional c-Jun product is required for normal cell growth.

  • 15.
    Di Gennaro, Antonio
    et al.
    Karolinska Inst, Sweden.
    Araujo, Ana Carolina
    Karolinska Inst, Sweden.
    Busch, Albert
    Karolinska Inst, Sweden; Tech Univ Munich, Germany.
    Jin, Hong
    Karolinska Inst, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Caidahl, Kenneth
    Karolinska Inst, Sweden; Gothenburg Univ, Sweden.
    Eriksson, Per
    Karolinska Inst, Sweden.
    Samuelsson, Bengt
    Karolinska Inst, Sweden.
    Maegdefessel, Lars
    Karolinska Inst, Sweden; Tech Univ Munich, Germany.
    Haeggstrom, Jesper Z.
    Karolinska Inst, Sweden.
    Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 8, p. 1907-1912Article in journal (Refereed)
    Abstract [en]

    Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (amp;gt;50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.

  • 16.
    Di Gennaro, Antonio
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden.
    Mäyranpää, Mikko
    Wihuri Research Institute, Helsinki, Finland; University of Helsinki, Finland .
    Gabrielsen, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Swedenborg, Jesper
    Karolinska University Hospital, Stockholm, Sweden .
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Samuelsson, Bengt
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden.
    Häggström, Jesper
    Karolinska Institutet, Stockholm, Sweden.
    Increased expression of leukotriene C-4 synthase and predominant formation of cysteinyl-leukotrienes in human abdominal aortic aneurysm2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 49, p. 21093-21097Article in journal (Refereed)
    Abstract [en]

    Leukotrienes (LTs) are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC4, LTD4, and LTE4 are important mediators of asthma, and LTB4 has recently been implicated in atherosclerosis. Here we report that mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC4 synthase (LTC4S), are significantly increased in the wall of human abdominal aortic aneurysms (AAAs). In contrast, mRNA levels of LTA(4) hydrolase, the enzyme responsible for the biosynthesis of LTB4, are not increased. Immunohistochemical staining of AAA wall revealed focal expression of 5-LO, FLAP, and LTC4S proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA(4) into significant amounts of cysteinyl-leukotrienes and to a lesser extent LTB4. Furthermore, challenge of AAA wall tissue with exogenous LTD4 increases the release of matrix metalloproteinase (MMP) 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect. The increased expression of LTC4S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall and identify the components of the cysteinyl-leukotriene pathway as potential targets for prevention and treatment of AAA.

  • 17.
    Eklund, Anders
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Science & Engineering.
    Nichols, Thomas
    University of Warwick, England.
    Knutsson, Hans
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, Faculty of Science & Engineering.
    Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 28, p. 7900-7905Article in journal (Refereed)
    Abstract [en]

    The most widely used task functional magnetic resonance imaging (fMRI) analyses use parametric statistical methods that depend on a variety of assumptions. In this work, we use real resting-state data and a total of 3 million random task group analyses to compute empirical familywise error rates for the fMRI software packages SPM, FSL, and AFNI, as well as a nonparametric permutation method. For a nominal familywise error rate of 5%, the parametric statistical methods are shown to be conservative for voxelwise inference and invalid for clusterwise inference. Our results suggest that the principal cause of the invalid cluster inferences is spatial autocorrelation functions that do not follow the assumed Gaussian shape. By comparison, the nonparametric permutation test is found to produce nominal results for voxelwise as well as clusterwise inference. These findings speak to the need of validating the statistical methods being used in the field of neuroimaging.

  • 18.
    Eklund, Anders
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Nichols, Thomas
    Department of Statistics, University of Warwick, UK / WMG, University of Warwick, UK.
    Knutsson, Hans
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Reply to BROWN AND BEHRMANN, COX ET AL., AND KESSLER ET AL.: Data and code sharing is the way forward for fMRI2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, p. 1-2Article in journal (Other academic)
    Abstract [en]

    We are glad that our paper (1) has generated intense discussions in the fMRI field (2⇓–4), on how to analyze fMRI data, and how to correct for multiple comparisons. The goal of the paper was not to disparage any specific fMRI software, but to point out that parametric statistical methods are based on a number of assumptions that are not always valid for fMRI data, and that nonparametric statistical methods (5) are a good alternative. Through AFNI’s introduction of nonparametric statistics in the function 3dttest++ (3, 6), the three most common fMRI softwares now all support nonparametric group inference [SPM through the toolbox SnPM (www2.warwick.ac.uk/fac/sci/statistics/staff/academic-research/nichols/software/snpm), and FSL through the function randomise].

    Cox et al. (3) correctly point out that the bug in the AFNI function 3dClustSim only had a minor impact on the false-positive rate (FPR). This was also covered in our original paper (1): “We note that FWE [familywise error] rates are lower with the bug-fixed 3dClustSim function. As an example, the updated function reduces the degree of false …

  • 19.
    Eleonora Bove, Livia
    et al.
    University of Paris 06, France; Ecole Polytech Federal Lausanne, Switzerland.
    Gaal, Richard
    Ecole Polytech Federal Lausanne, Switzerland.
    Raza, Zamaan
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering. University of Paris 06, France.
    Ludl, Adriaan-Alexander
    University of Paris 06, France.
    Klotz, Stefan
    University of Paris 06, France.
    Marco Saitta, Antonino
    University of Paris 06, France.
    Goncharov, Alexander F.
    Carnegie Institute Science, DC 20015 USA.
    Gillet, Philippe
    Ecole Polytech Federal Lausanne, Switzerland.
    Effect of salt on the H-bond symmetrization in ice2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 27, p. 8216-8220Article in journal (Refereed)
    Abstract [en]

    The richness of the phase diagram of water reduces drastically at very high pressures where only two molecular phases, proton-disordered ice VII and proton-ordered ice VIII, are known. Both phases transform to the centered hydrogen bond atomic phase ice X above about 60 GPa, i.e., at pressures experienced in the interior of large ice bodies in the universe, such as Saturn and Neptune, where nonmolecular ice is thought to be the most abundant phase of water. In this work, we investigate, by Raman spectroscopy up to megabar pressures and ab initio simulations, how the transformation of ice VII in ice X is affected by the presence of salt inclusions in the ice lattice. Considerable amounts of salt can be included in ice VII structure under pressure via rock-ice interaction at depth and processes occurring during planetary accretion. Our study reveals that the presence of salt hinders proton order and hydrogen bond symmetrization, and pushes ice VII to ice X transformation to higher and higher pressures as the concentration of salt is increased.

