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The new reaction-diffusion code FACE (First wAll simulation CodE) is developed for modeling plasma-material–interaction processes taking place in the first wall of fusion devices. The code simulates implantation, desorption, transport, and interaction of an arbitrary number of particle and quasi-particle species, such as dissolved gases and intrinsic or induced defects, in a wall material. It allows descriptive and predictive modeling of retention and outgassing of plasma constituents in plasma-exposed materials for analysis of experimental data and assessment of performance of plasma-facing components under various static and transient plasma conditions. The physical model, capabilities, future development, and example applications of the code are presented.

The Liouville equation is considered for relaxing dusty plasmas consisting initially of equilibrium electrons and ions as well as neutral dust particles. The plasmas relax then due to a collection of electrons and ions by dust particles. The free and collected electrons and ions are considered as a common sub-system described by the common whole distribution function. It is shown that the sub-system is described by a complex integral-differential equation, which can be expected to lead to Non-Markovian kinetics and a memory effect. Free electrons and ions can be non-ideal components of relaxing dusty plasmas due to the intensive collection of electrons and ions by dust particles even in cases if numbers of electrons and ions in the Debye cube are large. 3D computer modeling of the relaxing dusty plasma in cubic plasma crystals shows that the selective collection of electrons and ions by dust particles causes a deviation from the initial equilibrium as well as a non-equilibrium evolution of the self-consistent electric charge of the dust particles

A rare collection of serum samples from patients with hepatitis C virus (HCV) infection followed up from the onset of clinical symptoms was acquired. RNA corresponding to the hypervariable region 1 (HVR1) of E2 protein of HCV isolated from nine patients was reverse‐transcribed, amplified, sequenced, and HVR1 amino acid sequences were deduced. These sequences and a selection of HVR1 amino acid sequences of matching HCV genotypes from protein and translated DNA sequence databanks were used to create the HVR1 amino acid consensus. The degenerated peptides mimicking N‐ and C‐termini of the consensus were synthesized. Most (76%) of 17 patients followed up for the period from 1 week to a minimum of 7 months from the onset of acute symptoms developed antibodies reacting with peptides representing N‐ and/or C‐ termini of HVR1. Antibody recognition of the consensus HVR1 peptides indicates that the variability of HVR1 sequence on the protein level is limited with certain conserved structure(s) being untouched. A tendency was observed for a slower development of anti‐HVR1 antibody response in patients developing chronic HCV, as compared to those with self‐limiting HCV infection. J. Med. Virol. 66:204–217, 2002. © 2002 Wiley‐Liss, Inc.

Although lipid oxidation products are usually associated with tissue injury, it is now recognized that they can also contribute to cell activation and elicit anti-inflammatory lipid mediators. In this study, we report that membrane phospholipid oxidation can modulate the hemostatic balance. Oxidation of natural phospholipids results in an increased ability of the membrane surface to support the function of the natural anticoagulant, activated protein C (APC), without significantly altering the ability to support thrombin generation. Lipid oxidation also potentiated the ability of protein S to enhance APC-mediated factor Va inactivation. Phosphatidylethanolamine, phosphatidylserine, and polyunsaturation of the fatty acids were all required for the oxidation-dependent enhancement of APC function. A subgroup of thrombotic patients with anti-phospholipid antibodies specifically blocked the oxidation-dependent enhancement of APC function. Since leukocytes are recruited and activated at the thrombus or sites of vessel injury, our findings suggest that after the initial thrombus formation, lipid oxidation can remodel the membrane surface resulting in increased anticoagulant function, thereby reducing the thrombogenicity of the thrombus or injured vessel surface. Anti-phospholipid antibodies that block this process would therefore be expected to contribute to thrombus growth and disease.

Among the mechanisms suggested for the prothrombotic activity of lupus anticoagulant and antiphospholipid antibodies is the direct inhibition of the anticoagulant activated protein C (APC) pathway. Although some pathological antibodies may be directed towards the proteins involved, we hypothesize that populations exist which selectively inhibit the APC complex as a result of differences in the phospholipid requirements of this complex as compared to those of the procoagulant complexes. The most prominent feature is the requirement for the presence of phosphatidylethanolamine in the membrane for APC anticoagulant function. This mimics the requirements for inhibitory activity of at least a subset of autoantibodies associated with thrombosis. The role of oxidation of the phospholipid in APC function and antibody reactivity is also discussed.

