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Two polypeptide isoforms of myelin-associated glycoprotein (MAG) with molecular masses of 72 and 67 kDa are produced by alternative splicing of the exon 12 portion. Our previous work has demonstrated that in the quaking mouse brain this alternative splicing is lacking and that the mRNA coding the large MAG isoform (L-MAG) is scarcely expressed, whereas that of small MAG isoform (S-MAG) is overexpressed. In the present study, we prepared antisera specific to the S-MAG and L-MAG amino acid residues, respectively. Immunoblots showed that the L-MAG band was scarcely detectable in the quaking mouse brain, whereas the S-MAG band had an apparently higher molecular mass than in the normal control. Our immunohistochemical study also showed that L-MAG was scarcely stained in the quaking mouse brain. These results seemed to reflect a reduction in content of L-MAG mRNA and abnormal glycosylation in the quaking mouse brain.  相似文献   
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Background/PurposeLysine-specific gingipain (Kgp) is a virulence factor secreted from Porphyromonas gingivalis (P. gingivalis), a major etiological bacterium of periodontal disease. Keratin intermediate filaments maintain the structural integrity of gingival epithelial cells, but are targeted by Kgp to produce a novel cytokeratin 6 fragment (K6F). We investigated the release of K6F and its induction of cytokine secretion.MethodsK6F present in the gingival crevicular fluid of periodontal disease patients and in gingipain-treated rat gingival epithelial cell culture supernatants was measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometer-based rapid quantitative peptide analysis using BLOTCHIP. K6F in gingival tissues was immunostained, and cytokeratin 6 protein was analyzed by immunofluorescence staining and flow cytometry. Activation of MAPK in gingival epithelial cells was evaluated by immunoblotting. ELISA was used to measure K6F and the cytokines release induced by K6F. Human gingival fibroblast migration was assessed using a Matrigel invasion chamber assay.ResultsWe identified K6F, corresponding to the C-terminus region of human cytokeratin 6 (amino acids 359–378), in the gingival crevicular fluid of periodontal disease patients and in the supernatant from gingival epithelial cells cultured with Kgp. K6F antigen was distributed from the basal to the spinous epithelial layers in gingivae from periodontal disease patients. Cytokeratin 6 on gingival epithelial cells was degraded by Kgp, but not by Arg-gingipain, P. gingivalis lipopolysaccharide or Actinobacillus actinomycetemcomitans lipopolysaccharide. K6F, but not a scrambled K6F peptide, induced human gingival fibroblast migration and secretion of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1. These effects of K6F were mediated by activation of p38 MAPK and Jun N-terminal kinase, but not p42/44 MAPK or p-Akt.ConclusionKgp degrades gingival epithelial cell cytokeratin 6 to K6F that, on release, induces invasion and cytokine secretion by human gingival fibroblasts. Thus, Kgp may contribute to the development of periodontal disease.  相似文献   
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Intrinsically disordered domains have been reported to play important roles in signal transduction networks by introducing cooperativity into protein–protein interactions. Unlike intrinsically disordered domains that become ordered upon binding, the EF-SAM domain in the stromal interaction molecule (STIM) 1 is distinct in that it is ordered in the monomeric state and partially unfolded in its oligomeric state, with the population of the two states depending on the local Ca2 + concentration. The oligomerization of STIM1, which triggers extracellular Ca2 + influx, exhibits cooperativity with respect to the local endoplasmic reticulum Ca2 + concentration. Although the physiological importance of the oligomerization reaction is well established, the mechanism of the observed cooperativity is not known. Here, we examine the response of the STIM1 EF-SAM domain to changes in Ca2 + concentration using mathematical modeling based on in vitro experiments. We find that the EF-SAM domain partially unfolds and dimerizes cooperatively with respect to Ca2 + concentration, with Hill coefficients and half-maximal activation concentrations very close to the values observed in vivo for STIM1 redistribution and extracellular Ca2 + influx. Our mathematical model of the dimerization reaction agrees quantitatively with our analytical ultracentrifugation-based measurements and previously published free energies of unfolding. A simple interpretation of these results is that Ca2 + loss effectively acts as a denaturant, enabling cooperative dimerization and robust signal transduction. We present a structural model of the Ca2 +-unbound EF-SAM domain that is consistent with a wide range of evidence, including resistance to proteolytic cleavage of the putative dimerization portion.  相似文献   
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Interleukin‐12 is one of the cytokines that induce acquired immunity by progressing the differentiation of T cells. When antigens are presented by APCs, including macrophages and DCs, T cells are activated and produce the Th1 cytokines IL‐2 and IFN‐γ. We have previously reported greater IL‐12 production from macrophages infected with early‐shared BCG sub‐strains (ex. BCG‐Japan, ‐Sweden) than from those infected with late‐shared BCG (ex. BCG‐Pasteur and ‐Connaught) 1 . In this study, we investigated the Th1 cytokine‐inducing activity of splenocytes co‐cultured with BCG‐infected DCs. Early‐shared BCG‐infected DCs produced IL‐12 and TNF‐α? Furthermore, when they were co‐cultured with purified protein derivative‐stimulated DCs, the splenocytes of mice immunized with BCG‐Tokyo/Japan produced more Th1 cytokine than did those of mice immunized with BCG‐Connaught. In conclusion, early‐shared BCG sub‐strains more strongly induce Th1 cytokine production in vivo. This study provides basic information to inform the selection of candidates for primary vaccination.
