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PubMed1999

Free energy calculations and molecular dynamics simulations of wild-type and variants of the DNA-EcoRI complex.

Molecular dynamics simulations and free energy calculations of the wild-type EcoRI-DNA complex and several variants have been performed in aqueous solvent. In general, he theoretical estimations of the free energy differences (DeltaDeltaA) qualitatively agree well with the corresponding experimental data. The modifications which were experimentally found unfavorable compared to the wild-type complex were also found to be so in theoretical estimates. The mutant where the amino group of the base Ade(6) was replaced by a hydrogen atom eliminating one H-bond between the DNA and the protein, was experimentally found to be more stable than the wild-type complex. It was speculated that the modification also caused a structural relaxation in the DNA making DeltaDeltaA favorable. Our theoretical estimate yields a positive DeltaDeltaA in this case, but the difference is small, and no significant local structural relaxation was observed. The major H-bonds between the DNA and the protein in the wild-type complex are found to be maintained in the different mutants although the specific and non-specific interaction energies between the interacting the DNA bases and the protein residues are different in different mutants. The interaction pattern of the other nearby nucleotides are significantly influenced by each modification. Thus, the alteration of the non-specific interactions may also play an indirect role in determining the specificity of the complex. The interaction of the Gua(4) of the DNA with the protein is found to be most sensitive to any alteration in the recognition site. Because Gua(4) is the nucleotide closest to the scissile bond, this extra sensitivity seems to play an important role in altering the functional activity of the complex.

Binding Sites↗

PubMed2000

Synthesis and structure determination of 6-methylbenzo[a]pyrene-deoxyribonucleoside adducts and their identification and quantitation in vitro and in mouse skin.

Activation of the moderate carcinogen 6-methylbenzo[a]pyrene (6-CH(3)BP) by one-electron oxidation to form DNA adducts was studied. Iodine oxidation of 6-CH(3)BP in the presence of dGuo produces BP-6-CH(2)-N(2)dGuo, BP-6-CH(2)-N7Gua and a mixture of 6-CH(3)BP-(1&3)-N7Gua, whereas in the presence of Ade the adducts BP-6-CH(2)-N1Ade, BP-6-CH(2)-N3Ade, BP-6-CH(2)-N7Ade and 6-CH(3)BP-(1&3)-N1Ade are obtained. Furthermore, for the first time an aromatic hydrocarbon radical cation afforded an adduct with dThd, the stable adduct BP-6-CH(2)-N3dThd. Formation of these adducts indicates that the 6-CH(3)BP radical cation has charge localized at the 6, 1 and 3 position. When 6-CH(3)BP was activated by horseradish peroxidase in the presence of DNA, two depurinating adducts were identified, BP-6-CH(2)-N7Gua (48%) and 6-CH(3)BP-(1&3)-N7Gua (23%), with 29% unidentified stable adducts. In the binding of 6-CH(3)BP catalyzed by rat liver microsomes, the same two depurinating adducts, BP-6-CH(2)-N7Gua (22%) and 6-CH(3)BP-(1&3)-N7Gua (10%), were identified, with 68% unidentified stable adducts. In 6-CH(3)BP-treated mouse skin, the two depurinating adducts, BP-6-CH(2)-N7Gua and 6-CH(3)BP-(1&3)-N7Gua, were identified. Although quantitation of these two adducts was not possible due to coelution of metabolites on HPLC, they appeared to be the major adducts found in mouse skin. These results show that 6-CH(3)BP forms depurinating adducts only with the guanine base of DNA, both in vitro and in mouse skin. The weaker reactivity of 6-CH(3)BP radical cation vs. BP radical cation could account for the weaker tumor-initiating activity of 6-CH(3)BP in comparison to that of BP.

Adenine↗

PubMed2000

CGS 21680 exerts marked antidystonic effects in a genetic model of paroxysmal dyskinesia.

