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301.
Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation 总被引:11,自引:0,他引:11
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Spahn CM Gomez-Lorenzo MG Grassucci RA Jørgensen R Andersen GR Beckmann R Penczek PA Ballesta JP Frank J 《The EMBO journal》2004,23(5):1008-1019
An 11.7-A-resolution cryo-EM map of the yeast 80S.eEF2 complex in the presence of the antibiotic sordarin was interpreted in molecular terms, revealing large conformational changes within eEF2 and the 80S ribosome, including a rearrangement of the functionally important ribosomal intersubunit bridges. Sordarin positions domain III of eEF2 so that it can interact with the sarcin-ricin loop of 25S rRNA and protein rpS23 (S12p). This particular conformation explains the inhibitory action of sordarin and suggests that eEF2 is stalled on the 80S ribosome in a conformation that has similarities with the GTPase activation state. A ratchet-like subunit rearrangement (RSR) occurs in the 80S.eEF2.sordarin complex that, in contrast to Escherichia coli 70S ribosomes, is also present in vacant 80S ribosomes. A model is suggested, according to which the RSR is part of a mechanism for moving the tRNAs during the translocation reaction. 相似文献
302.
303.
Bürli RW McMinn D Kaizerman JA Hu W Ge Y Pack Q Jiang V Gross M Garcia M Tanaka R Moser HE 《Bioorganic & medicinal chemistry letters》2004,14(5):1253-1257
Novel DNA minor-groove binding ligands with a promising antibacterial profile are described. Apart from excellent in vitro potency against multiple Gram-positive bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-intermediate Streptococcus pneumoniae (PISP), a small subset of compounds was active against Gram-negative bacteria such as Escherichia coli (E. coli). 相似文献
304.
Arnusch CJ André S Valentini P Lensch M Russwurm R Siebert HC Fischer MJ Gabius HJ Pieters RJ 《Bioorganic & medicinal chemistry letters》2004,14(6):1437-1440
A library of pentapeptides containing the sequence -Y-X-Y- based on rational design was screened with six different lectins. Sequences were identified that modulate galectin binding to its natural carbohydrate ligand. SPR showed inhibition values 2-3 times stronger than galactose and NMR studies suggested real carbohydrate mimicry. 相似文献
305.
Sanna V Kirschvink N Gustin P Gavini E Roland I Delattre L Evrard B 《AAPS PharmSciTech》2004,5(2):17-23
The purpose of this research was to investigate the effects of processing conditions on the characteristics of solid lipid
microparticles (SLM) with a potential application as carriers for pulmonary administration. Compritol (5.0% wt/wt) SLM dispersions
were prepared by rotor-stator homogenization, at different surfactant concentrations and emulsification times. The SLM were
characterized, in terms of morphology and size, after lyophilization and sterilization by autoclaving process. In vivo assessment
was carried out in rats by intratracheal instillation of either placebo or SLM dispersion, and by bronchoalveolar lavage for
cytological analysis. Mean particle size of 4 to 5 μm was achieved using 0.3% and 0.4% (wt/wt) of emulsifier (Poloxamer 188)
and emulsification times of 2 and 5 minutes. The particles showed spherical shape and smooth surface. The morphology of microparticles,
the size, and the size distribution were not substantially modified after lyophilization and sterilization. Total cell counts
showed no significant differences between placebo and SLM 0.5% or 2.5% groups. Regarding cytology, percentage of polymorphonuclear
neutrophils and macrophages did not significantly differ between groups. These results suggest that a single intratracheal
administration of the SLMs does not induce a significant inflammatory airway response in rats and that the SLMs might be a
potential carrier for encapsulated drug via the pulmonary route. 相似文献
306.
Maternal factors control development prior to the activation of the embryonic genome. In vertebrates, little is known about the molecular mechanisms by which maternal factors regulate embryonic development. To understand the processes controlled by maternal factors and identify key genes involved, we embarked on a maternal-effect mutant screen in the zebrafish. We identified 68 maternal-effect mutants. Here we describe 15 mutations in genes controlling processes prior to the midblastula transition, including egg development, blastodisc formation, embryonic polarity, initiation of cell cleavage, and cell division. These mutants exhibit phenotypes not previously observed in zygotic mutant screens. This collection of maternal-effect mutants provides the basis for a molecular genetic analysis of the maternal control of embryogenesis in vertebrates. 相似文献
307.
Starck JM Moser P Werner RA Linke P 《Proceedings. Biological sciences / The Royal Society》2004,271(1542):903-908
We investigated the energy source fuelling the post-feeding metabolic upregulation (specific dynamic action, SDA) in pythons (Python regius). Our goal was to distinguish between two alternatives: (i) snakes fuel SDA by metabolizing energy depots from their tissues; or (ii) snakes fuel SDA by metabolizing their prey. To characterize the postprandial response of pythons we used transcutaneous ultrasonography to measure organ-size changes and respirometry to record oxygen consumption. To discriminate unequivocally between the two hypotheses, we enriched mice (= prey) with the stable isotope of carbon (13C). For two weeks after feeding we quantified the CO2 exhaled by pythons and determined its isotopic 13C/12C signature. Ultrasonography and respirometry showed typical postprandial responses in pythons. After feeding, the isotope ratio of the exhaled breath changed rapidly to values that characterized enriched mouse tissue, followed by a very slow change towards less enriched values over a period of two weeks after feeding. We conclude that pythons metabolize their prey to fuel SDA. The slowly declining delta13C values indicate that less enriched tissues (bone, cartilage and collagen) from the mouse become available after several days of digestion. 相似文献
308.
