mortality/aging
• following i.p. injection of 5 x 104 virulent E.coli (018:K1:H7), all 8-week-old homozygotes die at 2 days after challenge, whereas all heterozygous littermates survive the infection
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immune system
• reduced formation of tartrate resistant alkaline phosphatase + (TRAP+) osteoclasts after stimulation with M-CSF/RANKL
• reduced number of TRAP+ ostoclasts in femoral bones of 18 week old mice, by 29%
• 37% reduction in osteoclast surface in the distal femoral metaphysis
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• in vitro, bone marrow-derived homozygous mutant PMNs do not bind particles coated with the PMN beta3 integrin ligand peptide KGAGDVA (K,Lys; G, Gly; A, Ala; D, Asp; V, Val) and fail to generate an oxidative burst in response to surface-bound peptide
• in contrast, binding of C3bi-opsonized particles by homozygous mutant PMNs is normal
• the effector response of homozygous mutant PMNs to control stimuli phorbol dibutyrate and fMLP is also normal
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• at 4 hrs after i.p. challenge with 3 x 104 virulent E. coli (018:K1:H7), homozygotes display a reduced influx of both PMNs and other cells (mainly mononuclear leukocytes) relative to heterozygous littermates
• at 24 hrs after i.p. challenge with 4.3 x 104 virulent E. coli (018:K1:H7), the % of PMNs in peritoneal lavages of homozygous mutant mice is reduced relative to that in heterozygous controls
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• upon stimulation with eight-KGAGDVA-valent peptide (AGD, 20 ug/ml), bone marrow-derived homozygous mutant PMNs exhibit a significant reduction in IgG Fc receptor-mediated phagocytosis relative to wild-type or heterozygous PMNs
• higher AGD concentrations (30-40 ug/ml) not only fail to activate but actually inhibit IgG Fc receptor-mediated phagocytosis by homozygous mutant PMNs
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• in vitro, purified PMNs from homozygous mutant mice display significant defects in several aspects of the antibacterial neutrophil activation process that lead to E. coli killing and effective host defense
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• at 24 hrs after i.p. challenge with 4.3 x 104 virulent E. coli (018:K1:H7), >100-fold more E. coli are recovered from the peritoneal cavities and spleens of homozygous mutant mice than from heterozygote controls, suggesting a reduced ability to control infection
• at 24 hrs after E. coli challenge, all homozygotes display more signs of severe infection than control littermates, including hunched posture, ruffled fur, hypothermia, impaired ambulation, and lethargy
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• following i.p. injection of 5 x 104 virulent E.coli (018:K1:H7), all 8-week-old homozygotes die at 2 days after challenge, whereas all heterozygous littermates survive the infection
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hematopoietic system
• mild thrombocytopenia
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• reduced formation of tartrate resistant alkaline phosphatase + (TRAP+) osteoclasts after stimulation with M-CSF/RANKL
• reduced number of TRAP+ ostoclasts in femoral bones of 18 week old mice, by 29%
• 37% reduction in osteoclast surface in the distal femoral metaphysis
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• in vitro, bone marrow-derived homozygous mutant PMNs do not bind particles coated with the PMN beta3 integrin ligand peptide KGAGDVA (K,Lys; G, Gly; A, Ala; D, Asp; V, Val) and fail to generate an oxidative burst in response to surface-bound peptide
• in contrast, binding of C3bi-opsonized particles by homozygous mutant PMNs is normal
• the effector response of homozygous mutant PMNs to control stimuli phorbol dibutyrate and fMLP is also normal
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• at 4 hrs after i.p. challenge with 3 x 104 virulent E. coli (018:K1:H7), homozygotes display a reduced influx of both PMNs and other cells (mainly mononuclear leukocytes) relative to heterozygous littermates
• at 24 hrs after i.p. challenge with 4.3 x 104 virulent E. coli (018:K1:H7), the % of PMNs in peritoneal lavages of homozygous mutant mice is reduced relative to that in heterozygous controls
|
• upon stimulation with eight-KGAGDVA-valent peptide (AGD, 20 ug/ml), bone marrow-derived homozygous mutant PMNs exhibit a significant reduction in IgG Fc receptor-mediated phagocytosis relative to wild-type or heterozygous PMNs
• higher AGD concentrations (30-40 ug/ml) not only fail to activate but actually inhibit IgG Fc receptor-mediated phagocytosis by homozygous mutant PMNs
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• in vitro, purified PMNs from homozygous mutant mice display significant defects in several aspects of the antibacterial neutrophil activation process that lead to E. coli killing and effective host defense
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• platelets show a considerably shorter half life when injected in wild-type recipients
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skeleton
• reduced formation of tartrate resistant alkaline phosphatase + (TRAP+) osteoclasts after stimulation with M-CSF/RANKL
• reduced number of TRAP+ ostoclasts in femoral bones of 18 week old mice, by 29%
• 37% reduction in osteoclast surface in the distal femoral metaphysis
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homeostasis/metabolism
• platelets show a considerably shorter half life when injected in wild-type recipients
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behavior/neurological
• increased immobility times on second day of forced swimming test
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cellular
• at 4 hrs after i.p. challenge with 3 x 104 virulent E. coli (018:K1:H7), homozygotes display a reduced influx of both PMNs and other cells (mainly mononuclear leukocytes) relative to heterozygous littermates
• at 24 hrs after i.p. challenge with 4.3 x 104 virulent E. coli (018:K1:H7), the % of PMNs in peritoneal lavages of homozygous mutant mice is reduced relative to that in heterozygous controls
|
• upon stimulation with eight-KGAGDVA-valent peptide (AGD, 20 ug/ml), bone marrow-derived homozygous mutant PMNs exhibit a significant reduction in IgG Fc receptor-mediated phagocytosis relative to wild-type or heterozygous PMNs
• higher AGD concentrations (30-40 ug/ml) not only fail to activate but actually inhibit IgG Fc receptor-mediated phagocytosis by homozygous mutant PMNs
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