The effect of the adenosine A(2A) receptor agonist CGS 21680 (2-carboxyethyl)phenylethylamino]-5'-N-ethylcarbonyamido-ade nosine) on severity of dystonia was examined in genetically dystonic hamsters which exhibit attacks of dystonic and choreoathetotic disturbances in response to mild stress. CGS 21680 significantly reduced the severity of dystonia (0.5, 1.0 and 2.0 mg/kg i.p.). The marked antidystonic effects of CGS 21680 in the hamster model suggest that this compound may represent an interesting candidate for the therapy of paroxysmal dystonia. Furthermore, the present data indicate that the precipitating effect of caffeine in patients with paroxysmal dystonia is probably due to its adenosine receptor antagonistic action.

Adenosine↗

PubMed1984

Quantitative reversed-phase high-performance liquid chromatography of major and modified nucleosides in DNA.

Improved, highly accurate high-performance liquid chromatographic methods for the measurement of the major and modified nucleosides in enzymatic digests of DNA using a single column are described. Four high resolution separation protocols (isocratic, binary, ternary and high speed) with specifically improved selectivity for 5-methyldeoxycytidine (m5dCyd) from Ade, dIno and Guo are presented. From a detailed study of the various factors contributing to the precision and accuracy of the measurement, optimized conditions and quantitative protocols were established. The ternary buffer allows for the first time the determination of N6-methyldeoxyadenosine (m6dAdo) in the same chromatographic analysis with the other deoxyribonucleosides. The binary system allows quantitation of the absolute amounts of each ribo- and deoxyribonucleoside as well as the mole % of each as the second buffer elutes 5'dA and the internal standard 8-bromoguanosine. The isocratic system allows precise quantitation of the mole % of each ribo- and deoxyribonucleoside while eliminating the need for buffer change valves, buffer cycling and column re-equilibration. Also, a high-speed isocratic system is described which permits separation of the deoxyribonucleosides in 6 min. The quantitative, enzymatic hydrolysis of DNA was evaluated by comparing a 40-h, three-enzyme system with a 4-h, two-enzyme procedure. The latter protocol proved to be an excellent hydrolysis method. These high resolution liquid chromatography techniques provide the most precise, sensitive and accurate measurement of m5dCyd available, in a straightforward method using as little as 1 microgram of DNA, and have allowed us to demonstrate: the existence of tissue-specific differences in levels of m5dCyd in DNA of humans, monkeys, rats and mice; that m5dCyd levels in DNA change during fetal development; that genomic undermethylation of DNA is correlated with cancer and the presence of m6dAdo in DNA of thermophilic organisms.

Animals↗

PubMed1984

High-performance liquid chromatographic investigations on the time-dependent reaction of cis-Pt(NH3)2Cl2, Pt(en)Cl2 and Pt(pn)Cl2 with RNA fragments.

The reaction of three platinum compounds, Pt(NH3)2Cl2, Pt(en)Cl2 and Pt(pn)Cl2 with nucleic acid fragments (Ade, Gua; GpG, GpA and ApA), both reactants (1:1, 1 X 10(-2) M; 1 X 10(-3) M) being dissolved in water, has been studied. UV measurements have been used to characterize the products. Kinetics and adduct formation in the nucleoside-Pt compound system were studied by reversed-phase high-performance liquid chromatography [gradient 0-30% methanol in 30 min, ammonium acetate buffer (0.1 M) at pH 4.25] at fixed intervals of time and the product formation was examined by measuring the peak heights. After 10 h, the reaction was complete for guanosine and showed a steady state for adenosine. The increasing lipophilicity in the sequence of the platinum compounds resulted in a shift to longer retention times.

Adenosine↗

PubMed2000

Evidence that error-prone DNA repair converts dibenzo[a,l]pyrene-induced depurinating lesions into mutations: formation, clonal proliferation and regression of initiated cells carrying H-ras oncogene mutations in early preneoplasia.

