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  • 1
    Publication Date: 2011-08-02
    Description: Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Welz, Patrick-Simon -- Wullaert, Andy -- Vlantis, Katerina -- Kondylis, Vangelis -- Fernandez-Majada, Vanesa -- Ermolaeva, Maria -- Kirsch, Petra -- Sterner-Kock, Anja -- van Loo, Geert -- Pasparakis, Manolis -- England -- Nature. 2011 Jul 31;477(7364):330-4. doi: 10.1038/nature10273.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genetics, Centre for Molecular Medicine, University of Cologne, Zulpicher Str. 47a, 50674 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21804564" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Chronic Disease ; Colitis/enzymology/metabolism/*pathology ; Colon/enzymology/metabolism/*pathology ; Cysteine Endopeptidases/metabolism ; Enteritis/enzymology/metabolism/*pathology ; Epithelial Cells/enzymology/metabolism/*pathology ; Fas-Associated Death Domain Protein/deficiency/*metabolism ; Inflammatory Bowel Diseases/enzymology/metabolism/pathology ; Intracellular Signaling Peptides and Proteins/deficiency/metabolism ; Metagenome/physiology ; Mice ; Myeloid Differentiation Factor 88/deficiency/metabolism ; Necrosis ; Paneth Cells/pathology ; Receptor-Interacting Protein Serine-Threonine Kinases/*antagonists & ; inhibitors/*metabolism ; Signal Transduction ; Tumor Necrosis Factors/deficiency
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-06-24
    Description: More than half of the world's population now lives in cities, making the creation of a healthy urban environment a major policy priority. Cities have both health risks and benefits, but mental health is negatively affected: mood and anxiety disorders are more prevalent in city dwellers and the incidence of schizophrenia is strongly increased in people born and raised in cities. Although these findings have been widely attributed to the urban social environment, the neural processes that could mediate such associations are unknown. Here we show, using functional magnetic resonance imaging in three independent experiments, that urban upbringing and city living have dissociable impacts on social evaluative stress processing in humans. Current city living was associated with increased amygdala activity, whereas urban upbringing affected the perigenual anterior cingulate cortex, a key region for regulation of amygdala activity, negative affect and stress. These findings were regionally and behaviourally specific, as no other brain structures were affected and no urbanicity effect was seen during control experiments invoking cognitive processing without stress. Our results identify distinct neural mechanisms for an established environmental risk factor, link the urban environment for the first time to social stress processing, suggest that brain regions differ in vulnerability to this risk factor across the lifespan, and indicate that experimental interrogation of epidemiological associations is a promising strategy in social neuroscience.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lederbogen, Florian -- Kirsch, Peter -- Haddad, Leila -- Streit, Fabian -- Tost, Heike -- Schuch, Philipp -- Wust, Stefan -- Pruessner, Jens C -- Rietschel, Marcella -- Deuschle, Michael -- Meyer-Lindenberg, Andreas -- England -- Nature. 2011 Jun 22;474(7352):498-501. doi: 10.1038/nature10190.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, 68159 Mannheim, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21697947" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/*physiology ; Anxiety Disorders/epidemiology ; *Cities/epidemiology ; Gyrus Cinguli/*physiology ; Humans ; Hydrocortisone/blood ; *Life Style ; Magnetic Resonance Imaging ; Mental Health/statistics & numerical data ; Models, Neurological ; Mood Disorders/epidemiology ; Rural Health/statistics & numerical data ; Sample Size ; Schizophrenia/epidemiology ; Stress, Psychological/blood/epidemiology/*physiopathology ; Time Factors ; Urban Health/statistics & numerical data ; Urbanization
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-08-19
    Description: Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206266/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dannappel, Marius -- Vlantis, Katerina -- Kumari, Snehlata -- Polykratis, Apostolos -- Kim, Chun -- Wachsmuth, Laurens -- Eftychi, Christina -- Lin, Juan -- Corona, Teresa -- Hermance, Nicole -- Zelic, Matija -- Kirsch, Petra -- Basic, Marijana -- Bleich, Andre -- Kelliher, Michelle -- Pasparakis, Manolis -- R01 AI075118/AI/NIAID NIH HHS/ -- R01AI075118/AI/NIAID NIH HHS/ -- T32 AI095213/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Sep 4;513(7516):90-4. doi: 10.1038/nature13608. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2]. ; Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Tierforschungszentrum, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany. ; Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany. ; 1] Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132550" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Apoptosis ; Caspase 8/metabolism ; Cell Survival ; Epithelial Cells/*cytology/metabolism/*pathology ; Fas-Associated Death Domain Protein/deficiency/metabolism ; Female ; *Homeostasis ; Inflammation/metabolism/pathology ; Intestines/cytology/metabolism/pathology ; Keratinocytes/metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Myeloid Differentiation Factor 88/metabolism ; *Necrosis ; Paneth Cells/metabolism/pathology ; Receptor-Interacting Protein Serine-Threonine ; Kinases/deficiency/genetics/*metabolism ; Receptors, Tumor Necrosis Factor, Type I/deficiency/metabolism ; Skin/cytology/metabolism/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
