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  • Evolving targets for lipid‐modifying therapy
    1. Rose Q Do1,,
    2. Stephen J Nicholls2 and
    3. Gregory G Schwartz*,1,
    1. 1VA Medical Center, University of Colorado School of Medicine, Denver, CO, USA
    2. 2South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, SA, Australia
    1. *Corresponding author. Tel: +1 303 393 2826; Fax: +1 303 393 5054; E‐mail: Gregory.Schwartz{at}va.gov
    1. This article has been contributed to by US Government employees and their work is in the public domain in the USA

    This review article summarizes existing and emerging therapeutic strategies to modify all types of lipoproteins, whose concentration and function are critical in the progression of atherosclerosis.

    • atherosclerosis
    • cholesterol
    • lipoproteins
    • triglycerides
    • Received April 28, 2014.
    • Revision received June 26, 2014.
    • Accepted July 23, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Rose Q Do, Stephen J Nicholls, Gregory G Schwartz
  • The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer
    1. Alice Melotti1,,
    2. Christophe Mas1,,
    3. Monika Kuciak1,,
    4. Aiala Lorente‐Trigos1,
    5. Isabel Borges1 and
    6. Ariel Ruiz i Altaba*,1
    1. 1Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
    1. *Corresponding author. Tel: +41 22 379 5646; E‐mail: Ariel.RuizAltaba{at}unige.ch
    1. Equal first authorship

    A repositioning screen of clinically approved compounds for WNT‐TCF blockers reveals selective activity in the anti‐parasitic Avermectin macrocyclic lactone family.

    Synopsis

    A repositioning screen of clinically approved compounds for WNT‐TCF blockers reveals selective activity in the anti‐parasitic Avermectin macrocyclic lactone family.

    • The EMEA‐ and FDA‐approved drug Ivermectin is an active WNT‐TCF response blocker in human cancer, mimicking dominant‐negative TCF. Ivermectin blocks human cancer xenograft growth.

    • Initial exploration of Avermectin single molecule derivatives shows that Selamectin is 10 times more potent than Ivermectin, suggesting its clinical testing.

    • Ivermectin and Selamectin show selective anti‐WNT‐TCF activities at low concentrations and these are rescued by direct activation of TCF.

    • Ivermectin is a widely used anti‐parasitic drug with a great safety profile suggesting its additional use to treat WNT‐TCF‐dependent diseases, notably including multiple cancers.

    • cancer
    • Ivermectin
    • TCF
    • WNT
    • xenograft
    • Received March 18, 2014.
    • Revision received July 14, 2014.
    • Accepted July 15, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Alice Melotti, Christophe Mas, Monika Kuciak, Aiala Lorente‐Trigos, Isabel Borges, Ariel Ruiz i Altaba
  • Insulin‐like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice
    1. Maria Pascual‐Lucas1,
    2. Silvia Viana da Silva2,
    3. Marianna Di Scala3,
    4. Carolina Garcia‐Barroso1,
    5. Gloria González‐Aseguinolaza3,
    6. Christophe Mulle2,
    7. Cristina M Alberini4,
    8. Mar Cuadrado‐Tejedor1,5 and
    9. Ana Garcia‐Osta*,1
    1. 1Neurosciences Division, Center for Applied Medical Research, CIMA University of Navarra, Pamplona, Spain
    2. 2Interdisciplinary Institute for Neuroscience, Université of Bordeaux CNRS UMR 5297, Bordeaux, France
    3. 3Gene Therapy and Hepatology Division, Center for Applied Medical Research CIMA University of Navarra, Pamplona, Spain
    4. 4Center for Neural Science, New York University, New York, NY, USA
    5. 5Department of Anatomy, School of Medicine University of Navarra, Pamplona, Spain
    1. *Corresponding author. Tel: +1 34 948 19 47 00 (2023); Fax: +1 34 948 19 47 15; E‐mail: agosta{at}unav.es

    An important role for hippocampal insulin‐like growth factor II (IGF2) was reported for brain plasticity, learning and memory. This study exploits this finding by reporting the role of IGF2 in the pathogenesis of Alzheimer´s disease and suggests a possible strategy for therapeutic use.

    Synopsis

    An important role for hippocampal insulin‐like growth factor II (IGF2) was reported for brain plasticity, learning and memory. This study exploits this finding by reporting the role of IGF2 in the pathogenesis of Alzheimer´s disease and suggests a possible strategy for therapeutic use.

    • Hippocampal IGF2 levels are decreased with aging and in pathological conditions related to AD.

    • IGF2 overexpression in the hippocampus of aged mice enhances memory and prevents dendritic spine loss in CA1 hippocampal neurons.

    • IGF2 overexpression in the hippocampus of AD mice reverse memory and synaptic deficits and prevents dendritic spine loss in CA1 hippocampal neurons.