The endothelial cell protein C receptor (EPCR) functions as an important regulator of the protein C anticoagulant pathway by binding protein C and enhancing activation by the thrombin-thrombomodulin complex. EPCR binds to both protein C and activated protein C (APC) with high affinity. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits APC anticoagulant activity. In this study, we investigate the mechanisms by which sEPCR modulates APC function. Soluble EPCR inhibited the inactivation of factor Va by APC only in the presence of phospholipid vesicles. By using flow cytometric analysis in the presence of 3 mM CaCl(2) and 0. 6 mM MgCl(2), sEPCR inhibited the binding of protein C and APC to phospholipid vesicles (K(i) = 40 +/- 7 and 33 +/- 4 nM, respectively). Without MgCl(2), the K(i) values increased approximately 4-fold. Double label flow cytometric analysis using fluorescein-APC and Texas Red-sEPCR indicated that the APC.sEPCR complex does not interact with phospholipid vesicles. By using surface plasmon resonance, we found that sEPCR also inhibited binding of protein C to phospholipid in a dose-dependent fashion (K(i) = 32 nM). To explore the possibility that sEPCR evokes structural changes in APC, fluorescence spectroscopy studies were performed to monitor sEPCR/Fl-APC interactions. sEPCR binds saturably to Fl-APC (K(d) = 27 +/- 13 nM) with a maximum decrease in Fl-APC fluorescence of 10.8 +/- 0.6%. sEPCR also stimulated the amidolytic activity of APC toward synthetic substrates. We conclude that sEPCR binding to APC blocks phospholipid interaction and alters the active site of APC.

Relaxation phenomena in two-dimensional (2D) plasma crystals have been investigated, including both the self-consistent electric charge of dust particles and the electron and ion velocity distribution functions, by means of a modified 2D particle-in-cell (PIC) method. The results obtained show that the mutual interaction of dust particles in such crystals leads to special properties of the background electrons and ions due to their selective collection by dust particles during the relaxation. These electrons and ions can behave as non-ideal components of dusty plasmas in plasma crystals even in cases where their numbers in the Debye cube are large. This effect is caused by their intensive charge exchange with dust particles, which provides dusty plasmas with the status of open statistical systems. The selective collection of electrons and ions by dust particles also causes their deviation from the initial equilibrium as well as the non-equilibrium evolution of the self-consistent electric charge of the dust particles. Relaxation phenomena in plasma crystals have to be taken into account in all cases of strong changes of plasma parameters, for example due to strong oscillations and waves in these crystals.

In this study, we test the hypothesis that prothrombin levels may modulate activated protein C (APC) anticoagulant activity. Prothrombin in purified systems or plasma dramatically inhibited the ability of APC to inactivate factor Va and to anticoagulate plasma. This was not due solely to competition for binding to the membrane surface, as prothrombin also inhibited factor Va inactivation by APC in the absence of a membrane surface. Compared with normal factor Va, inactivation of factor Va Leiden by APC was much less sensitive to prothrombin inhibition. This may account for the observation that the Leiden mutation has less of an effect on plasma-based clotting assays than would be predicted from the purified system. Reduction of protein C levels to 20% of normal constitutes a significant risk of thrombosis, yet these levels are observed in neonates and patients on oral anticoagulant therapy. In both situations, the correspondingly low prothrombin levels would result in an increased effectiveness of the remaining functional APC of ˜5-fold. Thus, while the protein C activation system is impaired by the reduction in protein C levels, the APC that is formed is a more effective anticoagulant, allowing protein C levels to be reduced without significant thrombotic risk. In situations where prothrombin is high and protein C levels are low, as in early stages of oral anticoagulant therapy, the reduction in protein C would result only in impaired function of the anticoagulant system, possibly explaining the tendency for warfarin-induced skin necrosis.

The effect of replacing the gamma-carboxyglutamic acid domain of activated protein C (APC) with that of prothrombin on the topography of the membrane-bound enzyme was examined using fluorescence resonance energy transfer. The average distance of closest approach (assuming kappa2 = 2/3) between a fluorescein in the active site of the chimera and octadecylrhodamine at the membrane surface was 89 A, compared with 94 A for wild-type APC. The gamma-carboxyglutamic acid domain substitution therefore lowered and/or reoriented the active site, repositioning it close to the 84 A observed for the APC. protein S complex. Protein S enhances wild-type APC cleavage of factor Va at Arg306, but the inactivation rate of factor Va Leiden by the chimera alone is essentially equal to that by wild-type APC plus protein S. These data suggest that the activities of the chimera and of the APC.protein S complex are equivalent because the active site of the chimeric protein is already positioned near the optimal location above the membrane surface to cleave Arg306. Thus, one mechanism by which protein S regulates APC activity is by relocating its active site to the proper position above the membrane surface to optimize factor Va cleavage.

