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  1. Article: Inhalable siRNA: potential as a therapeutic agent in the lungs.

    Durcan, Niamh / Murphy, Charlotte / Cryan, Sally-Ann

    Molecular pharmaceutics

    2008  Volume 5, Issue 4, Page(s) 559–566

    Abstract: RNA interference (RNAi) is gaining increasing popularity both as a molecular biology tool and as a potential therapeutic agent. RNAi is a naturally occurring gene regulatory mechanism, which has a number of advantages over other gene/antisense therapies ... ...

    Abstract RNA interference (RNAi) is gaining increasing popularity both as a molecular biology tool and as a potential therapeutic agent. RNAi is a naturally occurring gene regulatory mechanism, which has a number of advantages over other gene/antisense therapies including specificity of inhibition, potency, the small size of the molecules and the diminished risk of toxic effects, e.g., immune responses. Targeted, local delivery of RNAi to the lungs via inhalation offers a unique opportunity to treat a range of previously untreatable or poorly controlled respiratory conditions. In this timely review we look at the potential applications of RNAi in the lungs for the treatment of a range of diseases including inflammatory and immune conditions, cystic fibrosis, infectious disease and cancer. In 2006 Alnylam initiated the first phase 1 clinical study of an inhaled siRNA for the treatment of respiratory syncytial virus. If its potential as a therapeutic is to be realized, then safe and efficient means of targeted delivery of small interfering RNA (siRNA) to the lungs must be developed. Therefore in this review we also present the latest developments in siRNA delivery to airway cells in vitro and the work to date on in vivo delivery of siRNA to the lungs for the treatment of a range of diseases.
    MeSH term(s) Administration, Inhalation ; Animals ; Genetic Therapy ; Genetic Vectors/genetics ; Humans ; Lung Diseases/genetics ; Lung Diseases/therapy ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/genetics ; RNA, Small Interfering/therapeutic use ; Titrimetry
    Chemical Substances RNA, Small Interfering
    Keywords covid19
    Language English
    Publishing date 2008-07
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/mp070048k
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Eosinophil-induced release of acetylcholine from differentiated cholinergic nerve cells.

    Sawatzky, Deborah A / Kingham, Paul J / Durcan, Niamh / McLean, W Graham / Costello, Richard W

    American journal of physiology. Lung cellular and molecular physiology

    2003  Volume 285, Issue 6, Page(s) L1296–304

    Abstract: One immunological component of asthma is believed to be the interaction of eosinophils with parasympathetic cholinergic nerves and a consequent inhibition of acetylcholine muscarinic M2 receptor activity, leading to enhanced acetylcholine release and ... ...

    Abstract One immunological component of asthma is believed to be the interaction of eosinophils with parasympathetic cholinergic nerves and a consequent inhibition of acetylcholine muscarinic M2 receptor activity, leading to enhanced acetylcholine release and bronchoconstriction. Here we have used an in vitro model of cholinergic nerve function, the human IMR32 cell line, to study this interaction. IMR32 cells, differentiated in culture for 7 days, expressed M2 receptors. Cells were radiolabeled with [3H]choline and electrically stimulated. The stimulation-induced release of acetylcholine was prevented by the removal of Ca2+. The muscarinic M1/M2 receptor agonist arecaidine reduced the release of acetylcholine after stimulation (to 82 +/- 2% of control at 10(-7) M), and the M2 receptor antagonist AF-DX 116 increased it (to 175 +/- 23% of control at 10(-5) M), indicating the presence of a functional M2 receptor that modulated acetylcholine release. When human eosinophils were added to IMR32 cells, they enhanced acetylcholine release by 36 +/- 10%. This effect was prevented by inhibitors of adhesion of the eosinophils to the IMR32 cells. Pretreatment of IMR32 cells with 10 mM carbachol, to desensitize acetylcholine receptors, prevented the potentiation of acetylcholine release by eosinophils or AF-DX 116. Acetylcholine release was similarly potentiated (by up to 45 +/- 7%) by degranulation products from eosinophils that had been treated with N-formyl-methionyl-leucyl-phenylalanine or that had been in contact with IMR32 cells. Contact between eosinophils and IMR32 cells led to an initial increase in expression of M2 receptors, whereas prolonged exposure reduced M2 receptor expression.
    MeSH term(s) Acetylcholine/metabolism ; Asthma/immunology ; Asthma/metabolism ; Cell Communication/immunology ; Cell Differentiation ; Cell Line, Tumor ; Choline/pharmacokinetics ; Cholinergic Fibers/metabolism ; Eosinophils/metabolism ; Gene Expression/immunology ; Humans ; Neuroblastoma ; Neurons/cytology ; Neurons/immunology ; Neurons/metabolism ; Parasympathetic Nervous System/cytology ; Parasympathetic Nervous System/immunology ; Parasympathetic Nervous System/metabolism ; Receptor, Muscarinic M2/genetics ; Receptor, Muscarinic M2/metabolism ; Tritium
    Chemical Substances Receptor, Muscarinic M2 ; Tritium (10028-17-8) ; Choline (N91BDP6H0X) ; Acetylcholine (N9YNS0M02X)
    Language English
    Publishing date 2003-08-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00107.2003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Diverse effects of eosinophil cationic granule proteins on IMR-32 nerve cell signaling and survival.

