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41.
Yamamoto N Kawakami K Kinjo Y Miyagi K Kinjo T Uezu K Nakasone C Nakamatsu M Saito A 《Microbes and infection / Institut Pasteur》2004,6(14):1241-1249
Interleukin (IL)-12 is a critical cytokine in the T helper (Th)1 response and host defense against intracellular microorganisms, while its role in host resistance to extracellular bacteria remains elusive. In the present study, we elucidated the role of IL-12 in the early-phase host defense against acute pulmonary infection with Streptococcus pneumoniae, a typical extracellular bacterium, using IL-12p40 gene-disrupted (IL-12p40KO) mice. IL-12p40KO mice were highly susceptible to S. pneumoniae infection, as indicated by the shortened survival time, which was completely restored by the replacement therapy with recombinant (r) IL-12, and increased bacterial counts in the lung. In these mice, recruitment of neutrophils in the lung was significantly attenuated when compared to that in wild-type (WT) mice, which correlated well with the reduced production of macrophage inflammatory protein (MIP-2) and tumor necrosis factor (TNF)-alpha in the infected tissues at the early phase of infection. In vitro synthesis of both cytokines by S. pneumoniae-stimulated lung leukocytes was significantly lower in IL-12p40KO mice than in WT mice, and addition of rIL-12 or interferon (IFN)-gamma restored the reduced production of MIP-2 and TNF-alpha in IL-12p40KO mice. Neutralizing anti-IFN-gamma monoclonal antibody (mAb) significantly decreased the effect of rIL-12. Anti-IFN-gamma mAb shortened the survival time of infected mice and reduced the recruitment of neutrophils and production of MIP-2 and TNF-alpha in the lungs. Our results indicated that IL-12p40 plays a critical role in the early-phase host defense against S. pneumoniae infection by promoting the recruitment of neutrophils to the infected tissues. 相似文献
42.
The single-particle analysis is a structure-determining method for electron microscope (EM) images which does not require crystal. In this method, the projections are picked up and averaged by the images of similar Euler angles to improve the signal to noise ratio, and then create a 3-D reconstruction. The selection of a large number of particles from the cryo-EM micrographs is a pre-requisite for obtaining a high resolution. To pickup a low-contrast cryo-EM protein image, we have recently found that a three-layer pyramidal-type neural network is successful in detecting such a faint image, which had been difficult to detect by other methods. The connection weights between the input and hidden layers, which work as a matching filter, have revealed that they reflect characters of the particle projections in the training data. The images stored in terms of the connection weights were complex, more similar to the eigenimages which are created by the principal component analysis of the learning images rather than to the averages of the particle projections. When we set the initial learning weights according to the eigenimages in advance, the learning period was able to be shortened to less than half the time of the NN whose initial weights had been set randomly. Further, the pickup accuracy increased from 90 to 98%, and a combination of the matching filters were found to work as an integrated matching filter there. The integrated filters were amazingly similar to averaged projections and can be used directly as references for further two-dimensional averaging. Therefore, this research also presents a brand-new reference-free method for single-particle analysis. 相似文献
43.
Kai M Kaito C Fukamachi H Higo T Takayama E Hara H Ohya Y Igarashi K Shiokawa K 《Cell research》2003,13(3):147-158
In Xenopus, injection of S-adenosylmethionine decarboxylase (SAMDC) mRNA into fertilized eggs or 2-cell stage embryos induces massive cell dissociation and embryo-lysis at the early gastrula stage due toactivation of the maternal program of apoptosis. We injected SAMDC mRNA into only one of the animalside blastomeres of embryos at different stages of cleavage, and examined the timing of the onset of theapoptotic reaction. In the injection at 4-and 8-cell stages, a considerable number of embryos developed intotadpoles and in the injection at 16-and 32-cell stages, all the embryos became tadpoles, although tadpolesobtained were sometimes abnormal. However, using GFP as a lineage tracer, we found that descendant cellsof the blastomere injected with SAMDC mRNA at 8-to 32-cell stages are confined within the blastocoel atthe early gastrula stage and undergo apoptotic cell death within the blastocoel, in spite of the continued development of the injected embryos. These results indicate that cells overexpressed with SAMDC undergo apoptotic cell death consistently at the early gastrula stage, irrespective of the timing of the mRNA injection.We assume that apoptosis is executed in Xenopus early gastrulae as a “fall-safe“ mechanism to eliminate physiologically-severely damaged cells to save the rest of the embryo. 相似文献
44.