Thiolation of 3-nitro-4-chlorocoumarin in the presence of a substituted or unsubstituted ammonium ion can be used to isolate 3-mtro-4-coumarinylthiolates, which are stabilized by the corresponding ammonium cation, while 3-nitro-4-mercaptocoumarin or its potassium or sodium salts decompose during the reaction. Ammonium 3-nitro-4-coumarinylthiolates are decomposed by acids, and the unsubstituted ammonium salt is S-alkylated in the reaction with benzyl chloride.

A study of the oxidation of 6-bromo-2,4-di-tert-butylphenol by manganese triacetate in neutral and acid media indicated a two-step method for the synthesis of 1-hydroxy-2,4,6,8-tetra-tert-butyldibenzofuran.

Conclusions 1.A study has been made of the influence of temperature on the pH of aqueous solutions of 5-hydroxypyrimidine-1-oxide and 4,6-dimethyl-5-hydroxypyrimidine-1-oxide in the pH range 0.5–10.0, at 25–90‡.2.In the rÉaction of H/D exchange of the ring protons in 5-hydroxypyrimidine-1-oxide and 4,6-dimethyl-5-hydroxypyrimidine-1-oxide at 160‡ in the pD interval 0.5–10.0, the anionic; and neutral forms are the most reactive; with pD > 6, the reaction proceeds more readily through the SE1 mechanism, and at lower levels of pD through the SE2 mechanism. In the reaction of 4,6-dimethyl-5-hydroxypyrimidine-1-oxide along the SE2 path, the cationic form also participates.3.Values have been determined for the rate constants of H/D exchange of ring protons, characterizing the contributions of different forms of these compounds to the reaction of isotope exchange of the ring protons.

Conclusions 1.The effect of temperature on the value of the pH of an aqueous solution of 5-hydroxypyrimidine and 4,6-dimethyl-5-hydroxypyrimidine in the pH range of 0.5–10 and the temperature range of 24–90°C was investigated, and equations describing the dependence of the ionization constants on the temperature were derived.2.Based on the analysis of the kinetic mechanisms of H/D exchange in 5-hydroxypyrimidine in the pD region of 0.5–10 and at 160°, it was found that the reaction takes place according to an electrophilic mechanism with participation of the anionic and neutral forms: The cationic form also participates in the reaction in the case of 4,6-dimethyl-5-hydroxypyrimidine.3.The exchange rate constants characterizing the contribution of the cationic, neutral, and anionic forms of 5-hydroxypyrimidine derivatives in H/D exchange of the protons in the ring were determined.

1.Based on kinetic regularities of the H/D exchange of hydrogen in 5-hydroxynicotinic, 5-hydroxypicolinic, and 3-hydroxyisonicotinic acids at 160° in the region pD > 5.0 it has been found that the reaction follows an electrophilic mechanism and that the a position of the ring, vicinal to the OH group, is the most reactive.2.The proton exchange rate constants have been determined which characterize the contribution of the anionic form of theß-hydroxypyridinecarboxylic acids to the H/D exchange reaction.

1.A study has been made of the effect of temperature on the pH of aqueous solutions of 3-hydroxypyridine N-oxide, working over the pH range from 1.0 to 9.5 and at temperatures in the 24–90‡C interval.2.Equations describing the effect of temperature on the protonzation and ionization constants of aqueous solutions of 3-hydroxypyridine N-oxide have been developed.3.Analysis of the kinetics of H/D exchange in 3-hydroxypyridine N-oxide at 160‡C and pD 1.0–9.5 showed electrophilic substitution at high pD to involve the D3O+ ion and the anion form of 3-hydroxypyridine N-oxide; at pD < 6 H/D exchange involves the OD- ion and the cation and neutral forms of the compound.

1.The influence of the temperature on the pH of solutions of 3-hydroxypyridine has been studied in the pH range of 2.0–10.0 and the temperature interval of 26–90°C, and equations have been derived describing the dependence of the ionization constants on the temperature.2.The rate constants of exchange characterizing the contribution of the neutral and ionic forms of 3-hydroxypyridine in the deuterium exchange reactions of the H2, H6, and H4 protons have been obtained with corrections for the temperature changes in the pH values of the solutions.