    Morgan, Ross K / Costello, Richard W / Durcan, Niamh / Kingham, Paul J / Gleich, Gerald J / McLean, W Graham / Walsh, Marie-Therese

    American journal of respiratory cell and molecular biology

    2005  Volume 33, Issue 2, Page(s) 169–177

    Abstract: Activated eosinophils release potentially toxic cationic granular proteins, including the major basic proteins (MBP) and eosinophil-derived neurotoxin (EDN). However, in inflammatory conditions including asthma and inflammatory bowel disease, ... ...

    Abstract Activated eosinophils release potentially toxic cationic granular proteins, including the major basic proteins (MBP) and eosinophil-derived neurotoxin (EDN). However, in inflammatory conditions including asthma and inflammatory bowel disease, localization of eosinophils to nerves is associated with nerve plasticity, specifically remodeling. In previous in vitro studies, we have shown that eosinophil adhesion to IMR-32 nerve cells, via nerve cell intercellular adhesion molecule-1, results in an adhesion-dependent release of granule proteins. We hypothesized that released eosinophil granule proteins may affect nerve cell signaling and survival, leading to nerve cell remodeling. Culture in serum-deprived media induced apoptosis in IMR-32 cells that was dose-dependently abolished by inclusion of MBP1 but not by EDN. Both MBP1 and EDN induced phosphorylation of Akt, but with divergent time courses and intensities, and survival was independent of Akt. MBP1 induced activation of neural nuclear factor (NF)-kappaB, from 10 min to 12 h, declining by 24 h, whereas EDN induced a short-lived activation of NF-kappaB. MBP1-induced protection was dependent on phosphorylation of ERK 1/2 and was related to a phospho-ERK-dependent upregulation of the NF-kappaB-activated anti-apoptotic gene, Bfl-1. This signaling pathway was not activated by EDN. Thus, MBP1 released from eosinophils at inflammatory sites may regulate peripheral nerve plasticity by inhibiting apoptosis.
    MeSH term(s) Apoptosis/drug effects ; Apoptosis/genetics ; Base Sequence ; Cell Line ; Cell Survival/drug effects ; DNA, Complementary/genetics ; Eosinophil Major Basic Protein/pharmacology ; Eosinophil-Derived Neurotoxin/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Minor Histocompatibility Antigens ; NF-kappa B/metabolism ; Neurons/cytology ; Neurons/drug effects ; Neurons/physiology ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-bcl-2/genetics ; Signal Transduction/drug effects ; Up-Regulation/drug effects
    Chemical Substances BCL2-related protein A1 ; DNA, Complementary ; Minor Histocompatibility Antigens ; NF-kappa B ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; AKT1 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Eosinophil-Derived Neurotoxin (EC 3.1.-) ; Eosinophil Major Basic Protein (EC 3.1.27.-)
    Language English
    Publishing date 2005-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2005-0056OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Mechanism of eosinophil induced signaling in cholinergic IMR-32 cells.

    Curran, David R / Morgan, Ross K / Kingham, Paul J / Durcan, Niamh / McLean, W Graham / Walsh, Marie Therese / Costello, Richard W

    American journal of physiology. Lung cellular and molecular physiology

    2004  Volume 288, Issue 2, Page(s) L326–32

    Abstract: Eosinophils interact with nerve cells, leading to changes in neurotransmitter release, altered nerve growth, and protection from cytokine-induced apoptosis. In part, these interactions occur as a result of activation of neural nuclear factor (NF)-kappaB, ...

