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61.
62.
Vanessa Parmenopoulou Demetra S.M. Chatzileontiadou Stella Manta Stamatina Bougiatioti Panagiotis Maragozidis Dimitra-Niki Gkaragkouni Eleni Kaffesaki Anastassia L. Kantsadi Vassiliki T. Skamnaki Spyridon E. Zographos Panagiotis Zounpoulakis Nikolaos A.A. Balatsos Dimitris Komiotis Demetres D. Leonidas 《Bioorganic & medicinal chemistry》2012,20(24):7184-7193
Five ribofuranosyl pyrimidine nucleosides and their corresponding 1,2,3-triazole derivatives have been synthesized and characterized. Their inhibitory action to Ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are potent competitive inhibitors of RNase A with low μM inhibition constant (Ki) values with the ones having a triazolo linker being more potent than the ones without. The most potent of these is 1-[(β-d-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with Ki = 1.6 μM. The high resolution X-ray crystal structures of the RNase A in complex with three most potent inhibitors of these inhibitors have shown that they bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B1 subsite while the triazole moiety binds at the main subsite P1, where P-O5′ bond cleavage occurs, and the ribose at the interface between subsites P1 and P0 exploiting interactions with residues from both subsites. The effect of a susbsituent group at the 5-pyrimidine position at the inhibitory potency has been also examined and results show that any addition at this position leads to a less efficient inhibitor. Comparative structural analysis of these RNase A complexes with other similar RNase A—ligand complexes reveals that the triazole moiety interactions with the protein form the structural basis of their increased potency. The insertion of a triazole linker between the pyrimidine base and the ribose forms the starting point for further improvement of these inhibitors in the quest for potent ribonucleolytic inhibitors with pharmaceutical potential. 相似文献
63.
Sebastien Apcher Anastassia Komarova Chrysoula Daskalogianni Yili Yin Laurence Malbert-Colas Robin F?hraeus 《Journal of virology》2009,83(3):1289-1298
The glycine-alanine repeat (GAr) sequence of the Epstein-Barr virus-encoded EBNA-1 prevents presentation of antigenic peptides to major histocompatibility complex class I molecules. This has been attributed to its capacity to suppress mRNA translation in cis. However, the underlying mechanism of this function remains largely unknown. Here, we have further investigated the effect of the GAr as a regulator of mRNA translation. Introduction of silent mutations in each codon of a 30-amino-acid GAr sequence does not significantly affect the translation-inhibitory capacity, whereas minimal alterations in the amino acid composition have strong effects, which underscores the observation that the amino acid sequence and not the mRNA sequence mediates GAr-dependent translation suppression. The capacity of the GAr to repress translation is dose and position dependent and leads to a relative accumulation of preinitiation complexes on the mRNA. Taken together with the surprising observation that fusion of the 5′ untranslated region (UTR) of the c-myc mRNA to the 5′ UTR of GAr-carrying mRNAs specifically inactivates the effect of the GAr, these results indicate that the GAr targets components of the translation initiation process. We propose a model in which the nascent GAr peptide delays the assembly of the initiation complex on its own mRNA.Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA-1) and latency-associated nuclear antigen 1 (LANA-1), from Kaposi''s sarcoma-associated herpesvirus (KSHV), are major latency proteins of these two gammaherpesviruses that are essential for maintaining viral episomes in infected cells (21, 22). Independent studies suggest that both proteins have evolved mechanisms to remain largely invisible to the immune system, which could otherwise eliminate latently infected cells (8, 9, 19, 25). These mechanisms act in cis and are mediated via an internal repeat region. In the case of EBNA-1 this region consists of an N-terminal glycine-alanine repeat (GAr), and for LANA-1 the region consists of a glutamine-glutamate-aspartate central repeat (QED-CR). Although the two domains do not share amino acid homology, both retard their own synthesis to reduce the production of defective ribosomal products that can be processed for the major histocompatibility complex (MHC) class I-restricted antigen presentation pathway (23, 24), highlighting the importance of translation control in regulating MHC class I-restricted antigen presentation. To compensate for their low rates of synthesis, both proteins also have slow turnover rates (4, 8).Regulation of translation for most prokaryotic and eukaryotic mRNAs occurs at the level of initiation, but there are examples where regulation of protein synthesis depends on the elongation stage (17). The two main types of translation initiation are the classic cap-dependent and the less frequent cap-independent translation mechanisms (5, 7, 11, 14, 16). In the former, the preinitiation complex is formed around the cap structure in the 5′ untranslated region (UTR) of the message, whereas in the latter the 40S subunit is directed toward the mRNA via an internal ribosome entry site (IRES). The mechanism of GAr- and LANA-1-mediated control of