  • 5
    Keywords: ANGIOGENESIS ; CELLS ; EXPRESSION ; INVASION ; MODEL ; GENE-EXPRESSION ; PROTEIN ; transcription ; LINES ; NERVOUS-SYSTEM ; FUSION PROTEINS ; MAMMALIAN-CELLS ; HeLa cells ; SODIUM-BUTYRATE ; western blot ; GENE- EXPRESSION ; hrGFP ; K562 CELLS ; live cell fluorescence microscopy ; PCR analysis ; stable transfection
    Abstract: The green fluorescent protein (GFP), obtained from Aequorea victoria, is widely used in transfection experiments to study the dynamics and characteristics of gene expression in a non- invasive manner. However, generation of cell lines displaying long-term expression of the GFP protein has repeatedly been reported unsuccessful. In the present study a different marker protein, humanized GFP (hrGFP) obtained from a sea pansy, Renilla reniformis, was used for transfection, and the time course of protein expression was studied by live cell fluorescence microscopy, PCR technology, and immunoblotting. HeLa cells were transfected with a plasmid, phrGFP-IRES-Neo containing the neomycin cassette and the hrGFP gene together with an internal ribosome entry site (IRES) sequence under the control of a CMV promotor. Cells were selected for three weeks after transfection using G418. During this time, hrGFP fluorescence was highest around day 4 and decreased thereafter eventually disappearing until the end of the selection period. In parallel, the proportion of cells staining positive for propidium iodide (i.e. dead cells) increased steadily. Three weeks after transfection non-fluorescent clones were present throughout. A couple of clones were subcultured for another week and used for further analyses. PCR methodology revealed the insertion of the hrGFP into the HeLa genome and the presence of mRNA species coding for hrGFP following reverse transcription. However, immunoblot analysis failed to show expression of the protein. These observations suggest a down- regulation of hrGFP expression at both transcriptional and post-transcriptional levels similar to results previously obtained with GFP. Thus, use of hrGFP does not appear to offer an advantage over GFP in transfection experiments aiming at permanent expression of the marker protein
    Type of Publication: Journal article published
    PubMed ID: 12872990
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  • 6
    Abstract: Background: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression. Methods: We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects. Results: Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER I. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward. Conclusion: Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes
    Type of Publication: Journal article published
    PubMed ID: 20673876
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  • 7
    ISSN: 1433-0407
    Keywords: Schlüsselwörter Alexithymie ; Entkopplungshypothese ; Key words Alexithymia ; Elektrodermal activity ; Decoupling hypothesis ; Dissociation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary The theoretical background of the present investigation was the decoupling hypothesis of alexithymia, which presumes for alexithymic individuals a dissociation of psychophysiological indicators of emotion from verbal cognitive awareness of one’s emotional state. To study alterations in reactivity to emotionally distressing stimuli in alexithymic individuals, 12 high-alexithymic and 14 low-alexithymic subjects (separated by TAS) out of a general sample of 54 were investigated. All subjects were exposed to cognitive (CPT) and affect inductive (film sequences) distress. During stimulus exposition electrodermal activity (sponateous fluctuations) was recorded. After stimulus exposition the subjects assessed their emotional reaction towards the film sequences (DAS). Concerning electrodermal activity no differences were found between high and low alexithymics under cognitive distress. In any case a significant autonomous arousal was registered. However, only the low alexithymic subjects but not the high alexithymics showed a significant increase of spontaneous fluctuations as expression of autonomous arousal during presentation of affect inductive stimuli. The altered psychophysiological reactivity found in high alexithymics in contrast to low alexithymic subjects was revealed specifically for the processing of emotional qualified stimuli. However, there was no difference between the groups in cognitive self assessment of emotional response towards the film sequences. The findings are discussed with reference to neurophysiological and psychodynamic models and the decoupling hypothesis of alexithymia.
