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991.
Kuduk SD DiPardo RM Chang RK Di Marco CN Murphy KL Ransom RW Reiss DR Tang C Prueksaritanont T Pettibone DJ Bock MG 《Bioorganic & medicinal chemistry letters》2007,17(13):3608-3612
SAR study of the biphenyl region of cyclopropanecarboxamide derived bradykinin B(1) antagonists was examined. Incorporation of a pyridine in place of the proximal phenyl ring and chlorination of the distal phenyl ring proved to be well tolerated and provided compounds with improved pharmacokinetic profiles, CNS penetration, and enhanced receptor occupancy. 相似文献
992.
993.
Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, "such as thiazolidinediones-" a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients. Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappaB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis. Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption. 相似文献
994.
Cohn RD van Erp C Habashi JP Soleimani AA Klein EC Lisi MT Gamradt M ap Rhys CM Holm TM Loeys BL Ramirez F Judge DP Ward CW Dietz HC 《Nature medicine》2007,13(2):204-210
Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy. 相似文献
995.
Genome sequencing and analysis of the versatile cell factory Aspergillus niger CBS 513.88 总被引:1,自引:0,他引:1
Pel HJ de Winde JH Archer DB Dyer PS Hofmann G Schaap PJ Turner G de Vries RP Albang R Albermann K Andersen MR Bendtsen JD Benen JA van den Berg M Breestraat S Caddick MX Contreras R Cornell M Coutinho PM Danchin EG Debets AJ Dekker P van Dijck PW van Dijk A Dijkhuizen L Driessen AJ d'Enfert C Geysens S Goosen C Groot GS de Groot PW Guillemette T Henrissat B Herweijer M van den Hombergh JP van den Hondel CA van der Heijden RT van der Kaaij RM Klis FM Kools HJ Kubicek CP van Kuyk PA Lauber J 《Nature biotechnology》2007,25(2):221-231
996.
997.
Graham LD Pilling PA Eaton RE Gorman JJ Braybrook C Hannan GN Pawlak-Skrzecz A Noyce L Lovrecz GO Lu L Hill RJ 《Protein expression and purification》2007,53(2):309-324
Cloned EcR and USP cDNAs encoding the ecdysone receptors of four insect pests (Lucilia cuprina, Myzus persicae, Bemisia tabaci, Helicoverpa armigera) were manipulated to allow the co-expression of their ligand binding domains (LBDs) in insect cells using a baculovirus vector. Recombinant DE/F segment pairs (and additionally, for H. armigera, an E/F segment pair) from the EcR and USP proteins associated spontaneously with high affinity to form heterodimers that avidly bound an ecdysteroid ligand. This shows that neither ligand nor D-regions are essential for the formation of tightly associated and functional LBD heterodimers. Expression levels ranged up to 16.6mg of functional apo-LBD (i.e., unliganded LBD) heterodimer per liter of recombinant insect cell culture. Each recombinant heterodimer was affinity-purified via an oligo-histidine tag at the N-terminus of the EcR subunit, and could be purified further by ion exchange and/or gel filtration chromatography. The apo-LBD heterodimers appeared to be more easily inactivated than their ligand-containing counterparts: after purification, populations of the former were <40% active, whereas for the latter >70% could be obtained as the ligand-LBD heterodimer complex. Interestingly, we found that the amount of ligand bound by recombinant LBD heterodimer preparations could be enhanced by the non-denaturing detergent CHAPS (3-[(3-cholamidopropyl)dimethyl-ammonio]-1-propanesulfonate). Purity, integrity, size and charge data are reported for the recombinant proteins under native and denaturing conditions. Certain intra- and intermolecular disulfide bonds were observed to form in the absence of reducing agents, and thiol-specific alkylation was shown to suppress this phenomenon but to introduce microheterogeneity. 相似文献
998.
Three-dimensional reconstruction of bovine brain V-ATPase by cryo-electron microscopy and single particle analysis 总被引:1,自引:0,他引:1
Bovine V-ATPase from brain clathrin-coated vesicles was investigated by cryo-electron microscopy and single particle analysis. Our studies revealed great flexibility of the central linker region connecting V1 and V0. As a consequence, the two sub-complexes were processed separately and the resulting volumes were merged computationally. We present the first three-dimensional (3D) map of a V-ATPase obtained from cryo-electron micrographs. The overall resolution was estimated 34 Å by Fourier shell correlation (0.5 cutoff). Our 3D reconstruction shows a large peripheral stalk and a smaller, isolated peripheral density, suggesting a second, less well-resolved peripheral connection. The 3D map reveals new features of the large peripheral stator and of the collar-like density attached to the membrane domain. Our analyses of the membrane domain indicate the presence of six proteolipid subunits. In addition, we could localize the V0 subunit a flanking the large peripheral stalk. 相似文献
999.
Lehtinen RM Nussbaum RA Richards CM Cannatella DC Vences M 《Molecular phylogenetics and evolution》2007,44(3):1121-1129
One group of mantellid frogs from Madagascar (subgenus Pandanusicola of Guibemantis) includes species that complete larval development in the water-filled leaf axils of rainforest plants. This group consists of six described species: G. albolineatus, G. bicalcaratus, G. flavobrunneus, G. liber, G. pulcher, and G. punctatus. We sequenced the 12S and 16S mitochondrial rRNA genes ( approximately 1.8 kb) from multiple specimens (35 total) of all six species to assess phylogenetic relationships within this group. All reconstructions strongly supported G. liber as part of the Pandanusicola clade, even though this species does not breed in plant leaf axils. This result confirms a striking reversal of reproductive specialization. However, all analyses also indicated that specimens assigned to G. liber include genetically distinct allopatric forms that do not form a monophyletic group. Most other taxa that were adequately sampled (G. bicalcaratus, G. flavobrunneus, and G. pulcher) likewise consist of several genetically distinct lineages that do not form monophyletic groups. These results suggest that many of the recognized species in this group are complexes of cryptic species. 相似文献
1000.
Ontogeny of human hepatic cytochromes P450 总被引:1,自引:0,他引:1
Hines RN 《Journal of biochemical and molecular toxicology》2007,21(4):169-175
Significant changes in drug-metabolizing enzyme (DME) expression occur during ontogeny. Such changes can have a profound effect on therapeutic efficacy in the fetus and child, as well as the risk for adverse drug reactions. To gain a better understanding of DME ontogeny, enzyme contents for six key cytochromes P450 were measured in 240 human liver samples representing ages from 8 weeks gestation to 18 years. Where possible, both quantitative western blotting and activity assays with probe substrates were performed. Although oversimplified, the DME can be grouped into one of three categories. As typified by CYP3A7, some enzymes are expressed at their highest level during the first trimester and either remain at high concentrations or decrease during gestation and are silenced or expressed at low levels within 1-2 years after birth. These data cause one to query whether these enzymes have an important endogenous function. Representatives of a second group, CYP3A5 and CYP2C19, are expressed at relatively constant levels throughout gestation. Postnatal increases in CYP2C19 are observed within the first year, but not for CYP3A5. CYP2C9, 2E1, and 3A4 are more typical of a third group of enzymes that are not expressed or are expressed at low levels in the fetus with the onset of expression generally in either the second or third trimester. Substantial increases in expression are observed within the first 1-2 years after birth; however, considerable interindividual variability is observed in the immediate postnatal (1-6 months) onset or increase in expression of these enzymes, often resulting in a window of hypervariability. 相似文献