Xu J Zheng SL Komiya A Mychaleckyj JC Isaacs SD Chang B Turner AR Ewing CM Wiley KE Hawkins GA Bleecker ER Walsh PC Meyers DA Isaacs WB 《American journal of human genetics》2003,72(1):208-212
Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were reported to be associated with prostate cancer risk in families with hereditary prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC who underwent prostate cancer treatment and in 250 control subjects who participated in prostate cancer-screening programs and had normal digital rectal examination and PSA levels (<4 ng/ml). Significantly different allele frequencies between case subjects and control subjects were observed for each of the five variants (P value range.01-.04). Haplotype analyses provided consistent findings, with a significant difference in the haplotype frequencies from a global score test (P=.01). Because the haplotype that is associated with the increased risk for prostate cancer did not harbor any of the known rare mutations, it appears that the observed association of common variants and prostate cancer risk are independent of the effect of the known rare mutations. These results consistently suggest that MSR1 may play an important role in prostate carcinogenesis. 相似文献
45.
Fuda H Lee YC Shimizu C Javitt NB Strott CA 《The Journal of biological chemistry》2002,277(39):36161-36166
As a result of an alternative exon 1, the gene for human hydroxysteroid sulfotransferase (SULTB1) encodes for two peptides differing only at their amino termini. The SULT2B1b isoform preferentially sulfonates cholesterol. Conversely, the SULT2B1a isoform avidly sulfonates pregnenolone but not cholesterol. The outstanding structural feature that distinguishes the SULT2B1 isoforms from the prototypical SULT2A1 isozyme is the presence of extended amino- and carboxyl-terminal ends in the former. Investigating the functional significance of this unique characteristic reveals that removal of 53 amino acids from the relatively long carboxyl-terminal end that is common to both SULT2B1 isoforms has no effect on the catalytic activity of either isoform. On the other hand, removal of 23 amino acids from the amino-terminal end that is unique to SULT2B1b results in loss of cholesterol sulfotransferase activity, whereas removal of 8 amino acids from the amino-terminal end that is unique to SULT2B1a has no effect on pregnenolone sulfotransferase activity. Deletion analysis along with site-directed mutagenesis of SULT2B1b reveal that the amino acid segment 19-23 residues from the amino terminus and particularly isoleucines at positions 21 and 23 are crucial for cholesterol catalysis. In the gene for SULT2B1, exon 1B encodes for only the unique amino-terminal region of SULT2B1b; however, exon 1A encodes for the unique amino-terminal end of SULT2B1a plus an additional 48 amino acids. Thus, if the gene for SULT2B1 employs exon 1B, cholesterol sulfotransferase is synthesized, whereas if exon 1A is used, pregnenolone sulfotransferase is produced. 相似文献
46.
Nakamura J Tajima G Sato C Furukohri T Konishi K 《The Journal of biological chemistry》2002,277(27):24180-24190
The effect of ATP on calcium binding of the Ca2+-ATPase of the sarcoplasmic reticulum has not been clarified. By comparing the calcium dependence of the ATPase activity and of phosphorylation of the ATPase molecules with that of calcium binding in the absence of ATP, we show the existence of two types of regulatory site of the enzyme molecules at which ATP binding variously improves the calcium binding performance of the molecules depending on the aggregation state of the molecules and pH; the two regulatory sites bind ATP at submillimolar (0.25 mm) and millimolar (5 mm) ATP, respectively. The results are discussed based on a model of two conformational variants (A and B forms) of the chemically equivalent ATPase molecules (Nakamura, J., and Furukohri, T. (1994) J. Biol. Chem. 269, 30818-30821). For example, in the sarcoplasmic reticulum membrane at pH 7.40, submillimolar ATP converted the calcium binding manner of the A form from noncooperative (Hill number (n(H)) of approximately 1) to cooperative (n(H) approximately 2), concurrent with a decrease in the apparent calcium affinity (K(0.5)) from 2-6 to 0.1-0.3 microm. The binding of the A form became almost the same as that of the B form (n(H) approximately 2, K(0.5) approximately 0.2 microm), which was not affected by ATP. Millimolar ATP further decreased the K(0.5) of the cooperative binding of the two forms to approximately 0.05 microm. Regulation of the calcium binding performance by ATP is discussed in terms of monomeric and oligomeric pathway models. 相似文献
47.