  • 20.
    Eleonora Hedlund, Eva-Maria
    et al.
    Karolinska Institute, Sweden .
    Yang, Xiaojuan
    Karolinska Institute, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Shibuya, Masabumi
    Tokyo Medical and Dent University, Japan .
    Zhong, Weide
    Guangzhou Medical University, Peoples R China .
    Sun, Baocun
    Tianjin Medical University, Peoples R China .
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China .
    Hosaka, Kayoko
    Karolinska Institute, Sweden .
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden .
    Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 2, p. 654-659Article in journal (Refereed)
    Abstract [en]

    The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.

  • 21. Erdal, H
    et al.
    Berndtsson, M
    Castro, J
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Shoshan, M C
    Linder, S
    Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 1, p. 192-197Article in journal (Refereed)
    Abstract [en]

    The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set, 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at ≤5 μM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.

  • 22.
    Foti, M.
    et al.
    Department of Morphology, Faculty of Medicine, 1211 Geneva 4, Switzerland.
    Phelouzat, M.-A.
    Department of Morphology, Faculty of Medicine, 1211 Geneva 4, Switzerland.
    Holm, A.
    Rasmusson, Birgitta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Carpentier, J.-L.
    Department of Morphology, Faculty of Medicine, 1211 Geneva 4, Switzerland, Department of Morphology, Centre Médical Universitaire, 1 Rue Michel-Ser-vet, 1211 Geneva 4, Switzerland.
    P56Lck anchors CD4 to distinct microdomains on microvilli2002In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 4, p. 2008-2013Article in journal (Refereed)
    Abstract [en]

    Cell-surface microvilli play a central role in adhesion, fusion, and signaling processes. Some adhesion and signaling receptors segregate on microvilli but the determinants of this localization remain mostly unknown. In this study, we considered CD4, a receptor involved in immune response and HIV infection, and p56Lck, a CD4-associated tyrosine kinase. Analysis of CD4 trafficking reveals that p56Lck binds tightly to CD4 independently of its activation state and inhibits CD4 internalization. Electron microscopy analysis established that p56Lck mediates CD4 association with microvilli whereas biochemical data indicate that p56Lck expression renders CD4 insoluble by the nonionic detergent Triton X-100. In addition, cytoskeleton-disrupting agent increased CD4 solubility, suggesting the involvement of cytoskeletal elements in CD4 anchoring to microvilli. This concept was supported further by the observation that the lateral mobility of CD4 within the plasma membrane was decreased in cells expressing p56Lck. Finally, isolation of detergent-resistant membranes revealed that the complex CD4-p56Lck is enriched within these domains as opposed to conditions in which CD4 does not interact with p56Lck. In conclusion, our results show that p56Lck targets CD4 to specialized lipid microdomains preferentially localized on microvilli. This localization, which prevents CD4 internalization, might facilitate CD4-mediated adhesion processes and could correspond to the signaling site of the receptor.

  • 23.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, Å.
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Hospital, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Acoustic overstimulation increases outer hair cell Ca2+ concentrations and causes dynamic contractions of the hearing organ1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 12, p. 7127-7132Article in journal (Refereed)
    Abstract [en]

    The dynamic responses of the hearing organ to acoustic overstimulation were investigated using the guinea pig isolated temporal bone preparation. The organ was loaded with the fluorescent Ca2+ indicator Fluo-3, and the cochlear electric responses to low-level tones were recorded through a microelectrode in the scala media. After overstimulation, the amplitude of the cochlear potentials decreased significantly. In some cases, rapid recovery was seen with the potentials returning to their initial amplitude. In 12 of 14 cases in which overstimulation gave a decrease in the cochlear responses, significant elevations of the cytoplasmic [Ca2+] in the outer hair cells were seen. [Ca2+] increases appeared immediately after terminating the overstimulation, with partial recovery taking place in the ensuing 30 min in some preparations. Such [Ca2+] changes were not seen in preparations that were stimulated at levels that did not cause an amplitude change in the cochlear potentials. The overstimulation also gave rise to a contraction, evident as a decrease of the width of the organ of Corti. The average contraction in 10 preparations was 9 microm (SE 2 microm). Partial or complete recovery was seen within 30-45 min after the overstimulation. The [Ca2+] changes and the contraction are likely to produce major functional alterations and consequently are suggested to be a factor contributing strongly to the loss of function seen after exposure to loud sounds.

  • 24.
    Fridberger, Anders
    et al.
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden .
    Tomo, Igor
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Imaging hair cell transduction at the speed of sound: dynamic behavior of mammalian stereocilia2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 6, p. 1918-1923Article in journal (Refereed)
    Abstract [en]

    The cochlea contains two types of sensory cells, the inner and outer hair cells. Sound-evoked deflection of outer hair cell stereocilia leads to fast force production that will enhance auditory sensitivity up to 1,000-fold. In contrast, inner hair cells are thought to have a purely receptive function. Deflection of their stereocilia produces receptor potentials, transmitter release, and action potentials in the auditory nerve. Here, we describe a method for rapid confocal imaging. The method was used to image stereocilia during simultaneous sound stimulation in an in vitro preparation of the guinea pig cochlea. We show that inner hair cell stereocilia move because they interact with the fluid surrounding the hair bundles, but stereocilia deflection occurs at a different phase of the stimulus than is generally expected. In outer hair cells, stereocilia deflections were approximately 1/3 of the reticular lamina displacement. Smaller deflections were found in inner hair cells. The ratio between stereocilia deflection and reticular lamina displacement is important for auditory function, because it determines the stimulus applied to transduction channels. The low ratio measured here suggests that amplification of hair-bundle movements may be necessary in vivo to preserve transduction fidelity at low stimulus levels. In the case of the inner hair cells, this finding would represent a departure from traditional views on their function.