    Abstract Eosinophils interact with nerve cells, leading to changes in neurotransmitter release, altered nerve growth, and protection from cytokine-induced apoptosis. In part, these interactions occur as a result of activation of neural nuclear factor (NF)-kappaB, which is activated by adhesion of eosinophils to neural intercellular adhesion molecule-1 (ICAM-1). The mechanism and consequence of signaling after eosinophil adhesion to nerve cells were investigated. Eosinophil membranes, which contain eosinophil adhesion molecules but not other eosinophil products, were coincubated with IMR-32 cholinergic nerve cells. The studies showed that there were two mechanisms of activation of NF-kappaB, one of which was dependent on reactive oxygen species, since it was inhibited with diphenyleneiodonium. This occurred at least 30 min after coculture of eosinophils and nerves. An earlier phase of NF-kappaB activation occurred within 2 min of eosinophil adhesion and was mediated by tyrosine kinase-dependent phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1). Coimmunoprecipitation experiments showed that both extracellular signal-regulated kinase 1/2 and IRAK-1 were recruited to ICAM-1 rapidly after coculture with eosinophil membranes. This was accompanied by an induction of ICAM-1, which was mediated by an IRAK-1-dependent pathway. These data indicate that adhesion of eosinophils to IMR-32 nerves via ICAM-1 leads to important signaling events, mediated via IRAK-1, and these in turn lead to expression of adhesion molecules.
    MeSH term(s) Cell Adhesion/physiology ; Cells, Cultured ; Cholinergic Fibers ; Coculture Techniques ; Eosinophils/physiology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Immunoprecipitation ; Intercellular Adhesion Molecule-1/metabolism ; Interleukin-1 Receptor-Associated Kinases ; NF-kappa B/metabolism ; Neurons/metabolism ; Oxidative Stress/physiology ; Protein Kinases/metabolism ; Protein-Tyrosine Kinases/metabolism ; Signal Transduction/physiology ; Up-Regulation
    Chemical Substances NF-kappa B ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Protein Kinases (EC 2.7.-) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Interleukin-1 Receptor-Associated Kinases (EC 2.7.11.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2004-10-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00254.2004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Eosinophil-mediated cholinergic nerve remodeling.

    Durcan, Niamh / Costello, Richard W / McLean, W Graham / Blusztajn, Jan / Madziar, Beata / Fenech, Anthony G / Hall, Ian P / Gleich, Gerard J / McGarvey, Lorcan / Walsh, Marie-Therese

    American journal of respiratory cell and molecular biology

    2006  Volume 34, Issue 6, Page(s) 775–786

    Abstract: Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling. ...

    Abstract Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling. We hypothesized that a consequence of eosinophil localization to cholinergic nerves would involve a neural remodeling process. Eosinophil co-culture with cholinergic IMR32 cells led to increased expression of the M2 muscarinic receptor, with this induction being mediated via an adhesion-dependent release of eosinophil proteins, including major basic protein and nerve growth factor. Studies on the promoter sequence of the M2 receptor indicated that this induction was initiated at a transcription start site 145 kb upstream of the gene-coding region. This promoter site contains binding sites for a variety of transcription factors including SP1, AP1, and AP2. Eosinophils also induced the expression of several cholinergic genes involved in the synthesis, storage, and metabolism of acetylcholine, including the enzymes choline acetyltransferase, vesicular acetylcholine transferase, and acetylcholinesterase. The observed eosinophil-induced changes in enzyme content were associated with a reduction in intracellular neural acetylcholine but an increase in choline content, suggesting increased acetylcholine turnover and a reduction in acetylcholinesterase activity, in turn suggesting reduced catabolism of acetylcholine. Together these data suggest that eosinophil localization to cholinergic nerves induces neural remodeling, promoting a cholinergic phenotype.
    MeSH term(s) Acetylcholine/metabolism ; Acetylcholinesterase/genetics ; Acetylcholinesterase/metabolism ; Cell Adhesion ; Cell Line, Tumor ; Choline O-Acetyltransferase/genetics ; Choline O-Acetyltransferase/metabolism ; Coculture Techniques ; Eosinophil Granule Proteins/metabolism ; Eosinophils/metabolism ; Gene Expression Regulation ; Humans ; Nerve Growth Factor/metabolism ; Neurons/enzymology ; Neurons/metabolism ; Paracrine Communication ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; Receptor, Muscarinic M2/biosynthesis ; Receptor, Muscarinic M2/genetics ; Receptor, Muscarinic M2/metabolism ; Transcription Initiation Site ; Vesicular Acetylcholine Transport Proteins/genetics ; Vesicular Acetylcholine Transport Proteins/metabolism
    Chemical Substances Eosinophil Granule Proteins ; RNA, Messenger ; Receptor, Muscarinic M2 ; SLC18A3 protein, human ; Vesicular Acetylcholine Transport Proteins ; Nerve Growth Factor (9061-61-4) ; Choline O-Acetyltransferase (EC 2.3.1.6) ; Acetylcholinesterase (EC 3.1.1.7) ; Acetylcholine (N9YNS0M02X)
    Language English
    Publishing date 2006-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2005-0196OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Effect of eosinophil adhesion on intracellular signaling in cholinergic nerve cells.

    Walsh, Marie-Thérèse / Curran, David R / Kingham, Paul J / Morgan, Ross K / Durcan, Niamh / Gleich, Gerald J / McLean, W Graham / Costello, Richard W

    American journal of respiratory cell and molecular biology

    2004  Volume 30, Issue 3, Page(s) 333–341

    Abstract: Eosinophil localization to cholinergic nerves occurs in a variety of inflammatory conditions, including asthma. This localization is mediated by interactions between eosinophil integrins and neuronal vascular cell adhesion molecule-1 (VCAM-1) and ... ...