Strong RK 《Structure (London, England : 1993)》2004,12(11):1919-1920
In this issue, we report the structure of the terminal domain of the polymeric immunoglobulin receptor (pIgR), which mediates the "suicide" transcytosis of multimeric immunoglobulins (IgA, IgM). This assists in reconciling decades of biochemistry, revealing a long-puzzling interaction. 相似文献
309.
18F]Galacto-RGD: synthesis, radiolabeling, metabolic stability, and radiation dose estimates 总被引:3,自引:0,他引:3
Haubner R Kuhnast B Mang C Weber WA Kessler H Wester HJ Schwaiger M 《Bioconjugate chemistry》2004,15(1):61-69
It has been demonstrated in various murine tumor models that radiolabeled RGD-peptides can be used for noninvasive determination of alphavbeta3 integrin expression. Introduction of sugar moieties improved the pharmacokinetic properties of these peptides and led to tracer with good tumor-to-background ratios. Here we describe the synthesis, radiolabeling, and the metabolic stability of a glycosylated RGD-peptide ([18F]Galacto-RGD) and give first radiation dose estimates for this tracer. The peptide was assembled on a solid support using Fmoc-protocols and cyclized under high dilution conditions. It was conjugated with a sugar amino acid, which can be synthesized via a four-step synthesis starting from pentaacetyl-protected galactose. For radiolabeling of the glycopeptide, 4-nitrophenyl-2-[18F]fluoropropionate was used. This prosthetic group allowed synthesis of [18F]Galacto-RGD with a maximum decay-corrected radiochemical yield of up to 85% and radiochemical purity >98%. The overall radiochemical yield was 29 +/- 5% with a total reaction time including final HPLC preparation of 200 +/- 18 min. The metabolic stability of [18F]Galacto-RGD was determined in mouse blood and liver, kidney, and tumor homogenates 2 h after tracer injection. The average fraction of intact tracer in these organs was approximately 87%, 76%, 69%, and 87%, respectively, indicating high in vivo stability of the radiolabeled glycopeptide. The expected radiation dose to humans after injection of [18F]Galacto-RGD has been estimated on the basis of dynamic PET studies with New Zealand white rabbits. According to the residence times in these animals the effective dose was calculated using the MIRDOSE 3.0 program as 2.2 x 10(-2) mGy/MBq. In conclusion, [18F]Galacto-RGD can be synthesized in high radiochemical yields and radiochemical purity. Despite the time-consuming synthesis of the prosthetic group 185 MBq of [18F]Galacto-RGD, a sufficient dose for patient studies, can be produced starting with approximately 2.2 GBq of [18F]flouride. Moreover, the fast excretion, the suitable metabolic stability and the low estimated radiation dose allow to evaluate this tracer in human studies. 相似文献
310.
Tyrosine phosphatase epsilon is a positive regulator of osteoclast function in vitro and in vivo 总被引:7,自引:0,他引:7
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Chiusaroli R Knobler H Luxenburg C Sanjay A Granot-Attas S Tiran Z Miyazaki T Harmelin A Baron R Elson A 《Molecular biology of the cell》2004,15(1):234-244
Protein tyrosine phosphorylation is a major regulator of bone metabolism. Tyrosine phosphatases participate in regulating phosphorylation, but roles of specific phosphatases in bone metabolism are largely unknown. We demonstrate that young (<12 weeks) female mice lacking tyrosine phosphatase epsilon (PTPepsilon) exhibit increased trabecular bone mass due to cell-specific defects in osteoclast function. These defects are manifested in vivo as reduced association of osteoclasts with bone and as reduced serum concentration of C-terminal collagen telopeptides, specific products of osteoclast-mediated bone degradation. Osteoclast-like cells are generated readily from PTPepsilon-deficient bone-marrow precursors. However, cultures of these cells contain few mature, polarized cells and perform poorly in bone resorption assays in vitro. Podosomes, structures by which osteoclasts adhere to matrix, are disorganized and tend to form large clusters in these cells, suggesting that lack of PTPepsilon adversely affects podosomal arrangement in the final stages of osteoclast polarization. The gender and age specificities of the bone phenotype suggest that it is modulated by hormonal status, despite normal serum levels of estrogen and progesterone in affected mice. Stimulation of bone resorption by RANKL and, surprisingly, Src activity and Pyk2 phosphorylation are normal in PTPepsilon-deficient osteoclasts, indicating that loss of PTPepsilon does not cause widespread disruption of these signaling pathways. These results establish PTPepsilon as a phosphatase required for optimal structure, subcellular organization, and function of osteoclasts in vivo and in vitro. 相似文献