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51.
Bartlett NW Walton RP Edwards MR Aniscenko J Caramori G Zhu J Glanville N Choy KJ Jourdan P Burnet J Tuthill TJ Pedrick MS Hurle MJ Plumpton C Sharp NA Bussell JN Swallow DM Schwarze J Guy B Almond JW Jeffery PK Lloyd CM Papi A Killington RA Rowlands DJ Blair ED Clarke NJ Johnston SL 《Nature medicine》2008,14(2):199-204
Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations. 相似文献
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53.
Insulin inhibits PDGF-directed VSMC migration via NO/ cGMP increase of MKP-1 and its inactivation of MAPKs 总被引:9,自引:0,他引:9
Jacob A Molkentin JD Smolenski A Lohmann SM Begum N 《American journal of physiology. Cell physiology》2002,283(3):C704-C713
In this study, we examined the roleof insulin in the control of vascular smooth muscle cell (VSMC)migration in the normal vasculature. Platelet-derived growth factor(PDGF) increased VSMC migration, which was inhibited by pretreatmentwith insulin in a dose-dependent manner. Insulin also caused a 60%decrease in PDGF-stimulated mitogen-activated protein kinase (MAPK)phosphorylation and activation. Insulin inhibition of MAPK wasaccompanied by a rapid induction of MAPK phosphatase (MKP-1), whichinactivates MAPKs by dephosphorylation. Pretreatment with inhibitors ofthe nitric oxide (NO)/cGMP pathway, blocked insulin-induced MKP-1 expression and restored PDGF-stimulated MAPK activation and migration. In contrast, adenoviral infection of VSMCs with MKP-1 or cGMP-dependent protein kinase I (cGK I), the downstream effector of cGMPsignaling, blocked the activation of MAPK and prevented PDGF-directedVSMC migration. Expression of antisense MKP-1 RNA prevented insulin's inhibitory effect and restored PDGF-directed VSMC migration and MAPKphosphorylation. We conclude that insulin inhibition of VSMC migrationmay be mediated in part by NO/cGMP/cGK I induction of MKP-1 andconsequent inactivation of MAPKs. 相似文献
54.
Goodin JL Nellis DF Powell BS Vyas VV Enama JT Wang LC Clark PK Giardina SL Adamovicz JJ Michiel DF 《Protein expression and purification》2007,53(1):63-79
The F1-V vaccine antigen, protective against Yersinia pestis, exhibits a strong tendency to multimerize that affects larger-scale manufacture and characterization. In this work, the sole F1-V cysteine was replaced with serine by site-directed mutagenesis for characterization of F1-V non-covalent multimer interactions and protective potency without participation by disulfide-linkages. F1-V and F1-V(C424S) proteins were overexpressed in Escherichia coli, recovered using mechanical lysis/pH-modulation and purified from urea-solubilized soft inclusion bodies, using successive ion-exchange, ceramic hydroxyapatite, and size-exclusion chromatography. This purification method resulted in up to 2mg/g of cell paste of 95% pure, mono-disperse protein having < or =0.5 endotoxin units per mg by a kinetic chromogenic limulus amoebocyte lysate reactivity assay. Both F1-V and F1-V(C424S) were monomeric at pH 10.0 and progressively self-associated as pH conditions decreased to pH 6.0. Solution additives were screened for their ability to inhibit F1-V self-association at pH 6.5. An L-arginine buffer provided the greatest stabilizing effect. Conversion to >500-kDa multimers occurred between pH 6.0 and 5.0. Conditions for efficient F1-V adsorption to the cGMP-compatible alhydrogel adjuvant were optimized. Side-by-side evaluation for protective potency against subcutaneous plague infection in mice was conducted for F1-V(C424S) monomer; cysteine-capped F1-V monomer; cysteine-capped F1-V multimer; and a F1-V standard reported previously. After a two-dose vaccination with 2 x 20 microg of F1-V, respectively, 100%, 80%, 80%, and 70% of injected mice survived a subcutaneous lethal plague challenge with 10(8) LD(50)Y. pestis CO92. Thus, vaccination with F1-V monomer and multimeric forms resulted in significant, and essentially equivalent, protection. 相似文献
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57.
Huan J Kaler LJ Mooney JL Subramanian S Hopke C Vandenbark AA Rosloniec EF Burrows GG Offner H 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(2):1249-1257
We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the alpha1 and beta1 domains of MHC class II molecules genetically linked with an immunodominant peptide, in experimental autoimmune encephalomyelitis. In the current study, we produced a monomeric murine I-Aq-derived RTL construct covalently linked with bovine collagen type II peptide (bCII257-270) suitable for use in DBA/1LacJ mice that develop collagen-induced arthritis (CIA), an animal model of human rheumatoid arthritis, after immunization with bCII protein in CFA. In this study, we demonstrate that the I-Aq-derived RTLs reduced the incidence of the disease, suppressed the clinical and histological signs of CIA and induced long-term modulation of T cells specific for arthritogenic Ags. Our results showed that the I-Aq/bCII257-270 molecule could systemically reduce proinflammatory IL-17 and IFN-gamma production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-Aq/bCII257-270 molecule could also selectively inhibit IL-1beta, IL-6, and IL-23 expression in local joint tissue. This is the first report demonstrating effective prevention of joint inflammation and clinical signs of CIA with an I-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans. 相似文献
58.