  • 25.
    Hammarström, Per
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Jiang, X.
    Department of Chemistry, Skaggs Inst. for Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road BCC265, San Diego, CA 92037, United States.
    Hurshman, A.R.
    Department of Chemistry, Skaggs Inst. for Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road BCC265, San Diego, CA 92037, United States.
    Powers, E.T.
    Department of Chemistry, Skaggs Inst. for Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road BCC265, San Diego, CA 92037, United States.
    Kelly, J.W.
    Department of Chemistry, Skaggs Inst. for Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road BCC265, San Diego, CA 92037, United States.
    Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity2002In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no SUPPL. 4, p. 16427-16432Conference paper (Other academic)
    Abstract [en]

    Several misfolding diseases commence when a secreted folded protein encounters a partially denaturing microenvironment, enabling its self assembly into amyloid. Although amyloidosis is modulated by numerous environmental and genetic factors, single point mutations within the amyloidogenic protein can dramatically influence disease phenotype. Mutations that destabilize the native state predispose an individual to disease, however, thermodynamic stability alone does not reliably predict disease severity. Here we show that the rate of transthyretin (TTR) tetramer dissociation required for amyloid formation is strongly influenced by mutation (V30M, L55P, T119M, V122I), with rapid rates exacerbating and slow rates reducing amyloidogenicity. Although these rates are difficult to predict a priori, they notably influence disease penetrance and age of onset. L55P TTR exhibits severe pathology because the tetramer both dissociates quickly and is highly destabilized. Even though V30M and L55P TTR are similarly destabilized, the V30M disease phenotype is milder because V30M dissociates more slowly, even slower than wild type (WT). Although WT and V122I TTR have nearly equivalent tetramer stabilities, V122I cardiomyopathy, unlike WT cardiomyopathy, has nearly complete penetrance-presumably because of its 2-fold increase in dissociation rate. We show that the T119M homotetramer exhibits kinetic stabilization and therefore dissociates exceedingly slowly, likely explaining how it functions to protect V30M/T119M compound heterozygotes from disease. An understanding of how mutations influence both the kinetics and thermodynamics of misfolding allows us to rationalize the phenotypic diversity of amyloid diseases, especially when considered in concert with other genetic and environmental data.

  • 26.
    He, Wenxuan
    et al.
    Oregon Health and Science University, Portland, USA.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Porsov, Edward
    Oregon Health and Science University, Portland, USA.
    Grosh, Karl
    University of Michigan, Ann Arbor, MI, USA .
    Ren, Tianying
    Oregon Health and Science University, Portland, USA.
    Reverse wave propagation in the cochlea2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 7, p. 2729-2733Article in journal (Refereed)
    Abstract [en]

    Otoacoustic emissions, sounds generated by the inner ear, are widely used for diagnosing hearing disorders and studying cochlear mechanics. However, it remains unclear how emissions travel from their generation sites to the cochlear base. The prevailing view is that emissions reach the cochlear base via a backward-traveling wave, a slow-propagating transverse wave, along the cochlear partition. A different view is that emissions propagate to the cochlear base via the cochlear fluids as a compressional wave, a fast longitudinal wave. These theories were experimentally tested in this study by measuring basilar membrane (BM) vibrations at the cubic distortion product (DP) frequency from two longitudinal locations with a laser interferometer. Generation sites of DPs were varied by changing frequencies of primary tones while keeping the frequency ratio constant. Here, we show that BM vibration amplitude and phase at the DP frequency are very similar to responses evoked by external tones. Importantly, the BM vibration phase at a basal location leads that at a more apical location, indicating a traveling wave that propagates in the forward direction. These data are in conflict with the backward- traveling-wave theory but are consistent with the idea that the emission comes out of the cochlea predominantly through compressional waves in the cochlear fluids.

  • 27.
    Hedlund, Petter
    et al.
    Lund University Hospital.
    Aszodi, A
    University of Lund.
    Pfeifer, A
    The Salk Institute.
    Alm, P
    Technische Universität, München.
    Hofmann, F
    Technische Universität, München.
    Ahmad, M
    University of Lund.
    Fassler, R
    University of Lund.
    Andersson, KE
    University of Lund.
    Erectile dysfunction in cyclic CMP-dependent kinase I-deficient mice2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 5, p. 2349-2354Article in journal (Refereed)
    Abstract [en]

    The generation of nitric oxide (NO) in penile erectile tissue and the subsequent elevation of cyclic GMP (cGMP) levels are important for normal penile erection. Current treatments of erectile dysfunction elevate either cGMP levels by blocking cGMP degrading phosphodiesterase 5 or cyclic AMP (cAMP) levels by intrapenile injection of prostaglandin E1. The molecular target or targets of cGMP in erectile tissue and the role of cAMP for normal penile erection are not known. Herein, we report that mice lacking cGMP-dependent kinase I (cGKI) have a very low ability to reproduce and that their corpora cavernosa fail to relax on activation of the NO/cGMP signaling cascade. Elevation of cAMP by forskolin, however, induces similar relaxation in normal and cGKI-null corpus cavernosum. In addition, sperm derived from cGKI-null mice is normal, can undergo acrosomal reactions, and can efficiently fertilize eggs. Altogether, these data identify cGKI as the downstream target of cGMP in erectile tissue and provide evidence that cAMP signaling cannot compensate for the absence of the cGMP/cGKI signaling cascade in vivo.

