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  • 1
    Publication Date: 2013-11-01
    Description: Atopic dermatitis is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. Although the pathogenesis of atopic dermatitis is not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis. Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence. More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis. However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified delta-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by delta-toxin depended on phosphoinositide 3-kinase and calcium (Ca(2+)) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced delta-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of delta-toxin. Skin colonization with S. aureus, but not a mutant deficient in delta-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by delta-toxin was abrogated in Kit(W-sh/W-sh) mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify delta-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090780/" 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/PMC4090780/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakamura, Yuumi -- Oscherwitz, Jon -- Cease, Kemp B -- Chan, Susana M -- Munoz-Planillo, Raul -- Hasegawa, Mizuho -- Villaruz, Amer E -- Cheung, Gordon Y C -- McGavin, Martin J -- Travers, Jeffrey B -- Otto, Michael -- Inohara, Naohiro -- Nunez, Gabriel -- R01 AR059688/AR/NIAMS NIH HHS/ -- R01AR059688/AR/NIAMS NIH HHS/ -- R01HL062996/HL/NHLBI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Nov 21;503(7476):397-401. doi: 10.1038/nature12655. Epub 2013 Oct 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24172897" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Toxins/*metabolism/pharmacology ; Calcium Signaling/drug effects ; *Cell Degranulation/drug effects ; Culture Media, Conditioned/pharmacology ; Dermatitis, Atopic/immunology/metabolism/*microbiology/pathology ; Female ; Immunoglobulin E/biosynthesis/immunology ; Inflammation/immunology/metabolism/microbiology/pathology ; Interleukin-4/immunology ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Mast Cells/*cytology/drug effects ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Protein-Tyrosine Kinases/metabolism ; Proto-Oncogene Proteins c-kit/genetics/metabolism ; Staphylococcus aureus/metabolism/*pathogenicity
    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: 2016-01-28
    Description: Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1beta and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations. Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli. Despite extensive investigation, the molecular mechanism leading to NLRP3 activation in response to potassium efflux remains unknown. Here we report the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL-1beta release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the CAPS-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimaeras reconstituted with wild-type, Nek7(-/-) or Nlrp3(-/-) haematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. These studies demonstrate that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Yuan -- Zeng, Melody Y -- Yang, Dahai -- Motro, Benny -- Nunez, Gabriel -- R01AI063331/AI/NIAID NIH HHS/ -- R01DK091191/DK/NIDDK NIH HHS/ -- T32 HL007517/HL/NHLBI NIH HHS/ -- T32DK094775/DK/NIDDK NIH HHS/ -- T32HL007517/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Feb 18;530(7590):354-7. doi: 10.1038/nature16959. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814970" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/deficiency/genetics/metabolism ; Biocatalysis ; Carrier Proteins/chemistry/genetics/*metabolism ; Caspase 1/metabolism ; Catalytic Domain ; Cells, Cultured ; Cryopyrin-Associated Periodic Syndromes/genetics ; Enzyme Activation ; HEK293 Cells ; Humans ; Inflammasomes/*chemistry/*metabolism ; Interleukin-1beta/secretion ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Potassium/*metabolism ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/chemistry/deficiency/genetics/*metabolism
    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: 2012-05-15
    Description: The virulence mechanisms that allow pathogens to colonize the intestine remain unclear. Here, we show that germ-free animals are unable to eradicate Citrobacter rodentium, a model for human infections with attaching and effacing bacteria. Early in infection, virulence genes were expressed and required for pathogen growth in conventionally raised mice but not germ-free mice. Virulence gene expression was down-regulated during the late phase of infection, which led to relocation of the pathogen to the intestinal lumen where it was outcompeted by commensals. The ability of commensals to outcompete C. rodentium was determined, at least in part, by the capacity of the pathogen and commensals to grow on structurally similar carbohydrates. Thus, pathogen colonization is controlled by bacterial virulence and through competition with metabolically related commensals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439148/" 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/PMC3439148/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kamada, Nobuhiko -- Kim, Yun-Gi -- Sham, Ho Pan -- Vallance, Bruce A -- Puente, Jose L -- Martens, Eric C -- Nunez, Gabriel -- DK091191/DK/NIDDK NIH HHS/ -- DK61707/DK/NIDDK NIH HHS/ -- R01 DK061707/DK/NIDDK NIH HHS/ -- R01 DK091191/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2012 Jun 8;336(6086):1325-9. doi: 10.1126/science.1222195. Epub 2012 May 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22582016" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Load ; Bacterial Proteins/genetics/metabolism ; Bacteroides/*growth & development ; Citrobacter rodentium/genetics/growth & development/immunology/*pathogenicity ; Enterobacteriaceae Infections/immunology/*microbiology ; Escherichia coli/*growth & development ; Feces/microbiology ; Gene Expression Regulation, Bacterial ; Germ-Free Life ; Intestinal Mucosa/*microbiology ; Intestines/*microbiology ; *Metagenome ; Mice ; Mice, Inbred C57BL ; *Microbial Interactions ; Specific Pathogen-Free Organisms ; Virulence Factors/genetics/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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  • 4
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2012-09-18