1.The ionization constants of 3-hydroxypyridine, 3-hydroxypyridine N-oxide, ß-hydroxypyridinecarboxylic acids, and their ethyl esters were determined by NMR spectroscopy.2.The effect of the OH, COOH, COOEt, and NO groups on the chemical shifts and ionization constants was examined.

1.Ionization constants have been determined for the ß-hydroxypyridinecarboxylic acids and their ethyl esters.2.It has been shown that these acids can exist in various forms in aqueous solution, depending on the pH, and conditions for the transition from one of these forms to another have been marked out.

1.Kinetic studies have shown that isotopic hydrogen exchange in 3-hydroxypyridine at 161°C and pD 2.0–11.0 is a successive-reaction process, the initial act being substitution of the H2 proton.2.Rate constants have been determined for the contribution of the neutral and anion forms of 3-hydroxypyridine to the H2, H6, and H4 deuteroexchange.3.H4 proton exchange occurs only in the anion form of 3-hydroxypyridine.

Conclusions 1.The electrophilic reactions of 5-hydroxynicotinic acid and its ethyl ester are directed only to the 6 position.2.The insertion of a COOH group in the ß-position of the hydroxypyridine ring deactivates the latter toward electrophilic substitution, which proceeds in both alkaline and strongly acid media, in which connection the most marked deactivation is observed in nitration and sulfonation reactions.

1.The sequence and rate of exchange of various protons of theß-pyridol ring were investigated in 3 -hydroxypyridine, 2-methyl-, 2-phenyl-, 2- and 5-benzyl-3-hydroxypyridines, and their N-oxides, with the aid of basic deuteroexchange.2.Replacement of a methyl group by a benzyl group and then by a phenyl group is accompanied by a gradual decrease in the reactivity of theß-pyridol ring in basic deuteroechange.3.The introduction of an N-oxide group accelerates the exchange of the protons in theß-pyridol ring, especially in thea-positions.

The effect of a heterosubstituent on the result of the reduction of 3-nitro-4-substituted coumarins with sodium hydrosulfite, which generally leads to a mixture of three compounds, viz., the product of the reduction of the nitro group to an amino group and products of its replacement by hydrogen or a mercapto group, was studied. The result of the transformation is explained by the stabilizing effect of the heterosubstituent on the reaction intermediate.

It has been shown that the alkylation of 2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one takes place at the oxygen atom, but electrophilic substitution takes place mainly at position 8 of the molecule (the ortho position relative to the hydroxy group).

The acid-base equilibrium behavior of alkyl(phenyl)-substituted 3-hydroxypyridines and 5-hydroxypyrimidines, and their dependence on pH values in aqueous solution, on the solvent, and on the phase composition, have been studied using UV spectroscopy. It has been found that in neutral aqueous solution all of the substituted 3-hydroxypyridines examined contain, in addition to the neutral form, a bipolar form, whose concentration depends on the nature and position of the substituent. In contrast, methyl substituted 5-hydroxypyrimidines form significant amounts of the bipolar form only in more acidic media.

The principles of the changes in the chemical shifts of the protons of substituted pyridines, pyrimidines, 3-hydroxypridines, and 5-hydroxypyrimidines as a function of the basicity of the medium were investigated. The ionization constants and the possible forms of existence of the molecules were determined. The character of the effect of substituants (alkyl and hydroxy groups) on the basicities of the investigated compounds was ascertained. A spectral parameter that correlates satisfactorily with the pKa values is proposed.

The acid-base properties of some 5-hydroxypyrimidine derivatives and their N-oxides were investigated in comparison with the analogous 3-hydroxypyridine derivatives. It was found that 5-hydroxypyrimidines exist in the hydroxy form and are protonated at the nitrogen atom, whereas their N-oxides are protonated at the oxide oxygen atom, in contrast to the N-oxides of other diazines (pyridazine and quinoxaline). The character of the effect of ortho and para substituents (alkyl, benzyl, and phenyl) on the basicities and acidities of the indicated compounds was ascertained.

1-Oxides of a series of 5-hydroxypyrimidine derivatives were synthesized, and their reactivities in electrophilic-substitution reactions (aminomethylation) as compared with 3-hydroxypyridine 1-oxides were investigated. It is shown that the activity of the 5-hydroxypyrimidine ring in the case of ring substitution increases as a result of N-oxidation, whereas methyl groups become less active.