    Penile erection is produced by an increased blood flow to the corpus cavernosum (CC), made possible by opening of penile resistance vessels (helicine arteries), relaxation of the CC cells, and occlusion of the venous outflow (1). The erectile response in several animal models depends on nitric oxide (NO), produced by nerves as well as vascular endothelium (1, 2–4). NO activates soluble guanylate cyclase, which leads to the production of cyclic GMP (cGMP). cGMP signals via three different receptors in eukaryotic cells, including ion channels, phosphodiesterases, and protein kinases (5). At present, however, the molecular targets that are activated by cGMP and finally execute the relaxation of penile smooth muscle are not known. In addition, two different cGMP-dependent protein kinases (cGKI and cGKII) have been identified in mammals (6, 7). cGKII is expressed in the small intestine, brain, and cartilage (8–10), whereas high levels of cGKI are found in vascular and intestinal smooth muscle, platelets, Purkinje cells of the cerebellum, and CC cells (11, 12). Inactivation of cGKI in mice abolished both NO/cGMP-dependent relaxation of vascular and intestinal smooth muscle and inhibition of platelet aggregation, causing hypertension, intestinal dysmotility, and abnormal hemostasis (13). In the present study, we investigated the function of cGKI in erectile tissue and the capability of cGKI-deficient mice to reproduce. Furthermore, we analyzed whether a cross-talk exists between the cGMP and cyclic AMP (cAMP) signaling cascades in smooth muscle (5, 14), i.e., whether cAMP can cause relaxation via cGKI.

  • 28.
    Hedlund, Petter
    et al.
    Clinical Pharmacology, University of Lund, Lund, Sweden.
    Aszódi, Attila
    Experimental Pathology, University of Lund, Lund, Sweden.
    Pfeifer, Alexander
    Laboratory of Genetics, The Salk Institute, La Jolla, CA, USA.
    Alm, Per
    Pathology, University of Lund, Lund, Sweden.
    Hofmann, Franz
    Institut für Pharmakologie und Toxikologie, Technische Universität, München, Germany .
    Ahmad, Marianne
    Experimental Pathology, University of Lund, Lund, Sweden.
    Fässler, Reinhard
    Experimental Pathology, University of Lund, Lund, Sweden.
    Andersson, Karl-Erik
    Clinical Pharmacology, University of Lund, Lund, Sweden.
    Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice.2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 5, p. 2349-2354Article in journal (Refereed)
    Abstract [en]

    The generation of nitric oxide (NO) in penile erectile tissue and the subsequent elevation of cyclic GMP (cGMP) levels are important for normal penile erection. Current treatments of erectile dysfunction elevate either cGMP levels by blocking cGMP degrading phosphodiesterase 5 or cyclic AMP (cAMP) levels by intrapenile injection of prostaglandin E1. The molecular target or targets of cGMP in erectile tissue and the role of cAMP for normal penile erection are not known. Herein, we report that mice lacking cGMP-dependent kinase I (cGKI) have a very low ability to reproduce and that their corpora cavernosa fail to relax on activation of the NO/cGMP signaling cascade. Elevation of cAMP by forskolin, however, induces similar relaxation in normal and cGKI-null corpus cavernosum. In addition, sperm derived from cGKI-null mice is normal, can undergo acrosomal reactions, and can efficiently fertilize eggs. Altogether, these data identify cGKI as the downstream target of cGMP in erectile tissue and provide evidence that cAMP signaling cannot compensate for the absence of the cGMP/cGKI signaling cascade in vivo.

  • 29.
    Henrion, Ulrike
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Renhorn, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Börjesson, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nelson, Erin M
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Schwaiger, Christine S
    Royal Institute of Technology, Sweden .
    Bjelkmar, Par
    Royal Institute of Technology, Sweden Stockholm University, Sweden .
    Wallner, Björn
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Lindahl, Erik
    Royal Institute of Technology, Sweden Stockholm University, Sweden .
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Tracking a complete voltage-sensor cycle with metal-ion bridges2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, p. 8552-8557Article in journal (Refereed)
    Abstract [en]

    Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

  • 30.
    Herbstova, Miroslava
    et al.
    Washington State University, USA Academic Science Czech Republic, Czech Republic University of S Bohemia, Czech Republic .
    Tietz, Stefanie
    Washington State University, USA .
    Kinzel, Christopher
    Washington State University, USA .
    Turkina, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kirchhoff, Helmut
    Washington State University, USA .
    Architectural switch in plant photosynthetic membranes induced by light stress2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 49, p. 20130-20135Article in journal (Refereed)
    Abstract [en]

    Unavoidable side reactions of photosynthetic energy conversion can damage the water-splitting photosystem II (PSII) holocomplex embedded in the thylakoid membrane system inside chloroplasts. Plant survival is crucially dependent on an efficient molecular repair of damaged PSII realized by a multistep repair cycle. The PSII repair cycle requires a brisk lateral protein traffic between stacked grana thylakoids and unstacked stroma lamellae that is challenged by the tight stacking and low protein mobility in grana. We demonstrated that high light stress induced two main structural changes that work synergistically to improve the accessibility between damaged PSII in grana and its repair machinery in stroma lamellae: lateral shrinkage of grana diameter and increased protein mobility in grana thylakoids. It follows that high light stress triggers an architectural switch of the thylakoid network that is advantageous for swift protein repair. Studies of the thylakoid kinase mutant stn8 and the double mutant stn7/8 demonstrate the central role of protein phosphorylation for the structural alterations. These findings are based on the elaboration of mathematical tools for analyzing confocal laser-scanning microscopic images to study changes in the sophisticated thylakoid architecture in intact protoplasts.

  • 31.
    Honek, Jennifer
    et al.
    Karolinska Institute, Sweden.
    Seki, Takahiro
    Karolinska Institute, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Sweden.
    Fischer, Carina
    Karolinska Institute, Sweden.
    Li, Jingrong
    Simcere Pharmaceut Research and Dev, Peoples R China.
    Lim, Sharon
    Karolinska Institute, Sweden.
    Samani, Nilesh J.
    University of Leicester, England; Glenfield Hospital, England.
    Zang, Jingwu
    Simcere Pharmaceut Research and Dev, Peoples R China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden; University of Leicester, England.
    Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 41, p. 14906-14911Article in journal (Refereed)
    Abstract [en]

    Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti-VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.

