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881.
Déborah Harrus Neveen Ahmed-El-Sayed Philip C. Simister Steve Miller Martine Triconnet Curt H. Hagedorn Kathleen Mahias Félix A. Rey Thérèse Astier-Gin Stéphane Bressanelli 《The Journal of biological chemistry》2010,285(43):32906-32918
The hepatitis C virus (HCV) NS5b protein is an RNA-dependent RNA polymerase
essential for replication of the viral RNA genome. In vitro and
presumably in vivo, NS5b initiates RNA synthesis by a
de novo mechanism. Different structural elements of NS5b
have been reported to participate in RNA synthesis, especially a so-called
“β-flap” and a C-terminal segment (designated
“linker”) that connects the catalytic core of NS5b to a
transmembrane anchor. High concentrations of GTP have also been shown to
stimulate de novo RNA synthesis by HCV NS5b. Here we describe a
combined structural and functional analysis of genotype 1 HCV-NS5b of strains
H77 (subtype 1a), for which no structure has been previously reported, and J4
(subtype 1b). Our results highlight the linker as directly involved in lifting
the first boundary to processive RNA synthesis, the formation of the first
dinucleotide primer. The transition from this first dinucleotide primer state to
processive RNA synthesis requires removal of the linker and of the
β-flap with which it is shown to strongly interact in crystal
structures of HCV NS5b. We find that GTP specifically stimulates this transition
irrespective of its incorporation in neosynthesized RNA. 相似文献
882.
Exposure to stress causes differential neural modifications in various limbic regions, namely the prefrontal cortex, hippocampus and amygdala. We investigated whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation is involved with these stress effects. Using an acute inescapable stress protocol with rats, we found opposite effects on AMPA receptor phosphorylation in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) compared to the amygdala and ventral hippocampus (VH). After stress, the phosphorylation of Ser831-GluA1 was markedly decreased in the mPFC and DH, whereas the phosphorylation of Ser845-GluA1 was increased in the amygdala and VH. Stress also modulated the GluA2 subunit with a decrease in the phosphorylation of both Tyr876-GluA2 and Ser880-GluA2 residues in the amygdala, and an increase in the phosphorylation of Ser880-GluA2 in the mPFC. These results demonstrate that exposure to acute stress causes subunit-specific and region-specific changes in glutamatergic transmission, which likely lead to the reduced synaptic efficacy in the mPFC and DH and augmented activity in the amygdala and VH. In addition, these findings suggest that modifications of glutamate receptor phosphorylation could mediate the disruptive effects of stress on cognition. They also provide a means to reconcile the contrasting effects that stress has on synaptic plasticity in these regions. Taken together, the results provide support for a brain region-oriented approach to therapeutics. 相似文献
883.
Giraud MF Paumard P Sanchez C Brèthes D Velours J Dautant A 《Journal of structural biology》2012,177(2):490-497
The F1FO-ATP synthase is a rotary molecular nanomotor. F1 is a chemical motor driven by ATP hydrolysis while FO is an electrical motor driven by the proton flow. The two stepping motors are mechanically coupled through a common rotary shaft. Up to now, the three available crystal structures of the F1c10 sub-complex of the yeast F1FO-ATP synthase were isomorphous and then named yF1c10(I). In this crystal form, significant interactions of the c10-ring with the F1-head of neighboring molecules affected the overall conformation of the F1-c-ring complex. The symmetry axis of the F1-head and the inertia axis of the c-ring were tilted near the interface between the F1-central stalk and the c-ring rotor, resulting in an unbalanced machine. We have solved a new crystal form of the F1c10 complex, named yF1c10(II), inhibited by adenylyl-imidodiphosphate (AMP-PNP) and dicyclohexylcarbodiimide (DCCD), at 6.5 Å resolution in which the crystal packing has a weaker influence over the conformation of the F1-c-ring complex. yF1c10(II) provides a model of a more efficient generator. yF1c10(II) and bovine bF1c8 structures share a common rotor architecture with the inertia center of the F1-stator close to the rotor axis. 相似文献
884.