The principles of orientation and the mechanism of electrophilic substitution in a series of isomeric 2-, 3-, and 4-hydroxypyridines are examined.

The ratio of azo and quinonehydrazone forms of 3-hydroxy-6-phenylazopyridine derivatives was determined by IR and electronic spectroscopy. The formation of two crystalline modifications of 2-methoxy-3-hydroxy-6-phenylazopyridine is explained by crystallization of the molecules either in the form of dimers of predominantly the quinonehydrazone form or in the form of polyassociates of the azo form, which are formed by a strong hydrogen bond.

It has been established by UV spectroscopy that 3-hydroxypyridine N-oxide in aqueous and acid solutions exists in the form of the conjugate acid, and in an alkaline medium in the anionic form; no bipolar form has been detected in aqueous solution. Using Huckel's MO LCAO method the indices of the p-electronic structure have been calculated for various forms of 3-hydroxypyridine N-oxide. The values of the localization energies Lr+obtained agree with the experimentally observed sequence of electrophilic substitution in 3-hydroxypyridine N-oxide in acid and alkaline media.

A difference in the reactivities of the 2 and 6 positions of the 5-hydroxypyrimidine ring and an effect of the N-oxide group on the direction of electrophilicsubstitution reactions were demonstrated in the case of synthesized 4-phenyl-5-hydroxypyrimidine and its 1-oxide.

Features of the change in the chemical shifts of the protons of substituted pyridine-, pyrimidine-, 3-hydroxypyridine-, and 5-hydroxypyrimidine-1-oxides, as dependent on the basicity of the medium, were investigated. The ionization constants and the possible forms of the occurrence of the molecules were determined. The character of the influence of the substituents (alkyl, hydroxyl) on the pKa values and the PMR spectral parameters was obtained. The comparison of the results obtained with the data on substituted pyridines and pyrimidines was carried out.

Thus, increases in therapeutic effects can be achieved by various methods: by increasing ascorbic acid doses, by combing ascorbic acid with synergistic agents, and by using it as a chemoprotector against xenobiotics; the most effective way is by chemical modification. Increasing lipophilicity can widen the spectrum of biological activity in the desired direction, and substitution of the hydroxyl group or the carbon at position 2 prolongs the antioxidant activity of ascorbic acid and its associated pharmacological effects, as does complex formation (when the chemical structure of ascorbic acid is not changed), which increases the antioxidant activity — the most important prerequisite for its biological

Some results about the surface states and carrier mobility in p- and n-channel MOST structures, subjected to gamma radiation are presented. The experimental data are obtained by means of differential MOS inverter characteristics and Hall effect measurements in the conductive channel under the gate. The interpretation of the results is carried out on the basis of a theoretical analysis of the fast surface state spectrum at semiconductor/insulator interface. The assumptions and limitations of the physical model used are also discussed.

Lysis of avidin‐coated biotinylated sheep red blood cells (RBC) via the classical pathway of homologous (sheep) and heterologous (guinea pig) complement has been studied. The minimal surface density of avidin inducing antibody‐dependent lysis via the classical pathway is smaller than that inducing antibody‐independent lysis via the alternative pathway. Heterologous lysis via the classical pathway does not depend on the mode of avidin attachment: both biotinylation of membrane amino groups and insertion of biotinyl‐lipid into the membrane provide the same lysis of avidin‐coated RBCs by guinea pig serum in the presence of anti‐avidin antibody. Avidin‐free sheep RBC sensitized with hemolytic anti‐RBC antibody were lysed by guinea pig, but not by sheep serum, confirming high efficiency of homologous restriction of the complement. However, avidin‐coated RBCs were lysed by homologous serum in the presence of anti‐avidin antibody at low surface density of avidin attached. The elimination of the homologous restriction depends on the mode of avidin attachment: biotinylation of membrane amino groups provides antibodymediated lysis via the classical pathway of homologous complement, while insertion of biotinyl‐lipid does not provide lysis.

The reaction of 3-nitro-4-chlorocoumarin with thiolating agents in the presence of water leads to the formation of a mixture of 3-nitro-4-hydroxycoumarin, bis(3-nitro-4-coumarinyl) sulfide, and colored labile products of undetermined structure. The reaction path can be controlled by the choice of solvent, reagent ratio, and temperature regime and by the use of weakly basic additives.