Initiation of skin tumors in mice is associated with the formation of oncogenic mutations in the H-ras gene. Mice treated on the dorsal skin with the potent polycyclic aromatic hydrocarbon (PAH) carcinogen dibenzo[a,l]pyrene (DB[a,l]P) form papillomas carrying the H-ras codon 61 (CAA to CTA) mutations. These mutations are induced in early preneoplastic skin within 1 day after DB[a,l]P treatment (Oncogene 16 (1998) 3203-3210) and appear to be related to DB[a,l]P-Ade-depurinating adducts (Proc. Natl. Acad. Sci. U. S. A. 92 (1995) 10422-10426). The rapid kinetics of mutation induction suggests that abasic sites generated from base depurination may undergo error-prone excision repair in pre-S-phase cells to induce these mutations. Analysis of mutations in the H-ras exon 1 and 2 region in DB[a,l]P-treated early preneoplastic skin indicated great changes in mutation spectra in the preneoplastic period. The initial spectra contained abundant A-->G mutations, which frequently occurred 3' to a putative conserved sequence (TGN-doublet). These mutations appeared to be induced initially as mismatched (G.T) heteroduplexes and then converted into double-stranded mutations by one round of replication. Unlike the A-->G mutations found in DB[a, l]P-treated skin (which forms 99% depurinating adducts), A-->G mutations found in anti-DB[a,l]P-diol epoxide-treated skin (forms 97% stable adducts) did not appear to be G.T heteroduplexes. These results, therefore, suggest that under these conditions, the repair errors occurred only from abasic sites but not from stable adducts. Initiated cells carrying specific oncogenic mutations, formed presumably by misrepair, underwent rapid clonal expansion and regression (transient clonoplasia). The multiplication of initiated stem cells during transient clonoplasia may be a factor determining the tumor-initiating potential of some PAH carcinogens.

Animals↗

PubMed1998

Genotoxicity of ribo- and deoxyribonucleosides of 8-hydroxyguanine, 5-hydroxycytosine, and 2-hydroxyadenine: induction of SCE in human lymphocytes and mutagenicity in Salmonella typhimurium TA 100.

The induction of SCE by ribo- and deoxyribonucleosides of 8-hydroxyguanine, 5-hydroxycytosine, and 2-hydroxyadenine was tested using human peripheral blood lymphocytes. All of these compounds caused an increase in SCE frequency. The potency of SCE induction was as follows: 5-OH-C, 5-OH-dC > 8.OH-G > 8-OH-dG > 2-OH-A, 2-OH-dA. These results suggest that the oxidized nucleosides are incorporated into DNA with different efficiencies (or are repaired with different efficiencies) and exhibit genotoxicity in human blood cells. Ribo- and deoxyribo-derivatives of 5-OH-Cyt and 2-OH-Ade also showed mutagenic activity in Salmonella typhimurium TA 100.

Cytosine↗

PubMed2003

Neurobehavioral effects of alcohol in AMPA receptor subunit (GluR1) deficient mice.

Of the ionotropic glutamatergic receptors, the NMDA receptor is clearly implicated in the acute and chronic effects of ethanol; however, the role of the AMPA receptor in mediating the effects of ethanol in vivo is as yet unclear. Using mice deficient in the AMPA receptor subunit GluR1 (GluR1-/- mice), we investigated whether the AMPA receptor had a significant role in mediating the effects of ethanol. GluR1-/- mice showed greater locomotor activity in a novel environment, but by the fifth day of repeated testing their activity was the same as that of wild-type mice. In contrast to their enhanced locomotor activity, on an accelerating rotarod GluR1-/- mice performed consistently worse than wild-types. With regard to the effects of ethanol on motor responses, GluR1-/- mice did not differ significantly from wild-type mice in ethanol's sedative or incoordinating effects. However, the GluR1-/- mice were insensitive to the hypothermic effects of a hypnotic dose of ethanol in contrast to wild-types; this effect was dissociable from the hypnotic effects of ethanol. Further, tolerance to ethanol developed equally for GluR1-/- mice versus wild-type mice. In terms of alcohol drinking behavior, compared to wild-types, GluR1-/- mice differed neither in the acquisition of voluntary ethanol consumption nor in stress-induced ethanol drinking, nor in the expression of an alcohol deprivation effect (ADE) which is used as a model of relapse-like drinking behavior. In summary, although the loss of a hypothermic effect of ethanol in GluR1-/- mice indicates a critical role for the AMPA receptors in this effect, the GluR1 subunit of the AMPA receptor does not seem to play a critical role in the etiology of alcohol dependence. However, changes observed in activity patterns may be related to the putative role of AMPA receptors in attention deficit hyperactivity disorder.

