Proper neutrophil migration into inflammatory sites ensures host defense without tissue damage. Phosphoinositide 3-kinase (PI(3)K) and its lipid product phosphatidylinositol 3,4,5-trisphosphate ...(PtdIns(3,4,5)Psub3) regulate cell migration, but the role of PtdIns(3,4,5)Psub3-degrading enzymes in this process is poorly understood. Here, we show that Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1), a PtdIns(3,4,5)Psub3 phosphatase, is a key regulator of neutrophil migration. Genetic inactivation of SHIP1 led to severe defects in neutrophil polarization and motility. In contrast, loss of the PtdIns(3,4,5)Psub3 phosphatase PTEN had no impact on neutrophil chemotaxis. To study PtdIns(3,4,5)Psub3 metabolism in living primary cells, we generated a novel transgenic mouse (AktPH-GFP Tg) expressing a bioprobe for PtdIns(3,4,5)Psub3. Time-lapse footage showed rapid, localized binding of AktPH-GFP to the leading edge membrane of chemotaxing ship1super+/+AktPH-GFP Tg neutrophils, but only diffuse localization in ship1super-/-AktPH-GFP Tg neutrophils. By directing where PtdIns(3,4,5)Psub3 accumulates, SHIP1 governs the formation of the leading edge and polarization required for chemotaxis.
Proper neutrophil migration into inflammatory sites ensures host defense without tissue damage. Phosphoinositide 3-kinase (PI(3)K) and its lipid product phosphatidylinositol 3,4,5-trisphosphate ...(PtdIns(3,4,5)P(3)) regulate cell migration, but the role of PtdIns(3,4,5)P(3)-degrading enzymes in this process is poorly understood. Here, we show that Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1), a PtdIns(3,4,5)P(3) phosphatase, is a key regulator of neutrophil migration. Genetic inactivation of SHIP1 led to severe defects in neutrophil polarization and motility. In contrast, loss of the PtdIns(3,4,5)P(3) phosphatase PTEN had no impact on neutrophil chemotaxis. To study PtdIns(3,4,5)P(3) metabolism in living primary cells, we generated a novel transgenic mouse (AktPH-GFP Tg) expressing a bioprobe for PtdIns(3,4,5)P(3.) Time-lapse footage showed rapid, localized binding of AktPH-GFP to the leading edge membrane of chemotaxing ship1(+/+)AktPH-GFP Tg neutrophils, but only diffuse localization in ship1(-/-)AktPH-GFP Tg neutrophils. By directing where PtdIns(3,4,5)P(3) accumulates, SHIP1 governs the formation of the leading edge and polarization required for chemotaxis.
The metabolism of membrane phosphoinositides is critical for a variety of cellular processes. Phosphatidylinositol-3,5-bisphosphate PtdIns(3,5)P ₂ controls multiple steps of the intracellular ...membrane trafficking system in both yeast and mammalian cells. However, other than in neuronal tissues, little is known about the physiological functions of PtdIns(3,5)P ₂ in mammals. Here, we provide genetic evidence that type III phosphatidylinositol phosphate kinase (PIPKIII), which produces PtdIns(3,5)P ₂, is essential for the functions of polarized epithelial cells. PIPKIII-null mouse embryos die by embryonic day 8.5 because of a failure of the visceral endoderm to supply the epiblast with maternal nutrients. Similarly, although intestine-specific PIPKIII-deficient mice are born, they fail to thrive and eventually die of malnutrition. At the mechanistic level, we show that PIPKIII regulates the trafficking of proteins to a cell’s apical membrane domain. Importantly, mice with intestine-specific deletion of PIPKIII exhibit diarrhea and bloody stool, and their gut epithelial layers show inflammation and fibrosis, making our mutants an improved model for inflammatory bowel diseases. In summary, our data demonstrate that PIPKIII is required for the structural and functional integrity of two different types of polarized epithelial cells and suggest that PtdIns(3,5)P ₂ metabolism is an unexpected and critical link between membrane trafficking in intestinal epithelial cells and the pathogenesis of inflammatory bowel disease.
（4）Tunnel Series（part 2）Accretionary Complex KATAYAMA, Masahiro; ABE, Norikazu; IIZUKA, Ryota
Journal of the Japan Society of Engineering Geology,
2021/12/10, Letnik:
62, Številka:
5
Journal Article
（4）Tunnel Series（part 2）Accretionary Complex KATAYAMA, Masahiro; ABE, Norikazu; IIZUKA, Ryota
Journal of the Japan Society of Engineering Geology,
12/2021, Letnik:
62, Številka:
5
Journal Article
The authors have studied the buckling-restrained brace providing stable hysteretic characteristic even under high-strain conditions. Structural performance of the buckling-restrained brace is ...represented by the evaluation formula that is the lower limit of the cumulative plastic strain energy ratio. However, when the duration of earthquakes gets extraordinarily longer, it is necessary to research and develop a new buckling-restrained brace with more high capacity of energy dissipation. In this paper, our past studies are analyzed and the conditions of high-performance of buckling-restrained braces are extracted. The considered buckling-restrained brace is tested. As a result, the buckling-restrained brace having large cumulative plastic strain energy ratio has been proposed.
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