  • 32.
    Huang, C
    et al.
    Stanford Synchrotron Radiat Lightsource.
    Wikfeldt, K T
    Stockholm University.
    Tokushima, T
    RIKEN SPring 8, Mikazuki, Hyogo, Japan .
    Nordlund, D
    Stanford Synchrotron Radiat Lightsource.
    Harada, Y
    RIKEN SPring 8, Mikazuki, Hyogo Japan .
    Bergmann, U
    Stanford Synchrotron Radiat Lightsource.
    Niebuhr, M
    Stanford Synchrotron Radiat Lightsource.
    Weiss, T M
    Stanford Synchrotron Radiat Lightsource.
    Horikawa, Y
    RIKEN SPring 8, Mikazuki, Hyogo Japan .
    Leetmaa, M
    Stockholm University.
    Ljungberg, M P
    Stockholm University.
    Takahashi, O
    Hiroshima University.
    Lenz, Annika
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Ojamäe, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Physical Chemistry. Linköping University, The Institute of Technology.
    Lyubartsev, A P
    Stockholm University.
    Shin, S
    RIKEN SPring 8, Mikazuki, Hyogo Japan .
    Pettersson, L G M
    Stockholm University.
    Nilsson, A
    Stanford Synchrotron Radiat Lightsource.
    Letter: Reply to Soper et al.: Fluctuations in water around a bimodal distribution of local hydrogen-bonded structural motifs2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 12, p. E45-E45Article in journal (Other academic)
    Abstract [en]

    n/a

  • 33.
    Häggqvist, Bo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Näslund, J
    Sletten, K
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Mucchiano, G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Tjernberg, LO
    Nordstedt, C
    Engström, U
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common form of human amyloid. 1999In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, p. 8669-8674Article in journal (Refereed)
  • 34.
    Ingelsson, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bergh, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Loitto, Vesa-Matti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Spyrou, Giannis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed)
    Abstract [en]

    Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

  • 35.
    Jackson, Walker S
    et al.
    Department of Biology, and Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
    Borkowski, Andrew W
    Department of Biology, and Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
    Watson, Nicki E
    Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
    King, Oliver D
    Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
    Faas, Henryk
    Frances Bitter Magnet Laboratory, Cambridge, MA, 02139, USA.
    Jasanoff, Alan
    Frances Bitter Magnet Laboratory, Cambridge, MA, 02139, USA // Departments of Biological Engineering, Brain and Cognitive Sciences, and Nuclear Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
    Lindquist, Susan
    Department of Biology, and Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
    Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 36, p. 14759-14764Article in journal (Refereed)
    Abstract [en]

    In man, mutations in different regions of the prion protein (PrP) are associated with infectious neurodegenerative diseases that have remarkably different clinical signs and neuropathological lesions. To explore the roots of this phenomenon, we created a knock-in mouse model carrying the mutation associated with one of these diseases [Creutzfeldt-Jakob disease (CJD)] that was exactly analogous to a previous knock-in model of a different prion disease [fatal familial insomnia (FFI)]. Together with the WT parent, this created an allelic series of three lines, each expressing the same protein with a single amino acid difference, and with all native regulatory elements intact. The previously described FFI mice develop neuronal loss and intense reactive gliosis in the thalamus, as seen in humans with FFI. In contrast, CJD mice had the hallmark features of CJD, spongiosis and proteinase K-resistant PrP aggregates, initially developing in the hippocampus and cerebellum but absent from the thalamus. A molecular transmission barrier protected the mice from any infectious prion agents that might have been present in our mouse facility and allowed us to conclude that the diseases occurred spontaneously. Importantly, both models created agents that caused a transmissible neurodegenerative disease in WT mice. We conclude that single codon differences in a single gene in an otherwise normal genome can cause remarkably different neurodegenerative diseases and are sufficient to create distinct protein-based infectious elements.

  • 36.
    Jensen, Lasse Dahl
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Cao, Renhai
    Karolinska Institute, Stockholm, Sweden.
    Hedlund, Eva-Maria
    Karolinska Institute, Stockholm, Sweden.
    Söll, Iris
    Södertörn University and BioNut, Karolinska Institute, Huddinge, Sweden.
    Lundberg, Jon O.
    Karolinska Institute, Stockholm, Sweden.
    Hauptmann, Giselbert
    Södertörn University and BioNut, Karolinska Institute, Huddinge, Sweden.
    Steffensen, John Fleng
    University of Copenhagen, Helsingor, Denmark .
    Cao, Yihai
    Karolinska Institute, Stockholm, Sweden.
    Nitric oxide permits hypoxia-induced lymphatic perfusion by controlling arterial-lymphatic conduits in zebrafish and glass catfish2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 43, p. 18408-18413Article in journal (Refereed)
    Abstract [en]

    The blood and lymphatic vasculatures are structurally and functionally coupled in controlling tissue perfusion, extracellular interstitial fluids, and immune surveillance. Little is known, however, about the molecular mechanisms that underlie the regulation of bloodlymphatic vessel connections and lymphatic perfusion. Here we show in the adult zebrafish and glass catfish (Kryptopterus bicirrhis) that blood-lymphatic conduits directly connect arterial vessels to the lymphatic system. Under hypoxic conditions, arterial-lymphatic conduits (ALCs) became highly dilated and linearized by NO-induced vascular relaxation, which led to blood perfusion into the lymphatic system. NO blockage almost completely abrogated hypoxia-induced ALC relaxation and lymphatic perfusion. These findings uncover mechanisms underlying hypoxia-induced oxygen compensation by perfusion of existing lymphatics in fish. Our results might also imply that the hypoxia-induced NO pathway contributes to development of progression of pathologies, including promotion of lymphatic metastasis by modulating arterial-lymphatic conduits, in the mammalian system.