Alcohol Drinking↗

PubMed2000

Preparation of high activity whole cell biocatalyst by permeabilization of recombinant flocculent yeast with alcohol.

Flocculent yeast Saccharomyces cerevisiae YF234 (MATa ura3-52 trp1Delta2 his ade 2-1 can1-100 sta1 FLO8) cells overexpressing glyoxalase I and having strong flocculation ability were permeabilized with isopropyl alcohol and ethanol under various conditions. The treatment with 40% isopropyl alcohol significantly improves the initial reaction rates of recombinant flocculent yeast cells. Moreover, the reactivity of permeabilized flocculent yeast cells was similar to that of dispersed cells with EDTA. On the other hand, the flocculation ability of yeast cells was not affected by the treatment with alcohol solutions of various concentrations and treatment time length. Therefore, the recombinant flocculent yeast cells permeabilized with alcohol are very effective whole cell biocatalysts.

Journal Article↗

PubMed1999

Adenine incorporation in human and rat endothelium.

Adenine (ADE) reutilisation is an important pathway of adenylate pool regeneration. Data on the rate of this process in different types of cells, its regulation and the importance of species differences is limited. In this study we evaluated adenine incorporation rate and the effect of metabolic factors on this process in human and rat endothelium and compared it to adenine phosphoribosyltransferase (APRT) activity. Microvascular endothelial cells from human (HE) and rat (RE) hearts and a transformed human microvascular endothelial cell line (HMEC-1) were investigated. The rate of adenine incorporation into the adenine nucleotide pool under control conditions was 3.1+/-0.3, 82.8+/-11.1 and 115.1+/-11.2 pmol/min per mg protein for HE, RE and HMEC-1, respectively. In the presence of 2.5 mM ribose or elevated inorganic phosphate concentration in the medium (4.8 mM), few changes were observed in all types of cells. In the presence of both ribose and high inorganic phosphate, the rate of adenine incorporation for RE and HMEC-1 was not significantly different from control, while in HE the rate of adenine incorporation into adenine nucleotides was increased by 75%. Activities of APRT in RE and HMEC-1 were 237.7+/-23.2 and 262.0+/-30.6 pmol/min per mg protein respectively while the activity in HE was markedly lower 48.7+/-3.0 pmol/min per mg protein. In conclusion, nucleotide synthesis from adenine seems to be a slow process in human cardiac microvascular endothelium but it is fast and efficient in rat heart microvascular endothelial cells. Low APRT activity in normal human endothelial cells seems to be the most likely mechanism for this. However, adenine incorporation rate and APRT activity could be greatly enhanced in human endothelium, as demonstrated in transformed cells.

Adenine↗

PubMed2003

Use of correspondence discriminant analysis to predict the subcellular location of bacterial proteins.

Correspondence discriminant analysis (CDA) is a multivariate statistical method derived from discriminant analysis which can be used on contingency tables. We have used CDA to separate Gram negative bacteria proteins according to their subcellular location. The high resolution of the discrimination obtained makes this method a good tool to predict subcellular location when this information is not known. The main advantage of this technique is its simplicity. Indeed, by computing two linear formulae on amino acid composition, it is possible to classify a protein into one of the three classes of subcellular location we have defined. The CDA itself can be computed with the ADE-4 software package that can be downloaded, as well as the data set used in this study, from the Pôle Bio-Informatique Lyonnais (PBIL) server at http://pbil.univ-lyon1.fr.

Bacterial Proteins↗

PubMed2001

One-dimensional simulation of solute transfer in saturated-unsaturated porous media using the discontinuous finite elements method.