Three abietane diterpenoids were isolated from the suspension cultured cells of Torreya nucifera var. radicans along with four known abietane diterpenoids. Based on spectroscopic evidence, the structures of the three were elucidated as (3S,5R,10S)-7-oxo-12-methoxyabieta-8,11,13-triene-3,11-diol, (3S,5R,10S)-7-oxo-12-methoxyabieta-8,11,13-triene-3,11,14-triol and (5R,10S)-3-oxo-7R,12-dimethoxyabieta-8,11,13-trien-11-ol, respectively. 相似文献
48.
Grit,a GTPase-activating protein for the Rho family,regulates neurite extension through association with the TrkA receptor and N-Shc and CrkL/Crk adapter molecules 总被引:6,自引:0,他引:6
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Nakamura T Komiya M Sone K Hirose E Gotoh N Morii H Ohta Y Mori N 《Molecular and cellular biology》2002,22(24):8721-8734
Neurotrophins are key regulators of the fate and shape of neuronal cells and act as guidance cues for growth cones by remodeling the actin cytoskeleton. Actin dynamics is controlled by Rho GTPases. We identified a novel Rho GTPase-activating protein (Grit) for Rho/Rac/Cdc42 small GTPases. Grit was abundant in neuronal cells and directly interacted with TrkA, a high-affinity receptor for nerve growth factor (NGF). Another pool of Grit was recruited to the activated receptor tyrosine kinase through its binding to N-Shc and CrkL/Crk, adapter molecules downstream of activated receptor tyrosine kinases. Overexpression of the TrkA-binding region of Grit inhibited NGF-induced neurite elongation. Further, we found some tendency for neurite promotion in full-length Grit-overexpressing PC12 cells upon NGF stimulation. These results suggest that Grit, a novel TrkA-interacting protein, regulates neurite outgrowth by modulating the Rho family of small GTPases. 相似文献
49.
Waste ammonia is re-assimilated into amino acids via the amide group of glutamine and the amino group of glutamate (i.e. through glutamine synthetase/glutamate synthase pathway) for silk synthesis in the silkworm, Bombyx mori, in the last larval stadium. Glutamine concentration in hemolymph gradually decreased with the progress of the fifth instar and it remained at very low levels during the spinning stage, then followed by a sharp increase at the larval-pupal ecdysis. The changes in glutamine synthetase (GS) activity in silkworm tissues were relatively small through the larval development, while the changes in glutamate synthase (GOGAT) activity, especially in the posterior silk glands, were more drastic. In addition, activities of GOGAT in the tissues were much higher than those of the other enzymes involved in glutamine utilization, suggesting that glutamine pool was regulated mainly by the changes in GOGAT activity. Western blot analysis indicated that the changes in GOGAT protein level correlated with the changes in GOGAT activity. Topical application of a juvenile hormone analogue, methoprene, induced an accumulation of glutamine in the hemolymph of the fifth instar larvae. The levels of GOGAT protein and activity in the tissues of the methoprene treated larvae were much lower than those of the control larvae, whereas the methoprene treatment had no effect on the levels of GS activity. In conclusion, GOGAT expression promoted by reduction of juvenile hormone titer is quite important for enhanced utilization of nitrogen for synthesis of silk protein during the last larval instar. 相似文献
50.
We characterized the resistance of the common bean cv. Jolanda to Clover yellow vein virus no. 30 (ClYVV). After inoculation, the virus was detected in neither inoculated nor upper leaves, suggesting that the resistance operates at either the viral replication or cell-to-cell movement level. To analyze the mechanism of resistance, we developed a green fluorescent protein (GFP)-tagged ClYVV, and monitored GFP fluorescence at sites of infection on ClYVV-inoculated leaves. No GFP fluorescence was detected in Jolanda, whereas its expression in single cells and spread on inoculated leaves were observed clearly in susceptible cultivars. ClYVV-introduced Jolanda cells were found to be still viable; therefore, it is unlikely that the restriction of multiplication was due to rapid cell death. Genetic analysis indicated that a single recessive locus controlled the resistant phenotype of Jolanda. We designated this locus desc (determinant of susceptibility to ClYVV). Meanwhile, a spontaneous mutant virus that overcomes the resistance (ClYVV-Br) was isolated. Inoculation assays using chimeric viruses suggested that a viral genome-linked protein (VPg) might be the avirulence determinant. The resistance mechanism may be associated with the role of VPg in the viral infection cycle. 相似文献