    • IGF2 receptor is involved in the extracellular Aβ degradation and suggests that IGF2R may be involved in the Aβ clearance observed in IGF2‐treated Tg2576 mice.

    • Alzheimer's disease
    • IGF1
    • IGF2
    • IGF2R
    • synaptic plasticity
    • Received May 7, 2014.
    • Revision received July 11, 2014.
    • Accepted July 16, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Maria Pascual‐Lucas, Silvia Viana da Silva, Marianna Di Scala, Carolina Garcia‐Barroso, Gloria González‐Aseguinolaza, Christophe Mulle, Cristina M Alberini, Mar Cuadrado‐Tejedor, Ana Garcia‐Osta
  • Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno‐associated virus capsid and promoter
    1. Therese Cronin*,1,2,
    2. Luk H Vandenberghe1,3,
    3. Péter Hantz2,
    4. Josephine Juttner2,
    5. Andreas Reimann2,
    6. Ágota–Enikő Kacsó4,
    7. Rachel M Huckfeldt1,
    8. Volker Busskamp2,5,
    9. Hubertus Kohler2,
    10. Pamela S Lagali2,6,
    11. Botond Roska2 and
    12. Jean Bennett*,1
    1. 1Center for Advanced Retinal and Ophthalmic Therapeutics, F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA
    2. 2Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    3. 3Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    4. 4Faculty of Physics, Babes‐Bolyai University, Cluj‐Napoca, Romania
    5. 5Genetics Department, Harvard Medical School, Boston, MA, USA
    6. 6Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
    1. * Corresponding author. Tel: +1 215 898 0915; E‐mail: jebennet{at}mail.med.upenn.edu

      Corresponding author. Tel: +41 61 69 78681; E‐mail: therese.cronin{at}fmi.ch

    An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind rd1 mice.

    Synopsis

    An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind rd1 mice.

    • A synthetic AAV capsid and modified bipolar‐cell specific promoter were developed to enhance transgene expression in retinal bipolar cells.

    • The new virus transduced at least 59% of ON‐bipolar cells in mouse retina.

    • In the blind rd1 mouse the virus was used to drive expression of optogenetic channels at levels high enough to elicit strong and robust spiking responses from the ganglion cells.

    • This new virus‐promoter combination is thus presented as a candidate vector for clinical intervention in advanced forms of retinal degeneration.

    • adeno‐associated virus
    • capsid library
    • multi‐electrode array
    • optogenetics
    • promoter optimization
    • Received March 17, 2014.
    • Revision received July 4, 2014.
    • Accepted July 7, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Therese Cronin, Luk H Vandenberghe, Péter Hantz, Josephine Juttner, Andreas Reimann, Ágota–Enikő Kacsó, Rachel M Huckfeldt, Volker Busskamp, Hubertus Kohler, Pamela S Lagali, Botond Roska, Jean Bennett
  • Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross‐tolerance
    1. Vincent Flacher1,24,
    2. Christoph H Tripp1,2,
    3. David G Mairhofer1,
    4. Ralph M Steinman3,
    5. Patrizia Stoitzner*,1,,
    6. Juliana Idoyaga35 and
    7. Nikolaus Romani*,1,2,
    1. 1Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria
    2. 2Oncotyrol Center for Personalized Cancer Medicine, Innsbruck, Austria
    3. 3Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA
    4. 4Laboratory of Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, CNRS UPR3572 Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
    5. 5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
    1. * Corresponding author. Tel: +43 512 504 28559; Fax: +43 512 504 67 28559; E‐mail: nikolaus.romani{at}i-med.ac.at

      Corresponding author. Tel: +43 512 504 23016; Fax: +43 512 504 67 28592; E‐mail: patrizia.stoitzner{at}i-med.ac.at

    1. These authors contributed equally to this work.

    The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo. Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.

    Synopsis

    The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo. Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.

    • Both Langerin+ dermal DCs and epidermal Langerhans cells (LC) can present exogenous antigen to CD8+ T cells.

    • Langerin+ dermal DCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8+ T‐cell priming.

    • Specific adjuvants can be used to independently harness the different potential of distinct DC subsets simultaneously targeted by an antigen.

    • Treatment of skin with imiquimod, an agonist of TLR7, does not result in potent immune responses when the antigen is targeted to Langerin, thereby relativizing the paradigm stating that mature DCs always promote immunity.