Studies have reported an empirical link between the size of the semicircular canals and locomotor agility across adult primates. In this paper, we investigate the possibility that this relationship does not follow from the function of the semicircular canals to sense head rotations, but rather reflects spatial constraints imposed by the subarcuate fossa. The latter sits among the three canals and contains the petrosal lobule of the cerebellar paraflocculus, a structure involved in neural processing of locomotion-related eye movements. Hence, it is feasible that agility-related variations of lobule and fossa size affect the arc size of the surrounding semicircular canals. The present study tests such hypothetical correlations by evaluating canal size, fossa size, and agility among extant adult primates. Phylogenetically informed multivariate regression analyses show that, after controlling for body mass, the size of the subarcuate fossa has a significant positive effect on the overall size of the anterior canal and the width of the posterior canal. Multivariate regressions involving the height of the posterior canal and overall size of the lateral canal are not significant. Further bivariate analyses confirm that fossa size is unlikely to play a role in the previously reported link between agility and the size of the posterior and lateral canals. However, fossa size, especially its opening though the arc of the anterior canal, cannot be excluded as a factor that influences the size of the anterior canal more than agility. The findings show that the most reliable functional signals pertaining to locomotion in species that possess a patent subarcuate fossa are likely to come from the lateral canal and are least likely to come from the anterior canal. 相似文献
59.
Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress 总被引:2,自引:1,他引:2 下载免费PDF全文
Hepatic steatosis is a common histological feature of chronic hepatitis C. Hepatitis C virus (HCV) gene expression has been shown to alter host cell cholesterol/lipid metabolism and thus induce hepatic steatosis. Since sterol regulatory element binding proteins (SREBPs) are major regulators of lipid metabolism, we sought to determine whether genotype 2a-based HCV infection induces the expression and posttranslational activation of SREBPs. HCV infection stimulates the expression of genes related to lipogenesis. HCV induces the proteolytic cleavage of SREBPs. HCV core and NS4b derived from genotype 3a are also individually capable of inducing the proteolytic processing of SREBPs. Further, we demonstrate that HCV stimulates the phosphorylation of SREBPs. Our studies show that HCV-induced oxidative stress and subsequent activation of the phosphatidylinositol 3-kinase (PI3-K)-Akt pathway and inactivation (phosphorylation) of PTEN (phosphatase and tensin homologue) mediate the transactivation of SREBPs. HCV-induced SREBP-1 and -2 activities were sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca(2+) chelator 1,2-bis(aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetra(acetoxymethyl) ester (BAPTA-AM), and PI3-K inhibitor (LY294002). Collectively, these studies provide insight into the mechanisms of hepatic steatosis associated with HCV infection. 相似文献
60.
Extensive variations and basic features in the alcohol dehydrogenase-sorbitol dehydrogenase family 总被引:5,自引:0,他引:5
Structural comparisons of sorbitol dehydrogenase with zinc-containing 'long' alcohol dehydrogenases reveal distant but clear relationships. An alignment suggests 93 positional identities with horse liver alcohol dehydrogenase (25% of 374 positions) and 73 identities with yeast alcohol dehydrogenase (20%). Sorbitol dehydrogenase forms a link between these distantly related alcohol dehydrogenases and is in some regions more similar to one of them that they are to each other. 43 residues (11%) are common to all three enzymes and include a heavy over-representation of glycine (half of all glycine residues in sorbitol dehydrogenase), showing the importance of space restrictions in protein structures. Four regions are well conserved, two in each domain of horse liver alcohol dehydrogenase. They are two segments close to the active-site zinc atom of the catalytic domain, and two in the central beta-pleated sheet strands of the coenzyme-binding domain. These similarities demonstrate the general importance of internal and central building units in proteins. Large variations affect a region adjacent to the third protein ligand to the active-site zinc atom in horse liver alcohol dehydrogenase. Such changes at active sites of related enzymes are unusual. Other large differences concern the segment around the non-catalytic zinc atom of horse liver alcohol dehydrogenase; three of its four cysteine ligands are absent from sorbitol dehydrogenase. Three segments with several exchanges correspond to a continuous region with superficial areas, inter-domain contacts and inter-subunit interactions in the catalytic domain of alcohol dehydrogenase. They may correlate with the altered quaternary structure of sorbitol dehydrogenase. Regions corresponding to top and bottom beta-strands in the coenzyme-binding domain of the alcohol dehydrogenase are also little conserved. Within sorbitol dehydrogenase, a large segment shows an internal similarity. The two distantly related alcohol dehydrogenases and sorbitol dehydrogenase form a triplet of enzymes illustrating basic protein relationships. They are ancestrally close enough to establish similarities, yet sufficiently divergent to illustrate changes in all but fundamental properties. 相似文献