A one-dimensional transport model for simulating water flow and solute transport in homogeneous-heterogeneous, saturated-unsaturated porous media is presented. The model is composed of a combination of accurate numerical algorithms for solving the nonlinear Richard's and advection-dispersion equations (ADE). The mixed form of Richard's equation is solved using a standard finite element method (FEM) with primary variable switching. The transport equation is solved using operator splitting, with the discontinuous finite element method (DFE) for discretization of the advective term. A slope limiting procedure for DFE avoids numerical instabilities but creates very limited numerical dispersion for high Peclet numbers. An implicit finite differences scheme (FD) is used for the dispersive term. The unsaturated flow and transport model (Wamos-T) is applied to a variety of rigorous problems including transient flow, heterogeneous medium and abrupt variations of velocity in magnitude and direction due to time-varying boundary conditions. It produces accurate and mass-conservative solutions for a very large range of grid Peclet numbers. The Wamos-T model is a good and robust alternative for the simulation of mass transport in unsaturated domain.

Computer Simulation↗

PubMed2002

Application of the Weibull distribution to describe the vertical distribution of cesium-137 on a slope under permanent pasture in Luxembourg.

The application of solutions of the Advection-Dispersion-Equation (ADE) for soil profiles is sometimes questionable. An alternative method, based on the Weibull distribution, has been developed, which can approximate the vertical distribution of radiocesium (137Cs) and allows extrapolation to account for the complete inventory. The structure of the equation allows simple parameters describing the soil depth profile to be derived. Reliable estimates of the total 137Cs inventory can help to explain the lateral distribution. This equation was used to analyse the 137Cs-activities of Chernobyl fall-out measured on a slope under permanent pasture in Luxembourg.

Cesium Radioisotopes↗

PubMed2004

A new method to account for the depth distribution of 137Cs in soils in the calculation of external radiation dose-rate.

This work reports a new method for calculating the external dose-rate as a function of height above land that has been contaminated with a surface deposition of (137)Cs. Unlike previous work this method accounts for vertical migration of (137)Cs using the Advection Dispersion Equation (ADE) with appropriate parameters. The results have been successfully verified with field measurements from the (137)Cs contaminated regions within the Republic of Belarus. The method also correctly predicts the observed variation of dose-rate with elevation above the soil surface and it is shown how this method can be used to predict the reduction in surface dose-rate after remediation measures such as deep ploughing have taken place.

Cesium Radioisotopes↗

PubMed1998

Study of cytokinin metabolism using HPLC with radioisotope detection.

High performance liquid chromatography (HPLC) with an on-line flow-through radioactivity detector was used to monitor the metabolism of cytokinins ([3H]6-benzylaminopurine and [3H]6-benzylaminopurine riboside) after their incorporation into wheat seedlings. The production and conversion of individual metabolites was assayed within a short time interval (0.5-3 h). Extraction recoveries from plant tissue proved to be 85%. The uptake of both cytokinins was very rapid and differences in their metabolism were already perceptible after 30 min. The individual metabolites were identified as adenine (Ade), adenosine (Ado), benzyladenine-9-glucoside (BA-9G), 6-benzyladenine (BA) and benzyladenosine (BAR). The method is very fast, sensitive and very useful for metabolic studies. The detection limit was 40 pg (220 Bq) for BA at the level of 2 ng ml-1.

Adenine↗

PubMedDate not supplied

[Lung cancer--What has changed in two decades].