translation seems different from other types of viral regulation in several aspects. The EBNA-1 GAr is 60 to 300 amino acids long, depending on virus isolate, and is positioned in the N-terminal part of the protein. The GAr message is GC rich but does not activate protein kinase R and eukaryotic initiation factor 2α phosphorylation (25). The fact that the GAr has to be encoded to suppress translation, coupled with the restricted use of GGG and GGA codons to express Gly and of GCA to express Ala in the GAr (GAT, GAG, and CAG for aspartic acid, glutamic acid, and glutamine, respectively, in the LANA sequence), could suggest that codon exhaustion might explain the effect of these repeats. However, manipulations of sequence order, orientation, and composition of the QED-CR and GAr domains and the observation that antibodies directed toward the GAr can stimulate translation in vitro instead favor a direct role for the amino acid sequence (8, 25).Here, we have studied GAr-mediated regulation of translation in vitro and in vivo. The results presented suggest that, once synthesized, the nascent GAr peptide sequence prevents the assembly of the following upstream ribosomes. This knowledge should further understanding of how amino acid repeat sequences can affect mRNA translation in cis and should shed light on a novel type of viral control of mRNA translation and its implications in regulating MHC class I-restricted antigen presentation. 相似文献
64.
Hiie Hinrikus Deniss Karai Jaanus Lass Anastassia Rodina 《Nonlinear biomedical physics》2010,4(Z1):S5
Background
Information transmission and processing in the nervous system has stochastic nature. Multiple factors contribute to neuronal trial-to-trial variability. Noise and variations are introduced by the processes at the molecular and cellular level (thermal noise, channel current noise, membrane potential variations, biochemical and diffusion noise at synapses etc). The stochastic processes are affected by different physical (temperature, electromagnetic field) and chemical (drugs) factors. The aim of this study was experimental investigation of hypotheses that increase in the noise level in the brain affects processing of visual information. Change in the noise level was introduced by an external factor producing excess noise in the brain.Methods
An exposure to 450 MHz low-frequency modulated microwave radiation was applied to generate excess noise. Such exposure has been shown to increase diffusion, alter membrane resting potential, gating variables and intracellular Calcium efflux. Nine healthy volunteers passed the experimental protocol at the lower (without microwave) and the higher (with microwave) noise level. Two photos (visual stimuli) of unfamiliar, young male faces were presented to the subjects, one picture after another. The task was to identify later the photos from a group of six photos and to decide in which order they were presented. Each subject had a total of eight sessions at the lower and eight at the higher noise level. Each session consisted of 50 trials; altogether a subject made 800 trials, 400 at the lower and 400 at the higher noise level. Student t-test was applied for statistical evaluation of the results.Results
Correct recognition of both stimuli in the right order was better at the lower noise level. All the subjects under investigation showed higher numbers of right answers in trials at the lower noise level. Average number of correct answers from n=400 trials with microwave exposure was 50.3, without exposure 54.4, difference 7.5%, p<0.002. No difference between results at the lower and the higher noise level was revealed in the case of only partly correct or incorrect answers.Conclusions
Our experimental results showed that introduced excess noise reduced significantly ability of the nervous system in correct processing of visual information.65.
Izvol'skaia MS Voronova SN Makarenko IG Duittoz A Tillet I Kalas A Ugriumov MV 《Ontogenez》2004,35(1):23-32
The GnRH producing neurons are the key link of neuroendocrine regulation of the adult reproductive system. Synthesis and secretion of GnRH are, in turn, under the afferent catecholaminergic control. Taking into account that catecholamines exert morphogenetic effects on target cells during ontogenesis, this study was aimed at investigation of the effects of catecholamines on development of GnRH neurons in rats during ontogenesis. We carried out comparative quantitative and semiquantitative analyses of differentiation and migration of GnRH neurons in fetuses of both sexes under the conditions of normal metabolism of catecholamines (administration of saline) or their pharmacologically induced deficiency (administration of alpha-methylparatyrosine). The inhibition of catecholamine synthesis from day 11 of embryogenesis led to an increasing number of GnRH neurons in rostral regions of the trajectory of their migration over the brain: in the area of olfactory tubercles on day 17 and in the area of olfactory bulb on days 18 and 21. In addition, the optical density of GnRH neurons located in the rostral regions of migration was higher in the fetuses after administration of alpha-methylparatyrosine during embryogenesis, as compared to the control. It has been concluded that catecholamines stimulate the migration of GnRH neurons and affect their differentiation. 相似文献
66.