    Notes: Zusammenfassung Theoretischer Hintergrund dieser Untersuchung ist die sog. Entkopplungshypothese der Alexithymie. Diese postuliert für alexithyme Individuen eine Dissoziation psychophysiologischer Aktivierungsprozesse und des subjektiven Affekterlebens speziell unter affektinduktiven Belastungen. 12 hochalexithyme und 14 niedrigalexithyme Probanden aus einer Gesamtstichprobe von 54 Individuen wurden bezüglich der elektrodermaler Spontanfluktuationsrate unter affektneutraler (Reiz-Reaktions-Aufgabe) und affektinduktiver Stimulierung (Videofilme) untersucht. Ihr Affekterleben während der Filmbetrachtung schätzten die Probanden selbst ein. Unter kognitiver Belastung bestanden hinsichtlich der elektrodermalen Aktivierung keine Gruppenunterschiede. Es kam in jedem Falle zu einem signifikanten Anstieg der Spontanfluktuationsrate. Unter affektinduktiver Belastung kam es jedoch nur bei den Niedrigalexithymen nicht aber bei den hochalexithymen Probanden zu einem signifikanten Anstieg der Spontanfluktuationsrate als Ausdruck einer autonomen Aktivierung. In der Bewertung ihres reizbezogenen Affekterlebens unterschieden sich die Gruppen nicht. Diese Befunde sind in Übereinstimmung mit der Entkopplungshypothese, und werden im Hinblick auf neuropsychologische und psychodynamisch-interaktionsdynamische Modellvorstellungen diskutiert.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 90 (2001), S. 4256-4264 
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Chemical and thermal reduction of copper oxide thin films (∼20 Å) has been studied with x-ray photoelectron spectroscopy (XPS) and temperature programmed desorption (TPD) for application in microelectronic device interconnects. XPS showed that copper (I) oxide (Cu2O) and copper (II) oxide (CuO) were reduced to copper metal at 400 K within a 30 min exposure to deuterium atoms (D*) and molecules at 1×10−4 Torr. Similarly, XPS showed that Cu2O was reduced to copper metal at 400 K within a 30 min exposure to methyl radicals (CH3*) and acetone molecules at 1×10−4 Torr. After D* exposure, TPD showed O leaves the Cu2O surface as D2O from 400 K to 700 K with a peak desorption temperature of 510 K. After CH3* exposure, TPD showed O leaves the Cu2O surface as CO2 over a range from 400 to 700 K with a peak temperature at 590 K. With carbon impurity below the XPS detection limit, thermal reduction of CuO to Cu2O was verified by XPS near 890 K. TPD experiments showed that O leaves the CuO surface as O2 at 890 K. Without surface C, thermal reduction of Cu2O was not observed up to 1073 K. Reduction of Cu2O without reactive radical species (D* or CH3*) was negligible. These results suggest that thin films of copper oxide can be reduced at 400 K with D* and CH3*. © 2001 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Journal of Organometallic Chemistry 29 (1971), S. 269-274 
    ISSN: 0022-328X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0022-328X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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