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Death-feigning, also called tonic immobility, is found in a number of animal species across vertebrate and invertebrate taxa. To date, five hypotheses have been proposed for the adaptive significance of tonic immobility. These are that tonic immobility is effective for prey because (i) avoiding dead prey is safer for predators, (ii) immobility plays a role in physical defence, (iii) immobility plays a role in concealment and/or background matching, (iv) predators lose interest in unmoving prey, and (v) the characteristic immobilization posture signals a bad taste to predators. The fourth and fifth hypotheses have been considered suitable explanations for tonic immobility of the red flour beetle against its predator, the jumping spider. In the present study, we used chemical analyses of secretions by the red flour beetles under attack by the jumping spider to reject the fifth hypothesis for this system. More importantly, we tested a selfish-prey hypothesis for the adaptive significance of death-feigning as an anti-predator strategy, in which individuals adopting tonic immobility survive by sacrificing neighbours. Findings showed that survival rates of feigners were higher when in the presence of non-feigners or prey of a different species, compared to when alone, thus confirming our selfish-prey hypothesis. In summary, our results suggest that immobility following a spider attack is selfish; death-feigning prey increase their probability of survival at the expense of more mobile neighbours.  相似文献   
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Metastatic bone disease is often associated with bone pain, pathologic fractures, and nerve compression syndromes. Effective therapies to inhibit the progression of bone metastases would have important clinical benefits. Therefore, we developed a novel calcium phosphate-binding liposome for a bone-targeting drug delivery system. We synthesized a novel amphipathic molecule bearing a bisphosphonate (BP) head group to recognize and bind to hydroxyapatite (HA). We demonstrated that the liposomes having BP moieties show high affinity for HA. Doxorubicin-loaded liposomes adsorbed on the surface of HA significantly reduce the number of viable human osteosarcoma MG63 cells. This shows that the liposomes can be excellent carriers for anticancer drugs because they specifically target bone tissue. This calcium phosphate-binding liposome system could be used with many drugs for bone-related diseases such as osteoporosis, rheumatoid arthritis, and multiple myeloma.  相似文献   
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O2-inactivation of pyruvate:NADP+ oxidoreductase from mitochondria of Euglena gracilis was studied in vitro, and a mechanism which consists of two sequential stages was proposed. Initially, the enzyme is inactivated by the direct action of O2 in a process obeying second-order kinetics. Although the catalytic activity for pyruvate oxidation is lost by this initial inactivation, NADPH oxidation with artificial electron acceptors still occurs. Subsequently, a secondary, O2-independent inactivation occurs, rendering the enzyme completely inactive. Pyruvate stimulates the O2-inactivation while CoA and NADP+ protect the enzyme from O2. The O2-inactivation is accelerated by reduction of the enzyme with pyruvate and CoA. Reactivation of the O2-inactivated enzyme was studied in Ar by incubation with Fe2+ in the presence of some other reducing reagent such as dithiothreitol. The evidence obtained indicates that the partially inactivated enzyme, which retains catalytic activity for NADPH oxidation, can be reactivated, but the completely inactivated enzyme is not. When Euglena cells were exposed to 100% O2 the enzyme in the cells was inactivated by O2, but the rate was quite slow compared with that observed in vitro. The enzyme inactivated by O2 in the cells was almost completely reactivated in vitro by incubation with Fe2+ and other reducing reagents in Ar, suggesting that the secondary, O2-independent inactivation does not occur in situ. When the cells were returned to air, reactivation of the O2-inactivated enzyme in the cells began immediately. The enzyme, kept in isolated, intact mitochondria, was stable in air; however, the enzyme was inactivated by O2 when the mitochondria were incubated with a high concentration of pyruvate.  相似文献   
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