Lung cancer (LC) is a major public health problem and it is the most common form of cancer in men. It remains the most common cause of cancer death in men and women. In the initial decades of the smoking-caused epidemic, squamous cell carcinoma was the most frequent type. Recently there was a shift toward predominance of adenocarcinoma. The aim of our retrospective study was to compare the demographic factors and factors connected with the disease in patients whose LC was diagnosed in two distinct periods in H.S. João (1979-1982 and 1999-2002). A total of 750 LC were diagnosed. Between 1979-1982 a total of 236 patients were diagnosed LC (84.3% male; mean age 60.0 +/- 10.0). The most common histological type was squamous cell (46.2%). A total of 514 LC were diagnosed during the period 1999-2002 (83.9% male; mean age 64.7 +/- 10.8) and adenocarcinoma was the most frequent (47.1%). There were significant differences, between the two periods analysed concerning smoking (increase in the number of smokers; 73.7% vs 82.4%), age (increase in the mean age of patients) and histology (higher percentage of ade notnocarcinoma and reduction of squamous cell and small-cell lung cancer). The percentage of patients treated symptomatically decreased significantly in 20 years (26% vs 19%). As a conclusion we can say that there was an evolution of histological types in the last two decades and a reduction in the number of patients submitted to symptomatic treatment alone.

Adult↗

PubMed1999

SOS-dependent A-->G transitions induced by hydroxyl radical generating system hypoxanthine/xanthine oxidase/Fe3+/EDTA are accompanied by the increase of Fapy-adenine content in M13 mp18 phage DNA.

Gas chromatography/isotope dilution-mass spectrometry with selected ion monitoring (GC/IDMS-SIM) was used to measure oxidised bases in hypoxanthine/xanthine oxidase/Fe3+/EDTA modified ss M13 mp18 phage DNA. A dose-dependent increase of oxidised bases content in DNA was observed with the biggest augmentation of FapyGua, thymine glycol and FapyAde. The amount of 8-OH-Gua was relatively high both in non-oxidised and oxidised DNA, and increased to the same extent as FapyAde and ThyGly. DNA oxidation caused a dramatic decrease in phage survival after transfection to E. coli. Survival was improved 2.8-fold after induction of the SOS system by UV irradiation of bacteria and mutation frequency of the lacZ gene in SOS conditions increased 7-fold over that in non-irradiated bacteria. Spectrum of mutations was different from those reported previously and mutations were distributed rather randomly within M13 lacZ sequence, which was in contrast to previous findings, where with non-chelated metal ions other types of mutations were found in several clusters. Thus, conditions of DNA oxidation and accessibility of metal ions for DNA bases might be important factors for generating different DNA damages and mutations. Major base substitutions found both in SOS-induced and non-induced E. coli but with higher mutation frequency in SOS-induced cells were C-->A (approximately 20-fold increase in SOS-conditions), G-->A (9-fold increase) and G-->C (4.5-fold increase). Very few G-->T transitions were found. A particularly large group of A-->G transitions appeared only in SOS-induced bacteria and was accompanied by augmentation of FapyAde content in the phage DNA with undetectable 2-OH-Ade. It is then possible that imidazole ring-opened adenine mimics guanine during DNA replication and pairs with cytosine yielding A-->G transitions in SOS-induced bacteria.

Bacteriophage M13↗

PubMedDate not supplied

Olfactory memory in rats, cholinergic agents and benzodiazepine receptor ligands.

Drugs and their effects on olfactory learning processes in rats were tested using a modified version of the runway apparatus developed by Ades. Rats were first exposed to a conspecific urine sample and 24 h later were exposed to the same stimulus in the runway. Observations recorded the time spent investigating the urine and the number of sniffs at the site, these being considered to be indices of memory. Diazepam-treated rats (4 or 6 mg/kg) and scopolamine-treated rats (0.5 or 1 mg/kg) showed increases for both parameters. When both drugs were administered simultaneously, the impairing effect was potentiated. However, no changes in learning responses were observed in rats treated with physostigmine (0.125, 0.25, 0.5 mg/kg) or methyl beta-carboline-3-carboxylate (0.3, 0.5, 1 mg/kg), although the administration of physostigmine or methyl beta-carboline-3-carboxylate was shown to antagonize the impairing effect of diazepam or scopolamine respectively. These observations support the hypothesis of interactions existing between cholinergic agents and benzodiazepine receptor ligands and of such interactions affecting olfactory acquisition processes. The runway apparatus appears to be a valid candidate model to be used for the assessment of pharmacological influences on olfactory learning in rats.

Animals↗