Voronova E. N. Volkova E. V. Kazimirko Yu. V. Chivkunova O. B. Merzlyak M. N. Pogosyan S. I. Rubin A. B. 《Russian Journal of Plant Physiology》2002,49(3):311-319
The response of the photosynthetic apparatus to high irradiance illumination (440–2200 W/m2) was studied in the diatom Thallassiosira weisflogii by fluorescence methods. Changes in the photosynthetic apparatus were monitored by measuring characteristics of chlorophyll fluorescence F
0, F
m, F
v/F
m, and qN for several hours after illumination of the alga with high-intensity light. Incubation of the alga with 2 mM DTT, an inhibitor of de-epoxidase of carotenoids in the diadinoxanthin cycle, led to a decrease in the nonphotochemical quenching of chlorophyll fluorescence and a drop in the F
v/F
m ratio, a characteristic that reflects the quantum efficiency of the functioning of the photosynthetic apparatus. Light-induced absorption changes associated with transformations of carotenoids of diadinoxanthin cycle were recorded in vivo in algal suspensions in the absence and in the presence of DTT. Using the microfluorometric method, we measured cell distribution over the efficiency of the primary processes of photosynthesis (F
v/F
m) after illumination. We found cells with a high tolerance of their photosynthetic apparatus to photooxidative damage. The relatively high tolerance of a portion of the cell population to high-light illumination can be related to light-induced transformation of carotenoids and to the functioning of other protective systems of the photosynthetic apparatus in diatoms. 相似文献
67.
68.
Protein S1 counteracts the inhibitory effect of the extended Shine-Dalgarno sequence on translation 总被引:2,自引:0,他引:2 下载免费PDF全文
There are two major components of Escherichia coli ribosomes directly involved in selection and binding of mRNA during initiation of protein synthesis-the highly conserved 3' end of 16S rRNA (aSD) complementary to the Shine-Dalgarno (SD) domain of mRNA, and the ribosomal protein S1. A contribution of the SD-aSD and S1-mRNA interactions to translation yield in vivo has been evaluated in a genetic system developed to compare efficiencies of various ribosome-binding sites (RBS) in driving beta-galactosidase synthesis from the single-copy (chromosomal) lacZ gene. The in vivo experiments have been supplemented by in vitro toeprinting and gel-mobility shift assays. A shortening of a potential SD-aSD duplex from 10 to 8 and to 6 bp increased the beta-galactosidase yield (four- and sixfold, respectively) suggesting that an extended SD-aSD duplex adversely affects translation, most likely due to its redundant stability causing ribosome stalling at the initiation step. Translation yields were significantly increased upon insertion of the A/U-rich S1 binding targets upstream of the SD region, but the longest SD remained relatively less efficient. In contrast to complete 30S ribosomes, the S1-depleted 30S particles have been able to form an extended SD-aSD duplex, but not the true ternary initiation complex. Taken together, the in vivo and in vitro data allow us to conclude that S1 plays two roles in translation initiation: It forms an essential part of the mRNA-binding track even when mRNA bears a long SD sequence, and through the binding to the 5' untranslated region, it can ensure a substantial enhancing effect on translation. 相似文献
69.
V. A. Knizhnikov V. A. Komleva N. K. Shandala Yu. B. Rybkin N. I. Rekhina Yu. G. Voronova 《Journal of applied phycology》1993,5(2):191-194
White rats were irradiated by both 131iodine, which was incorporated into the thyroid gland, and 137cesium; these were dosed at about 10 and 6 Gy, respectively. A portion of the experimental animals was fed a diet enriched
with powdered Laminaria japonica of known composition. In animals provided with this powder, the frequency of neoplasms was lessened, and the latent period
for the major types of tumours was increased, compared to rats not given the powder.
(*author for correspondence) 相似文献
70.