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  • 1
    Publication Date: 2011-07-02
    Description: Mucolipidosis II is a severe lysosomal storage disorder caused by defects in the alpha and beta subunits of the hexameric N-acetylglucosamine-1-phosphotransferase complex essential for the formation of the mannose 6-phosphate targeting signal on lysosomal enzymes. Cleavage of the membrane-bound alpha/beta-subunit precursor by an unknown protease is required for catalytic activity. Here we found that the alpha/beta-subunit precursor is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. S1P-deficient cells failed to activate the alpha/beta-subunit precursor and exhibited a mucolipidosis II-like phenotype. Thus, S1P functions in the biogenesis of lysosomes, and lipid-independent phenotypes of S1P deficiency may be caused by lysosomal dysfunction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marschner, Katrin -- Kollmann, Katrin -- Schweizer, Michaela -- Braulke, Thomas -- Pohl, Sandra -- New York, N.Y. -- Science. 2011 Jul 1;333(6038):87-90. doi: 10.1126/science.1205677.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21719679" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CHO Cells ; Cell Line ; Cholesterol/*metabolism ; Chondrocytes/cytology ; Cricetinae ; Cricetulus ; Enzyme Precursors/chemistry/*metabolism ; HeLa Cells ; Humans ; Lipid Metabolism ; Lysosomes/enzymology/*metabolism/ultrastructure ; Mannosephosphates/metabolism ; Mice ; Morphogenesis ; Mucolipidoses/enzymology/genetics/metabolism/pathology ; N-Acetylgalactosamine-4-Sulfatase/metabolism ; Osteogenesis ; Proprotein Convertases/genetics/*metabolism ; Protein Subunits/chemistry/metabolism ; RNA, Small Interfering ; Serine Endopeptidases/genetics/*metabolism ; Transferases (Other Substituted Phosphate Groups)/chemistry/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-09-03
    Description: The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and gamma-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Refojo, Damian -- Schweizer, Martin -- Kuehne, Claudia -- Ehrenberg, Stefanie -- Thoeringer, Christoph -- Vogl, Annette M -- Dedic, Nina -- Schumacher, Marion -- von Wolff, Gregor -- Avrabos, Charilaos -- Touma, Chadi -- Engblom, David -- Schutz, Gunther -- Nave, Klaus-Armin -- Eder, Matthias -- Wotjak, Carsten T -- Sillaber, Inge -- Holsboer, Florian -- Wurst, Wolfgang -- Deussing, Jan M -- New York, N.Y. -- Science. 2011 Sep 30;333(6051):1903-7. doi: 10.1126/science.1202107. Epub 2011 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Psychiatry, Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21885734" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/metabolism ; Animals ; *Anxiety ; Behavior, Animal ; Corticotropin-Releasing Hormone/metabolism ; Dopamine/*metabolism ; Fear ; Glutamic Acid/*metabolism ; Hippocampus/metabolism ; Male ; Memory ; Mesencephalon ; Mice ; Mice, Knockout ; Motor Activity ; Neurons/*metabolism ; Prefrontal Cortex/metabolism ; Prosencephalon/cytology/metabolism ; Receptors, Corticotropin-Releasing Hormone/antagonists & ; inhibitors/genetics/*metabolism ; Synaptic Transmission ; Ventral Tegmental Area/metabolism ; gamma-Aminobutyric Acid/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-11-16