  • 37.
    Jensen, Lasse
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Brautigam, Lars
    Karolinska Institute, Sweden.
    Li, Xuri
    Sun Yat Sen University, Peoples R China.
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China.
    Samani, Nilesh J.
    University of Leicester, England; Glenfield Hospital, England.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 44, p. E5944-E5953Article in journal (Refereed)
    Abstract [en]

    Physiological functions of vascular endothelial growth factor (VEGF)-B remain an enigma, and deletion of the Vegfb gene in mice lacks an overt phenotype. Here we show that knockdown of Vegfba, but not Vegfbb, in zebrafish embryos by specific morpholinos produced a lethal phenotype owing to vascular and neuronal defects in the brain. Vegfba morpholinos also markedly prevented development of hyaloid vasculatures in the retina, but had little effects on peripheral vascular development. Consistent with phenotypic defects, Vegfba, but not Vegfaa, mRNA was primarily expressed in the brain of developing zebrafish embryos. Interestingly, in situ detection of Neuropilin1 (Nrp1) mRNA showed an overlapping expression pattern with Vegfba, and knockdown of Nrp1 produced a nearly identically lethal phenotype as Vegfba knockdown. Furthermore, zebrafish VEGF-Ba protein directly bound to NRP1. Importantly, gain-of-function by exogenous delivery of mRNAs coding for NRP1-binding ligands VEGF-B or VEGF-A to the zebrafish embryos rescued the lethal phenotype by normalizing vascular development. Similarly, exposure of zebrafish embryos to hypoxia also rescued the Vegfba morpholino-induced vascular defects in the brain by increasing VEGF-A expression. Independent evidence of VEGF-A gain-of-function was provided by using a functionally defective Vhl-mutant zebrafish strain, which again rescued the Vegfba morpholino-induced vascular defects. These findings show that VEGF-B is spatiotemporally required for vascular development in zebrafish embryos and that NRP1, but not VEGFR1, mediates the essential signaling.

  • 38.
    Johan, Katarzyna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Engström, Ulla
    Ludwig Institute for Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Gustavsson, Åsa
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, p. 2558-2563Article in journal (Refereed)
    Abstract [en]

    Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms β-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after ≈25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA–amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

  • 39.
    Jonsson, Amanda
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Inal, Sahika
    Department of Bioelectronics, Ecole Nationale Supérieure des Mines, CMP-EMSE, MOC, Gardanne, France .
    Uguz, Ilke
    Department of Bioelectronics, Ecole Nationale Supérieure des Mines, CMP-EMSE, MOC, Gardanne, France .
    Williamson, Adam
    Aix Marseille Université, INS, Marseille, France; Inserm, UMR_S 1106, Marseille, France.
    Kergoat, Loig
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering. Aix Marseille Université, INS, Marseille, France; Inserm, UMR_S 1106, Marseille, France.
    Rivnay, Jonathan
    Department of Bioelectronics, Ecole Nationale Supérieure des Mines, CMP-EMSE, MOC, Gardanne, France .
    Khodagholy, Dion
    Department of Bioelectronics, Ecole Nationale Supérieure des Mines, CMP-EMSE, MOC, Gardanne, France .
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Bernard, Christophe
    Aix Marseille Université, INS, Marseille, France; Inserm, UMR_S 1106, Marseille, France.
    Malliaras, George G
    Department of Bioelectronics, Ecole Nationale Supérieure des Mines, CMP-EMSE, MOC, Gardanne, France .
    Simon, Daniel T
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 34, p. 9440-9445Article in journal (Refereed)
    Abstract [en]

    Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules at the same site for the most efficient feedback regulation. Here, we address this challenge with an organic electronic multifunctional device that is capable of chemical stimulation and electrical sensing at the same site, at the single-cell scale. Conducting polymer electrodes recorded epileptiform discharges induced in mouse hippocampal preparation. The inhibitory neurotransmitter, γ-aminobutyric acid (GABA), was then actively delivered through the recording electrodes via organic electronic ion pump technology. GABA delivery stopped epileptiform activity, recorded simultaneously and colocally. This multifunctional “neural pixel” creates a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents.

  • 40.
    Jonsson, K.
    et al.
    Jönsson, K., Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
    Guo, B.P.
    Dept. of Microbiol./Molec. Genet., Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, United States.
    Monstein, Hans-Jurg
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Molecular Biological Techniques.
    Mekalanos, J.J.
    Dept. of Microbiol./Molec. Genet., Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, United States.
    Kronvall, G.
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
    Molecular cloning and characterization of two Helicobacter pylori genes coding for plasminogen-binding proteins2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 7, p. 1852-1857Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori binds a number of host cell proteins, including the plasma protein plasminogen, which is the proenzyme of the serine protease plasmin. Two H. pylori plasminogen-binding proteins have been described, however, no genes were identified. Here we report the use of a phage display library to clone two genes from the H. pylori CCUG 17874 genome that mediate binding to plasminogen. DNA sequence analysis of one of these genes revealed 96.6% homology with H. pylori 26695 HP0508. A subsequent database search revealed that the amino acid sequence of a lysine-rich C-terminal segment of HP0508 is identical to the C terminus of HP0863. Recombinant proteins expressed from HP0508 and HP0863 bound plasminogen specifically and in a lysine-dependent manner. We designate these genes pgbA and pgbB, respectively. These proteins are expressed by a variety of H. pylori strains, have surface-exposed domains, and do not inhibit plasminogen activation. These results indicate that pgbA and pgbB may allow H. pylori to coat its exterior with plasminogen, which subsequently can be activated to plasmin. The surface acquisition of protease activity may enhance the virulence of H. pylori.

  • 41.
    Kergoat, Loig
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Herlogsson, Lars
    Thin Film Elect AB, Sweden .
    Piro, Benoit
    University of Paris Diderot Sorbonne Paris Cite, France .
    Chau Pham, Minh
    University of Paris Diderot Sorbonne Paris Cite, France .
    Horowitz, Gilles
    Ecole Polytech, France .
    Crispin, Xavier
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Tuning the threshold voltage in electrolyte-gated organic field-effect transistors2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, p. 8394-8399Article in journal (Refereed)
    Abstract [en]

    Low-voltage organic field-effect transistors (OFETs) promise for low power consumption logic circuits. To enhance the efficiency of the logic circuits, the control of the threshold voltage of the transistors are based on is crucial. We report the systematic control of the threshold voltage of electrolyte-gated OFETs by using various gate metals. The influence of the work function of the metal is investigated in metal-electrolyte-organic semiconductor diodes and electrolyte-gated OFETs. A good correlation is found between the flat-band potential and the threshold voltage. The possibility to tune the threshold voltage over half the potential range applied and to obtain depletion-like (positive threshold voltage) and enhancement (negative threshold voltage) transistors is of great interest when integrating these transistors in logic circuits. The combination of a depletion-like and enhancement transistor leads to a clear improvement of the noise margins in depleted-load unipolar inverters.