The epicardial adipose tissue (EAT) is “hypertrophied” in the obese. Thiazolidinediones are anti-diabetic, hypolipidemic drugs and are selective agonists for the gamma isoform of peroxisome proliferator-activated receptor (PPARγ). We evaluated the short-term effects of the prototype rosiglitazone (RSG, 5 mg kg−1 day−1 for 4 days) on the expression of the genes and proteins (by real-time PCR and Western blot) involved in fatty acid (FA) metabolism in EAT of the obese fatty Zucker rat and compared the levels of expression with those in retroperitoneal adipose tissue (RAT). The glyceroneogenic flux leading to fatty acid re-esterification was assessed by the incorporation of 14C from [1-14C]-pyruvate into neutral lipids. RSG upregulated the mRNA for phosphoenolpyruvate carboxykinase, pyruvate dehydrogenase kinase 4, glycerol kinase, adipocyte lipid binding protein, adipose tissue triglyceride lipase and lipoprotein lipase in both RAT and EAT with a resulting increase in glyceroneogenesis that, however, was more pronounced in EAT than in RAT. Under RSG, fatty acid output was decreased in both tissues but unexpectedly less so in EAT than in RAT. RSG also induced the expression of the key genes for fatty acid oxidation [carnitinepalmitoyl transferase-1, medium chain acyl dehydrogenase and very long chain acyl dehydrogenase (VLCAD)]in EAT and RAT with a resulting significant rise of the expression of VLCAD protein. In addition, the expression of the genes encoding proteins involved in mitochondrial processing and density PPARγ coactivator 1 alpha (PGC-1α), NADH dehydrogenase 1 and cytochrome oxidase (COX4) were increased by RSG treatment only in EAT, with a resulting significant up-regulation of PGC1-α and COX4 protein. This was accompanied by a rise in the expression of PR domain containing 16 and uncoupling protein 1, two brown adipose tissue-specific proteins. In conclusion, this study reveals that PPAR-γ agonist could induce a rapid browning of the EAT that probably contributes to the increase in lipid turnover. 相似文献
885.
Giron-Michel J Azzi S Khawam K Mortier E Caignard A Devocelle A Ferrini S Croce M François H Lecru L Charpentier B Chouaib S Azzarone B Eid P 《PloS one》2012,7(2):e31624
The ability of Interleukin-15 (IL-15) to activate many immune antitumor mechanisms renders the cytokine a good candidate for the therapy of solid tumors, particularly renal cell carcinoma. Although IL-15 is being currently used in clinical trials, the function of the cytokine on kidney's components has not been extensively studied; we thus investigated the role of IL-15 on normal and tumor renal epithelial cells. Herein, we analyzed the expression and the biological functions of IL-15 in normal renal proximal tubuli (RPTEC) and in their neoplastic counterparts, the renal clear cell carcinomas (RCC). This study shows that RPTEC express a functional heterotrimeric IL-15Rαβγc complex whose stimulation with physiologic concentrations of rhIL-15 is sufficient to inhibit epithelial mesenchymal transition (EMT) commitment preserving E-cadherin expression. Indeed, IL-15 is not only a survival factor for epithelial cells, but it can also preserve the renal epithelial phenotype through the γc-signaling pathway, demonstrating that the cytokine possess a wide range of action in epithelial homeostasis. In contrast, in RCC in vitro and in vivo studies reveal a defect in the expression of γc-receptor and JAK3 associated kinase, which strongly impacts IL-15 signaling. Indeed, in the absence of the γc/JAK3 couple we demonstrate the assembly of an unprecedented functional high affinity IL-15Rαβ heterodimer, that in response to physiologic concentrations of IL-15, triggers an unbalanced signal causing the down-regulation of the tumor suppressor gene E-cadherin, favoring RCC EMT process. Remarkably, the rescue of IL-15/γc-dependent signaling (STAT5), by co-transfecting γc and JAK3 in RCC, inhibits EMT reversion. In conclusion, these data highlight the central role of IL-15 and γc-receptor signaling in renal homeostasis through the control of E-cadherin expression and preservation of epithelial phenotype both in RPTEC (up-regulation) and RCC (down-regulation). 相似文献
886.
Fogliani B Raharivelomanana P Bianchini JP Bouraïma-Madjèbi S Hnawia E 《Phytochemistry》2005,66(2):241-247
Chemical study of Cunonia macrophylla, a New Caledonian Cunoniaceae, based on bioactive effects of a crude methanol extract of the leaves, detected bioactive tannins for the first time in this plant family. These ellagitannins have been identified as ellagic acid-4-O-beta-D-xylopyranoside (6), mallorepanin (3), mallotinic acid (1) along with corilagin (2), chebulagic acid (4), ellagic acid (5) and gallic acid (7) and have been shown to possess antimicrobial activity and to inhibit xanthine oxidase. Antimicrobial effects on bacterial human pathogens (Staphylococcus aureus, Corynebacterium accolans) and on a plant pathogen (Erwinia carotovora) as well as on a human pathogenic yeast (Candida albicans) were investigated. Activity is reported here for the first time for compounds 1, 3, 4 and 6. The inhibitory effects of all molecules against xanthine oxidase in relation to their structure was evaluated and compared. Compound 6 presented the best activity and seems to be of considerable interest for further studies. 相似文献
887.