    Description: The geographic and temporal origins of the domestic dog remain controversial, as genetic data suggest a domestication process in East Asia beginning 15,000 years ago, whereas the oldest doglike fossils are found in Europe and Siberia and date to 〉30,000 years ago. We analyzed the mitochondrial genomes of 18 prehistoric canids from Eurasia and the New World, along with a comprehensive panel of modern dogs and wolves. The mitochondrial genomes of all modern dogs are phylogenetically most closely related to either ancient or modern canids of Europe. Molecular dating suggests an onset of domestication there 18,800 to 32,100 years ago. These findings imply that domestic dogs are the culmination of a process that initiated with European hunter-gatherers and the canids with whom they interacted.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thalmann, O -- Shapiro, B -- Cui, P -- Schuenemann, V J -- Sawyer, S K -- Greenfield, D L -- Germonpre, M B -- Sablin, M V -- Lopez-Giraldez, F -- Domingo-Roura, X -- Napierala, H -- Uerpmann, H-P -- Loponte, D M -- Acosta, A A -- Giemsch, L -- Schmitz, R W -- Worthington, B -- Buikstra, J E -- Druzhkova, A -- Graphodatsky, A S -- Ovodov, N D -- Wahlberg, N -- Freedman, A H -- Schweizer, R M -- Koepfli, K-P -- Leonard, J A -- Meyer, M -- Krause, J -- Paabo, S -- Green, R E -- Wayne, R K -- New York, N.Y. -- Science. 2013 Nov 15;342(6160):871-4. doi: 10.1126/science.1243650.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Section of Genetics and Physiology, University of Turku, Itainen Pitkakatu 4, 20014 Turku, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24233726" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Domestic/*genetics ; Base Sequence ; Breeding ; Dogs/*genetics ; Europe ; Genome, Mitochondrial/*genetics ; Molecular Sequence Data ; Phylogeny ; Wolves/genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Unknown
    German Medical Science GMS Publishing House; Düsseldorf
    In:  79. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20080430-20080504; Bonn; DOC08hnod404 /20080422/
    Publication Date: 2008-04-21
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 5
    Abstract: BACKGROUND: The non-pathogenic course of SIV infection in its natural host is characterized by robust viral replication in the absence of chronic immune activation and T cell proliferation. In contrast, acutely lethal enteropathic SIVsmm strain PBj induces a strong immune activation and causes a severe acute and lethal disease in pig-tailed macaques after cross-species transmission. One important pathogenicity factor of the PBj virus is the PBj-Nef protein, which contains a conserved diacidic motif and, unusually, an immunoreceptor tyrosine-based activation motif (ITAM). RESULTS: Mutation of the diacidic motif in the Nef protein of the SIVsmmPBj abolishes the acute phenotype of this virus. In vitro, wild-type and mutant PBj (PBj-Nef202/203GG) viruses replicated to similar levels in macaque PBMCs, but PBj-Nef202/203GG no longer triggers ERK mitogen-activated protein (MAP) kinase pathway including an alteration of a Nef-associated Raf-1/ERK-2 multiprotein signaling complex. Moreover, stimulation of IL-2 and down-modulation of CD4 and CD28 were impaired in the mutant virus. Pig-tailed macaques infected with PBj-Nef202/203GG did not show enteropathic complications and lethality as observed with wild-type PBj virus, despite efficient replication of both viruses in vivo. Furthermore, PBj-Nef202/203GG infected animals revealed reduced T-cell activation in periphery lymphoid organs and no detectable induction of IL-2 and IL-6. CONCLUSIONS: In sum, we report here that mutation of the diacidic motif in the PBj-Nef protein abolishes disease progression in pig-tailed macaques despite efficient replication. These data suggest that alterations in the ability of a lentivirus to promote T cell activation and proliferation can have a dramatic impact on its pathogenic potential.
    Type of Publication: Journal article published
    PubMed ID: 21366921
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  • 6
    Keywords: brain ; hormone ; BEHAVIOR ; MICE LACKING ; CORTICOTROPIN-RELEASING-FACTOR ; ANXIETY ; CRF ; FACTOR RECEPTOR 1-DEFICIENT ; I-H ; IMPAIRED STRESS-RESPONSE
    Abstract: The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and gamma-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.