  • 42. Kokaia, Merab
    et al.
    Holmberg, Kristina
    Nanobashvili, Avtandil
    Xu, Zhi-Qing
    Kokaia, Zaal
    Lendahl, Urban
    Hilke, Susanne
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry.
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Kahl, Ulrika
    Bartfai, Tamas
    Lindvall, Olle
    Hökfelt, Tomas
    Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin2001In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 98, no 24, p. 14006-14011Article in journal (Refereed)
    Abstract [en]

    The neuropeptide galanin has been shown to suppress epileptic seizures. In cortical and hippocampal areas, galanin is normally mainly expressed in noradrenergic afferents. We have generated a mouse overexpressing galanin in neurons under the platelet-derived growth factor B promoter. RIA and HPLC analysis revealed up to 8-fold higher levels of galanin in transgenic as compared with wild-type mice. Ectopic galanin overexpression was detected especially in dentate granule cells and hippocampal and cortical pyramidal neurons. Galanin-overexpressing mice showed retardation of seizure generalization during hippocampal kindling, a model for human complex partial epilepsy. The high levels of galanin in mossy fibers found in the transgenic mice were further increased after seizures. Frequency facilitation of field excitatory postsynaptic potentials, a form of short-term synaptic plasticity assessed in hippocampal slices, was reduced in mossy fiber-CA3 cell synapses of galanin-overexpressing mice, indicating suppressed glutamate release. This effect was reversed by application of the putative galanin receptor antagonist M35. These data provide evidence that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers.

  • 43.
    Korzhavyi, Pavel A
    et al.
    Royal Institute of Technology.
    Soroka, Inna L
    Royal Institute of Technology.
    Isaev, Eyvas
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, The Institute of Technology.
    Lilja, Christina
    Swedish Nuclear Fuel and Waste Management Co.
    Johansson, Borje
    Royal Institute of Technology.
    Exploring monovalent copper compounds with oxygen and hydrogen2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 3, p. 686-689Article in journal (Refereed)
    Abstract [en]

    New important applications of copper metal, e.g., in the areas of hydrogen production, fuel cell operation, and spent nuclear fuel disposal, require accurate knowledge of the physical and chemical properties of stable and metastable copper compounds. Among the copper(I) compounds with oxygen and hydrogen, cuprous oxide Cu(2)O is the only one stable and the best studied. Other such compounds are less known (CuH) or totally unknown (CuOH) due to their instability relative to the oxide. Here we combine quantum-mechanical calculations with experimental studies to search for possible compounds of monovalent copper. Cuprous hydride (CuH) and cuprous hydroxide (CuOH) are proved to exist in solid form. We establish the chemical and physical properties of these compounds, thereby filling the existing gaps in our understanding of hydrogen- and oxygen-related phenomena in Cu metal.

  • 44.
    Kovacs, Alexander
    et al.
    Atherosclerosis Research group KI.
    Tornvall, Per
    Cardiology Unit KI.
    Nilsson, Roland
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Computational Biology .
    Tegnér, Jesper
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Computational Biology .
    Hamsten, Anders
    Cardiology Unit KI.
    Björkegren, Johan
    Computional Medicine group KI.
    Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 34, p. 13768-13773Article in journal (Refereed)
    Abstract [en]

    Increased baseline values of the acute-phase reactant C-reactive protein (CRP) are significantly associated with future cardiovascular disease, and some in vitro studies have claimed that human CRP (hCRP) has proatherogenic effects. In vivo studies in apolipoprotein E-deficient mouse models, however, have given conflicting results. We bred atherosclerosis-prone mice (Apob 100/100Ldlr-/-), which have human-like hypercholesterolemia, with hCRP transgenic mice (hCRP+/0) and studied lesion development at 15, 30, 40, and 50 weeks of age. Atherosclerotic lesions were smaller in hCRP+/0 Apob100/100Ldlr-/- mice than in hCRP0/0Apob100/100Ldlr-/- controls, as judged from the lesion surface areas of pinned-out aortas from mice at 40 and 50 weeks of age. In lesions from 40-week-old mice, mRNA expression levels of several genes in the proteasome degradation pathway were higher in hCRP +/0Apob100/100Ldlr-/- mice than in littermate controls, as shown by global gene expression profiles. These results were confirmed by real-time PCR, which also indicated that the activities of those genes were the same at 30 and 40 weeks in hCRP+/0Apob 100/100Ldlr-/- mice but were significantly lower at 40 weeks than at 30 weeks in controls. Our results show that hCRP is not proatherogenic but instead slows atherogenesis, possibly through proteasome-mediated protein degradation. © 2007 by The National Academy of Sciences of the USA.

  • 45.
    Kurahashi, Yuko
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Herbertsson, Helena
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderström, Mats
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Rosenfeld, Michael G
    University of California, San Diego, La Jolla, CA, USA.
    Hammarström, Sven
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    A 12(S)-hydroxyeicosatetraenoic acid receptor interacts with steroid receptor coactivator-12000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 11, p. 5779-5783Article in journal (Refereed)
    Abstract [en]

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

  • 46.
    Laiho, Ari
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Herlogsson, Lars
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Forchheimer, Robert
    Linköping University, Department of Electrical Engineering. Linköping University, The Institute of Technology.
    Crispin, Xavier
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Controlling the dimensionality of charge transport in organic thin-film transistors2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 37, p. 15069-15073Article in journal (Refereed)
    Abstract [en]

    Electrolyte-gated organic thin-film transistors (OTFTs) can offer a feasible platform for future flexible, large-area and low-cost electronic applications. These transistors can be divided into two groups on the basis of their operation mechanism: (i) field-effect transistors that switch fast but carry much less current than (ii) the electrochemical transistors which, on the contrary, switch slowly. An attractive approach would be to combine the benefits of the field-effect and the electrochemical transistors into one transistor that would both switch fast and carry high current densities. Here we report the development of a polyelectrolyte-gated OTFT based on conjugated polyelectrolytes, and we demonstrate that the OTFTs can be controllably operated either in the field-effect or the electrochemical regime. Moreover, we show that the extent of electrochemical doping can be restricted to a few monolayers of the conjugated polyelectrolyte film, which allows both high current densities and fast switching speeds at the same time. We propose an operation mechanism based on self-doping of the conjugated polyelectrolyte backbone by its ionic side groups.