Boisselier-Dubayle MC Lambourdière J Bischler H 《Molecular phylogenetics and evolution》2002,24(1):66-77
The phylogeny of one of the putative basal-most group of land plants, the Marchantiidae, is estimated with morphological characters and with sequences of the nuclear (LSU) rDNA gene (first four domains of the 5' end of the 26S rRNA and four subsequent regions) from 34 species and 27 genera. Molecular and morphological data display high degrees of incongruence. The molecular tree topology predominates in the combined analysis. A trend from complex towards simpler morphological traits is apparent from the molecular and combined trees, whereas a trend from simple towards complex traits prevails in the morphological tree. Previously published molecular data corroborate the molecular results. It is suggested that the incongruence stems from the presence of coherent sets of reduction-related morphological traits varying in concert in the morphological data. Marchantiidae is traditionally subdivided into Marchantiales, Sphaerocarpales and Monocleales, with the majority of taxa referred to the first group. The molecular and the combined data both indicate unequivocally that Sphaerocarpales and Monocleales are nested within Marchantiales, and this result is not explicitly refuted by the morphological data. 相似文献
888.
Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients 总被引:4,自引:0,他引:4
Labarrière N Pandolfino MC Gervois N Khammari A Tessier MH Dréno B Jotereau F 《Cancer immunology, immunotherapy : CII》2002,51(10):532-538
Adoptive therapy for cancer using tumor-infiltrating lymphocytes (TIL) has mainly been investigated in cancer patients with advanced stage disease. The limited clinical success has not been encouraging, although this might be explained by poor TIL specificity and/or high tumor burden. To re-evaluate the effectiveness of adoptive therapy, we analyzed the capacity of tumor-reactive TIL injection in preventing the further development of disease in stage III melanoma patients after complete tumor resection. A phase II/III randomized trial was performed on 88 melanoma patients, who received autologous TIL plus interleukin-2 (IL-2) or IL-2 only. The duration of relapse-free survival was analyzed, taking into account the immunological specificity of injected TIL and the number of metastatic lymph nodes removed before treatment. Kaplan-Meyer analysis revealed that the injection of tumor-reactive TIL was statistically correlated with prolonged relapse-free survival in patients with only one metastatic lymph node. Therefore, improved clinical outcome could be obtained after adoptive therapy by selecting appropriate groups of patients and monitoring the specificity of the injected TIL populations. 相似文献
889.
Jean-Michel Robert Michèle Morançais Elisabeth Pradier Jean-Luc Mouget Gérard Tremblin 《Journal of applied phycology》2002,14(4):299-305
This study reports further information on mareninne, awater-soluble blue-green pigment synthesized by the diatom Hasleaostrearia, which is essential to the greening of maturing oysters inFrench production areas. The extraction process is reported, as well aspreliminary characterization of a partially purified marennine extract,including quantitative spectrophotometric analysis of intracellular pigment. Amean specific extinction coefficient, E 1%
1cm = 17.2 at 669 nm, is proposed. Results forquantitative determination of marennine accumulated in cells during batchcultures are presented, and their importance for pigment production isconsidered in relation to potential industrial applications. 相似文献
890.
Gontier E Cario-André M Lepreux S Vergnes P Bizik J Surlève-Bazeille JE Taïeb A 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》2002,15(1):41-48
Congenital nevi are composed of pigment cells bearing common features with melanocytes but showing altered differentiation which leads to nesting and dermal involvement. Using a dead de-epidermized dermis seeded with a combination of keratinocytes and various sources of pigment cells (normal melanocytes, dermal nevus cells from congenital nevi, Bowes melanoma cells), we have studied the formation of nests and the dermal migration of pigment cells together with their secretion profiles of matrix metalloproteinases (MMP). Dermal fibroblasts were also used as control cells in epidermal reconstructs. Besides their morphologic features, the absence of pigment donation to keratinocytes was the major characteristic of dermal nevus cells. A positive correlation was established between the increasing percentage of seeded nevus cells and the patchy pigmentation of reconstructs, as well as the clustering of cells in junctional nests. However, the presence of nevus cells in the dermis of reconstructs was never detected, whereas melanoma cells and dermal fibroblasts could invade the dermis during the time span of the experiments. MMP9 was never expressed in congenital dermal nevus cells but pro-MMP2 was constitutively expressed by all strains of congenital nevus cells and dermal fibroblasts. Melanocytes produced comparable amounts of both pro-MMP2 and pro-MMP9, and Bowes melanoma cells secreted a marginal level of pro-MMP2. In view of their three-dimensional behaviour and secretion of MMPs, we propose that dermal congenital nevus cells correspond to an intermediate status of differentiation between normal melanocytes and melanoma cells. Activation of MMPs by a cofactor or the activation of another signalling pathway seems necessary to induce the dermal passage of nevus cells. 相似文献