    Type of Publication: Journal article published
    PubMed ID: 21885734
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  • 7
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    Unknown
    German Medical Science; Düsseldorf, Köln
    In:  100 Jahre Phoniatrie in Deutschland; 22. Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie, 24. Kongress der Union der Europäischen Phoniater; 20050916-20050918; Berlin; DOC05dgppV17 /20050915/
    Publication Date: 2005-09-16
    Description: Durch den erhöhten Anteil von Kindern, die schon sehr früh zur Hördiagnostik vorgestellt werden, konnten wir in den letzten Jahren insgesamt 25 Kinder beobachten, bei denen trotz regelrechter Mittelohrverhältnisse zunächst in der Hirnstammaudiometrie und in der subjektiven Audiometrie erhöhte Hörschwellen vorlagen, die sich dann aber, in der Regel innerhalb des ersten Lebensjahres, normalisierten.Wir führten jetzt eine Nachuntersuchung durch, um festzustellen, ob Kinder mit einer Hörbahnreifungsverzögerung ein erhöhtes Risiko einer Sprachentwicklungsstörung haben.Es wurden 10 Kinder nachuntersucht, die zwischen 1999 und 2002 in unserer Klinik wegen einer Hörbahnreifungsverzögerung behandelt wurden und jetzt eine normale Innenohrfunktion aufwiesen. Von den 10 Kindern waren drei Kinder sprachlich auffällig. Lediglich ein Kind, welches zusätzlich therapieresistente Paukenergüsse bei einer Lippen-Kiefer-Gaumenspalte aufwies und zweisprachig aufwächst, litt im Deutschen unter einer Sprachentwicklungsstörung. Das zweite Kind zeigte lediglich eine deutlich eingeschränkte Hörgedächtnisspanne. Ein drittes Kind war wegen einer partiellen Dyslalie in logopädischer Behandlung.Zusammenfassend scheinen Kinder mit Hörbahnreifungsverzögerung kein erhöhtes Risiko einer Sprachentwicklungsstörung zu tragen. Ob es daran liegt, dass die passagere frühkindliche Hörstörung keine relevante Verzögerung der Sprachentwicklung bewirkt, oder die sensibilisierten Eltern ihrem Kind besonders viel Aufmerksamkeit widmen und es verstärkt fördern, ist offen.
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 8
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    Unknown
    German Medical Science GMS Publishing House; Düsseldorf
    In:  83. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20120516-20120520; Mainz; DOC12hnod475 /20120404/
    Publication Date: 2012-04-05
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 9
    facet.materialart.
    Unknown
    German Medical Science GMS Publishing House; Düsseldorf
    In:  Dreiländertagung D-A-CH, 24. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie e.V.; 20070928-20070930; Innsbruck, Österreich; DOC07dgppV32 /20070828/
    Publication Date: 2007-08-29
    Description: Hintergrund: Die vorliegende Literatur stützt die Auffassung, dass die Prozesse der Hör- und Sprachentwicklung hörgeschädigter Kinder um so besser verlaufen, je früher die Implantation erfolgt. Um dies zu belegen, führt die Klinik in Kooperation mit MED-EL ein Projekt zum frühen Spracherwerb bei früh implantierten Kindern durch. Methode: Vier bilateral mit einem Cochlea Implantat (CI) versorgte Kinder (Alter 0;09-1;05 Jahr;Monat) und fünf normal hörende Kinder (NH) im Alter von 0;04-0;05 Jahr;Monat wurden in die Studie aufgenommen. Ausgangspunkt der Untersuchung bildete eine semi-standardisierte Spielsituation zwischen Kind und einer Bezugsperson. Ergänzend erhielten die Eltern Fragebögen zur Hör- und Sprachentwicklung ihres Kindes. Analyse: Von jeder Videoaufnahme wurden jeweils 10 Minuten mit ELAN (EUDICO Linguistic Annotator) ausgewertet. Die Äußerungen der Mutter und die des Kindes wurden auf der Grundlage von GAT (Gesprächsanalytisches Transkriptionssystem) und IPA (Internationales Phonetisches Alphabet) analysiert. Vorläufige Ergebnisse: CI und NH-Kinder verfügen in jedem Lebensalter über ähnliche Fähigkeiten in der Produktion von Konsonanten. Bei der Betrachtung der expressiven und rezeptiven Sprachleistungen nähern sich die CI-Kinder den hörenden Kindern an. Die Ergebnisse weisen darauf hin, dass früh implantierte Kinder ihre verbalen Defizite im Vergleich zu normal hörenden Kindern aufholen können, wenn eine frühzeitige Erkennung und zeitnahe Versorgung mit einem CI erfolgt.
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 10
    Publication Date: 2018-11-08
    Description: WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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