  • 47. Lapointe, Jacques
    et al.
    Li, Chunde
    Higgins, John P
    van de Rijn, Matt
    Bair, Eric
    Montgomery, Kelli
    Ferrari, Michelle
    Egevad, Lars
    Rayford, Walter
    Bergerheim, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Ekman, Peter
    DeMarzo, Angelo M
    Tibshirani, Robert
    Botstein, David
    Brown, Patrick O
    Brooks, James D
    Pollack, Jonathan R
    Gene expression profiling identifies clinically relevant subtypes of prostate cancer2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 3, p. 811-816Article in journal (Refereed)
    Abstract [en]

    Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing ≈26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with "aggressive" clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

  • 48.
    Lee, Samantha Lin Chiou
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Rouhi, Pegah
    Karolinska Institute, Stockholm, Sweden.
    Jensen, Lasse Dahl
    Karolinska Institute, Stockholm, Sweden.
    Zhang, Danfang
    Karolinska Institute, Stockholm, Sweden.
    Ji, Hong
    Karolinska Institute, Stockholm, Sweden.
    Hauptmann, Giselbert
    Södertörns University College, Huddinge, Sweden.
    Ingham, Philip
    Institute of Molecular and Cell Biology, A*STAR, Singapore.
    Cao, Yihai
    Karolinska Institute, Stockholm, Sweden.
    Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 46, p. 19485-19490Article in journal (Refereed)
    Abstract [en]

    Mechanisms underlying pathological angiogenesis in relation to hypoxia in tumor invasion and metastasis remain elusive. Here, we have developed a zebrafish tumor model that allows us to study the role of pathological angiogenesis under normoxia and hypoxia in arbitrating early events of the metastatic cascade at the single cell level. Under normoxia, implantation of a murine T241 fibrosarcoma into the perivitelline cavity of developing embryos of transgenic fli1:EGFP zebrafish did not result in significant dissemination, invasion, and metastasis. In marked contrast, under hypoxia substantial tumor cells disseminated from primary sites, invaded into neighboring tissues, and metastasized to distal parts of the fish body. Similarly, expression of the hypoxia-regulated angiogenic factor, vascular endothelial growth factor (VEGF) to a high level resulted in tumor cell dissemination and metastasis, which correlated with increased tumor neovascularization. Inhibition of VEGF receptor signaling pathways by sunitinib or VEGFR2 morpholinos virtually completely ablated VEGF-induced tumor cell dissemination and metastasis. To the best of our knowledge, hypoxia- and VEGF-induced pathological angiogenesis in promoting tumor dissemination, invasion, and metastasis has not been described perviously at the single cell level. Our findings also shed light on molecular mechanisms of beneficial effects of clinically available anti-VEGF drugs for cancer therapy.

  • 49.
    Li, Fengfu
    et al.
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and National Research Council, Ottawa, Ontario, Canada.
    Carlsson, David
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and National Research Council, Ottawa, Ontario, Canada.
    Lohmann, Chris
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and Universitäts-Augenklinik, University of Regensburg, Regensburg, Germany.
    Suuronen, Erik
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Vascotto, Sandy
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Kobuch, Karin
    Universitäts-Augenklinik, University of Regensburg, Regensburg, Germany.
    Sheardown, Heather
    Department of Chemical Engineering, McMaster University, Hamilton, Ontario, Canada.
    Munger, Rejean
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Nakamura, Masatsugu
    Santen Pharmaceutical Company, Ltd., Ikoma-Shi, Japan .
    Griffith, May
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Cellular and nerve regeneration within a biosynthetic extracellular matrix for corneal transplantation2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 26, p. 15346-15351Article in journal (Refereed)
    Abstract [en]

    Our objective was to determine whether key properties of extracellular matrix (ECM) macromolecules can be replicated within tissue-engineered biosynthetic matrices to influence cellular properties and behavior. To achieve this, hydrated collagen and N-isopropylacrylamide copolymer-based ECMs were fabricated and tested on a corneal model. The structural and immunological simplicity of the cornea and importance of its extensive innervation for optimal functioning makes it an ideal test model. In addition, corneal failure is a clinically significant problem. Matrices were therefore designed to have the optical clarity and the proper dimensions, curvature, and biomechanical properties for use as corneal tissue replacements in transplantation. In vitro studies demonstrated that grafting of the laminin adhesion pentapeptide motif, YIGSR, to the hydrogels promoted epithelial stratification and neurite in-growth. Implants into pigs corneas demonstrated successful in vivo regeneration of host corneal epithelium, stroma, and nerves. In particular, functional nerves were observed to rapidly regenerate in implants. By comparison, nerve regeneration in allograft controls was too slow to be observed during the experimental period, consistent with the behavior of human cornea transplants. Other corneal substitutes have been produced and tested, but here we report an implantable matrix that performs as a physiologically functional tissue substitute and not simply as a prosthetic device. These biosynthetic ECM replacements should have applicability to many areas of tissue engineering and regenerative medicine, especially where nerve function is required.

  • 50.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Silverå Ejneby, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Barro-Soria, Rene
    University of Miami, FL 33136 USA.
    Alexander Skarsfeldt, Mark
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Larsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Starck Härlin, Frida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Miami, FL 33136 USA.
    Parkkari, Teija
    University of Eastern Finland, Finland.
    Hjorth Bentzen, Bo
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Schmitt, Nicole
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Peter Larsson, H.
    University of Miami, FL 33136 USA.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 18, p. 5714-5719Article in journal (Refereed)
    Abstract [en]

    Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the beta-subunit KCNE1 form the cardiac I-Ks channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as I-Ks channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pK(a) value, to preserve their negative charge at neutral pH, restore the sensitivity to open I-Ks channels. PUFA analogs with a positively charged head group inhibit I-Ks channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.

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