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340476/" 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/PMC4340476/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Franchi, Luigi -- Nunez, Gabriel -- R01 DK091191/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2012 Sep 14;337(6100):1299-300. doi: 10.1126/science.1229010.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22984056" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CARD Signaling Adaptor Proteins/genetics/*metabolism ; Calcium-Binding Proteins/genetics/*metabolism ; Enzyme Activation ; Gram-Negative Bacteria/*immunology ; Gram-Negative Bacterial Infections/enzymology/*immunology ; Humans ; Inflammasomes/*metabolism ; Mice ; Mice, Mutant Strains ; Mutation ; Phosphorylation ; Protein Kinase C-delta/*metabolism ; Serine/genetics/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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  • 5
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Hb Lepore is one of the most common abnormal haemoglobins in Caucasians in Central Portugal and in the Spanish Alta Extremadura (0.28% in a survey of school children). A group of 19 Portuguese and 14 Spanish Hb Lepore carriers (all unrelated) was characterised at the molecular level by the polymerase chain reaction, sequencing and restriction enzyme analysis. The Portuguese and one Spanish carrier were heterozygous for Hb Lepore-Baltimore, whereas all other Spanish subjects were Hb Lepore-Washington-Boston carriers. Sequencing of the Hb Lepore-Baltimore gene further established the crossover at δ68-β84, a region two codons (CDs) shorter than that previously described and easily confirmed by digestion with MaeI and BanI. Data from haplotype analysis suggest that this crossover occurred as an independent event on the lberian Peninsula. The haematological data were similar in both groups except for the levels of Hb F and the Gγ chain, which were significantly higher in the Hb Lepore-Baltimore heterozygotes. Quantification of the globin chains and the mRNA transcripts showed that the δβ gene is transcribed at a higher level than the δ gene with levels of translation giving rise to 10%–15% of Hb Lepore. The different levels of Hb F observed in the two groups are the results of the higher transcription rate of the γ genes in Hb Lepore-Baltimore heterozygotes and an apparently less efficient translation of Gγ genes in Hb Lepore-Washington-Boston heterozygotes.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1588-2837
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Abstract После обработки водородом при высокой температуре наблюдалось уменьшение водородной хемосорбции при комнатной температуре почти для всех элементов VIII группы, нанесенных на SiO2 или Al2O3. Этот эффект приписывается самоингибированию сильно хемосорбированного водорода на металлах.
    Notes: Abstract Following hydrogen treatments at high temperature a decrease in hydrogen chemisorption at room temperature is observed in almost all group VIII elements supported on SiO2 or Al2O3. The effect is attributed to self inhibition by strongly chemisorbed hydrogen on the metals.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Three monoclonal antibodies (63D3, 63D2, and 61D3) with reactivity against human monocytes have been studied. They reacted with most adherent mononuclear cells but not with pure populations of peripheral blood B and T lymphocytes. Two of these antibodies, 63D3 and 63D2, competed in fluorescence inhibition experiments, recognized a monocyte surface antigem of about 200,000 daltons, and werre idiotypically related. The third antibody, 61D3, did not compete with the others in fluorescence inhibition experiments, recognized a different surface molecule, and was idiotypically distinct from 63D3 and 63D2. Whereas 63D3 and 63D2 reacted very weakly with some granulucytes, 61D3 did not, suggesting that it is specific for monocytes alone.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1955
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Antisurface newborn larva (NBL) antibodies (Abs) were found in sera from individuals chronically infected with Trichinella spiralis. These Abs were incapable of inducing NBL death by activation of normal human leukocytes of peripheral blood as determined by in vitro assays of antibody-dependent cell cytotoxicity (ADCC). Besides, such sera blocked the cytotoxic reaction mediated by Abs produced a few weeks after infection. The blocking activity could not be attributed to any particular isotype by the indirect immunofluorescence technique. Purified antisurface NBL Abs obtained from sera from chronically infected patients recognized antigens of muscle-larva excretory-secretory products (ML-ESP) in an enzyme-linked immunosorbent assay (ELISA) and an immunoelectrotransfer blot assay. Likewise, as did chronic sera, a monoclonal Ab raised against ML-ESP blocked NBL death in ADCC assays. These results suggest that during the course of an infection by T. spiralis, Abs related to ML-ESP provide an immunoevasive mechanism for avoidance by NBL of an important anti-NBL host effector mechanism.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Trends in Cell Biology 4 (1994), S. 399-403 
    ISSN: 0962-8924
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 10
    Publication Date: 2018-07-10
    Description: There is increasing evidence that proton-coupled oligopeptide transporters (POTs) can transport bacterially derived chemotactic peptides and therefore reside at the critical interface of innate immune responses and regulation. However, there is substantial contention regarding how these bacterial peptides access the cytosol to exert their effects and which POTs are involved in facilitating this process. Thus, the current study proposed to determine the (sub)cellular expression and functional activity of POTs in macrophages derived from mouse bone marrow and to evaluate the effect of specific POT deletion on the production of inflammatory cytokines in wild-type, Pept2 knockout and Pht1 knockout mice. We found that PEPT2 and PHT1 were highly expressed and functionally active in mouse macrophages, but PEPT1 was absent. The fluorescent imaging of muramyl dipeptide–rhodamine clearly demonstrated that PEPT2 was expressed on the plasma membrane of macrophages, whereas PHT1 was expressed on endosomal membranes. Moreover, both transporters could significantly influence the effect of bacterially derived peptide ligands on cytokine stimulation, as shown by the reduced responses in Pept2 knockout and Pht1 knockout mice as compared with wild-type animals. Taken as a whole, our results point to PEPT2 (at plasma membranes) and PHT1 (at endosomal membranes) working in concert to optimize the uptake of bacterial ligands into the cytosol of macrophages, thereby enhancing the production of proinflammatory cytokines. This new paradigm offers significant insight into potential drug development strategies along with transporter-targeted therapies for endocrine, inflammatory, and autoimmune diseases.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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