    • CD8+ T‐cell responses
    • dendritic cells
    • Langerhans cells
    • skin
    • tolerance
    • Received July 12, 2013.
    • Revision received July 4, 2014.
    • Accepted July 8, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Vincent Flacher, Christoph H Tripp, David G Mairhofer, Ralph M Steinman, Patrizia Stoitzner, Juliana Idoyaga, Nikolaus Romani
  • Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa
    1. Yael Pewzner‐Jung*,1,
    2. Shaghayegh Tavakoli Tabazavareh2,
    3. Heike Grassmé2,
    4. Katrin Anne Becker2,
    5. Lukasz Japtok3,
    6. Jörg Steinmann4,
    7. Tammar Joseph1,
    8. Stephan Lang5,
    9. Burkhard Tuemmler6,
    10. Edward H Schuchman7,
    11. Alex B Lentsch8,
    12. Burkhard Kleuser3,
    13. Michael J Edwards8,
    14. Anthony H Futerman1 and
    15. Erich Gulbins*,2,8
    1. 1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
    2. 2Department of Molecular Biology, University Hospital Essen, University of Duisburg‐Essen, Essen, Germany
    3. 3Department of Nutritional Science, University of Potsdam, Potsdam, Germany
    4. 4Department of Microbiology, University Hospital Essen, University of Duisburg‐Essen, Essen, Germany
    5. 5Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg‐Essen, Essen, Germany
    6. 6Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany
    7. 7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    8. 8Department of Surgery, University of Cincinnati, Cincinnati, OH, USA
    1. * Corresponding author. Tel: +49 201 723 3118; Fax: 49 201 723 5974; E‐mail: erich.gulbins{at}uni-due.de

      Corresponding author. Tel: +972 8 9343256; Fax: +972 8 9344112; E‐mail: yael.pewzner-jung{at}weizmann.ac.il

    Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase.

    Synopsis

    Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase.

    • Sphingosine is present on the luminal side of trachea and bronchi epithelia in healthy individuals.

    • Sphingosine level is reduced on trachea and bronchi epithelia in diseases such as cystic fibrosis or in mice lacking ceramide synthase 2.

    • Acid ceramidase or sphingosine inhalation corrects sphingosine levels in cystic fibrosis and ceramide synthase 2‐deficient mice, prevents their infection with Pseudomonas aeruginosa and cures an existing Pseudomonas aeruginosa infection.

    • Sphingosine kills a broad spectrum of pathogens at nanomolar to low micromolar concentrations including Pseudomomas aeruginosa, Acinetobacter baumannii, Haemophilus influenzae, Moraxella catarrhalis and Burkholderia cepacia.

    • cystic fibrosis
    • long chain base
    • lung infection
    • Pseudomonas aeruginosa
    • sphingosine
    • Received March 17, 2014.
    • Revision received July 10, 2014.
    • Accepted July 11, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Yael Pewzner‐Jung, Shaghayegh Tavakoli Tabazavareh, Heike Grassmé, Katrin Anne Becker, Lukasz Japtok, Jörg Steinmann, Tammar Joseph, Stephan Lang, Burkhard Tuemmler, Edward H Schuchman, Alex B Lentsch, Burkhard Kleuser, Michael J Edwards, Anthony H Futerman, Erich Gulbins
  • Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB
    1. Vinicia A Polito1,,
    2. Hongmei Li1,,
    3. Heidi Martini‐Stoica1,2,3,,
    4. Baiping Wang1,4,
    5. Li Yang1,
    6. Yin Xu1,
    7. Daniel B Swartzlander1,
    8. Michela Palmieri4,5,
    9. Alberto di Ronza4,5,
    10. Virginia M‐Y Lee6,
    11. Marco Sardiello4,5,
    12. Andrea Ballabio4,5,7 and
    13. Hui Zheng*,1,3,4
    1. 1Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA
    2. 2Interdepartmental Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
    3. 3Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
    4. 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    5. 5Dan and Jan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
    6. 6Department of Pathology and Lab Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    7. 7Department of Translational Medical Sciences, Section of Pediatrics, Telethon Institute of Genetics and Medicine Federico II University, Naples, Italy
    1. *Corresponding author. Tel: +1 713 798 1568; Fax: +1 713 798 1610; E‐mail: huiz{at}bcm.edu
    1. These authors contributed equally to this work

    The autophagy and lysosomal Transcription Factor EB (TFEB) reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the Tau mouse model. This effect requires lysosomal activity and in vitro evidence highlight PTEN as a TFEB‐target.

    Synopsis

    The autophagy and lysosomal Transcription Factor EB (TFEB) reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the Tau mouse model. This effect requires lysosomal activity and in vitro evidence highlight PTEN as a TFEB‐target.

    • TFEB specifically targets aberrant tau proteins.

    • TFEB potently clears NFT pathology and rescues neurotoxicity in a tauopathy mouse model.

    • PTEN is a novel target of TFEB.

    • Upregulation of PTEN and lysosomal activity may underlie the TFEB effects.

    • Alzheimer's disease
    • tauopathy
    • TFEB
    • PTEN
    • autophagy‐lysosomal pathway
    • Received November 14, 2013.
    • Revision received June 26, 2014.
    • Accepted June 30, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Vinicia A Polito, Hongmei Li, Heidi Martini‐Stoica, Baiping Wang, Li Yang, Yin Xu, Daniel B Swartzlander, Michela Palmieri, Alberto di Ronza, Virginia M‐Y Lee, Marco Sardiello, Andrea Ballabio, Hui Zheng