    Abstract Eosinophil localization to cholinergic nerves occurs in a variety of inflammatory conditions, including asthma. This localization is mediated by interactions between eosinophil integrins and neuronal vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Eosinophil-nerve cell interactions lead to generation of neuronal reactive oxygen species and release of eosinophil proteins. The effects of eosinophil adhesion on neuronal intracellular signaling pathways were investigated. Eosinophil adhesion to IMR32 cholinergic nerves led to a rapid and sustained activation of the nuclear transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 in the nerve cells. Eosinophil binding to neuronal ICAM-1 led to a rapid activation of ERK1/2 in nerve cells. Inhibition of ERK1/2 prevented NF-kappaB activation. Eosinophil adhesion to VCAM-1 resulted in AP-1 activation, mediated partially by rapid activation of the p38 mitogen-activated protein kinase. These data show that adhesion of eosinophils induces mitogen-activated protein kinase-dependent activation of the transcription factors NF-kappaB and AP-1 in nerve cells, indicating that eosinophil adhesion may control nerve growth and phenotype.
    MeSH term(s) Acetylcholine/metabolism ; Cell Adhesion/physiology ; Cell Survival ; Eosinophils/metabolism ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Neurons/cytology ; Neurons/metabolism ; Signal Transduction ; Transcription Factor AP-1/genetics ; Transcription Factor AP-1/metabolism ; Tumor Cells, Cultured ; Vascular Cell Adhesion Molecule-1/metabolism ; p38 Mitogen-Activated Protein Kinases
    Chemical Substances NF-kappa B ; Transcription Factor AP-1 ; Vascular Cell Adhesion Molecule-1 ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Acetylcholine (N9YNS0M02X)
    Language English
    Publishing date 2004-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2003-0188OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Eosinophil adhesion to cholinergic IMR-32 cells protects against induced neuronal apoptosis.

    Morgan, Ross K / Kingham, Paul J / Walsh, Marie Therese / Curran, David R / Curran, David C / Durcan, Niamh / McLean, W Graham / Costello, Richard W

    Journal of immunology (Baltimore, Md. : 1950)

    2004  Volume 173, Issue 10, Page(s) 5963–5970

    Abstract: Eosinophils release a number of mediators that are potentially toxic to nerve cells. However, in a number of inflammatory conditions, such as asthma and inflammatory bowel disease, it has been shown that eosinophils localize to nerves, and this is ... ...

    Abstract Eosinophils release a number of mediators that are potentially toxic to nerve cells. However, in a number of inflammatory conditions, such as asthma and inflammatory bowel disease, it has been shown that eosinophils localize to nerves, and this is associated with enhanced nerve activity. In in vitro studies, we have shown that eosinophil adhesion via neuronal ICAM-1 leads to activation of neuronal NF-kappaB via an ERK1/2-dependent pathway. In this study, we tested the hypothesis that eosinophil adhesion to nerves promotes neural survival by protection from inflammation-associated apoptosis. Exposure of differentiated IMR-32 cholinergic nerve cells to IL-1beta, TNF-alpha, and IFN-gamma, or culture in serum-deprived medium, induced neuronal apoptosis, as detected by annexin V staining, caspase-3 activation, and DNA laddering. Addition of human eosinophils to IMR-32 nerve cells completely prevented all these features of apoptosis. The mechanism of protection by eosinophils was by an adhesion-dependent activation of ERK1/2, which led to the induced expression of the antiapoptotic gene bfl-1. Adhesion to nerve cells did not influence the expression of the related genes bax and bad. Thus, prevention of apoptosis by eosinophils may be a mechanism by which these cells regulate neural plasticity in the peripheral nervous system.
    MeSH term(s) Apoptosis/physiology ; Caspase 3 ; Caspases/metabolism ; Cell Adhesion/physiology ; Cell Line, Tumor ; Cell Survival/physiology ; Cells, Cultured ; Coculture Techniques ; DNA Fragmentation ; Enzyme Activation/physiology ; Eosinophils/physiology ; Humans ; Minor Histocompatibility Antigens ; Mitogen-Activated Protein Kinase 1/physiology ; Mitogen-Activated Protein Kinase 3/physiology ; Neuroblastoma/enzymology ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Neurons/enzymology ; Neurons/metabolism ; Neurons/physiology ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Signal Transduction/physiology
    Chemical Substances BCL2-related protein A1 ; Minor Histocompatibility Antigens ; Proto-Oncogene Proteins c-bcl-2 ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; CASP3 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2004-12-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.173.10.5963
    Database MEDical Literature Analysis and Retrieval System OnLINE

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