Structural evolution and strain induced mixing in Cu-Co composites studied by transmission electron microscopy and atom probe tomography.

A Cu-Co composite material is chosen as a model system to study structural evolution and phase formations during severe plastic deformation. The evolving microstructures as a function of the applied strain were characterized at the micro-, nano-, and atomic scale-levels by combining scanning electron microscopy and transmission electron microscopy including energy-filtered transmission electron microscopy and electron energy-loss spectroscopy. The amount of intermixing between the two phases at different strains was examined at the atomic scale using atom probe tomography as complimentary method. It is shown that Co particles are dissolved in the Cu matrix during severe plastic deformation to a remarkable extent and their size, number, and volume fraction were quantitatively determined during the deformation process. From the results, it can be concluded that supersaturated solid solutions up to 26 at.% Co in a fcc Cu-26 at.% Co alloy are obtained during deformation. However, the distribution of Co was found to be inhomogeneous even at the highest degree of investigated strain.

On the remarkable thermal stability of nanocrystalline cobalt via alloying.

Nanostructured Co materials are produced by severe plastic deformation via alloying with small amounts of C and larger amounts of Cu. The thermal stability of the different nanostructured Co materials is studied through isothermal annealing at different temperatures for various times and compared to the stability of severe plastically deformed high-purity nanocrystalline Co. The microstructural changes taking place during annealing are evaluated by scanning electron microscopy, transmission electron microscopy and microhardness measurements. In the present work it is shown that the least stable nanostructured material is the single-phase high purity Co. Alloying with C improves the thermal stability to a certain extent. A remarkable thermal stability is achieved by alloying Co with Cu resulting in stabilized nanostructures even after annealing for long times at high temperatures. The essential reason for the enhanced thermal stability is to be found in the immiscibility of both components of the alloy.

In vitro competition between adenosine(5')tetraphospho(5')adenosine and deoxyribonucleic acid in the reaction with diamminedichloroplatinum(II).

Competition between adenosine(5')tetraphospho(5')adenosine (Ap4A) and DNA for the synthesis of adducts with the cis or trans isomer of diamminedichloroplatinum(II) was measured in the presence and absence of magnesium and spermidinium ions. Reaction products were analysed by circular dichroism, poly(ethyleneimine) thin-layer chromatography and reversed-phase chromatography. Competition was affected by the oligovalent cations that bound specifically to the dinucleotide. Platination of DNA was favoured under all conditions. Chromatin was less competitive. The mechanism was kinetic competition, DNA reacting considerably faster than Ap4A. Platinum(II) did not exchange between adducts and free DNA and Ap4A, respectively. On that basis only low amounts of Ap4A adducts were estimated to be formed under conditions of clinical chemotherapy. The cis and trans isomers of diamminedichloroplatinum(II) were equally effective. Platinum(II) adducts of Ap4A were neither degraded by Ap4A-specific pyrophosphohydrolases nor by phosphodiesterase nor in the presence of unfractionated extract of calf thymus. Unphysiologically high concentrations of Crotalus durissus phosphodiesterase I were required for hydrolytic splitting, the amount of which was similar for both platinum(II) isomer adducts. The results suggest that Ap4A platinum(II) adducts might accumulate during chemotherapy of cancer treatment.

Diffusion-controlled receptor occupancy determines the rate of inotropic action of some cardioactive steroids.

In guinea-pig myocardium the rates of onset and offset of the inotropic effects of digitoxigenin-monodigitoxoside, digitoxin, ouabain, digoxin, digoxigenin, and dihydroouabain correlated negatively, and independently of the lipophilicity of the steroids, with their intropic and Na-K-ATPase inhibitory potencies. The intropic potency of ouabain was considerably higher than that of dihydroouabain whereas its inotropic effect developed much more slowly (T50 17 min v. 3 min). By contrast, the inhibition of sarcolemmal Na-K-ATPase by equieffective concentrations of these steroids appeared at similar rates within a few minutes. The homogeneity of the effects, as shown by parallel concentration-effect curves with similar order of potencies of the inotropic and the Na-K-ATPase inhibitory effects, excluded the different activation of inhomogeneous receptor populations. The correlation between the geometry of the papillary muscles and the rates of onset of the inotropic ouabain effect or tissue/medium ratios of 3H-ouabain indicated the relevance of diffusion. The discrepancy between the rates of action in sarcolemmal preparations and in papillary muscles could thus be related to the different diffusion distances. The apparently contradictory results in which receptor occupation (dependence of T50 on EC50) appeared as the rate-limiting step are explained by diffusion-controlled receptor occupancy: the reduced rate of diffusion due to an affinity-dependent reduction of the free drug concentration (receptor occupancy as a temporal 'site of loss') accounted for the slow onset of the inotropic effect of the highly potent cardioactive steroids.

Potassium changes the relationship between receptor occupancy and the inotropic effect of cardiac glycosides in guinea-pig myocardium.

K+ (2.4-15.6 mmol l-1) antagonized the positive inotropic effect of dihydro-ouabain. The concentration-effect curves became steeper with the shift to higher concentrations of the glycoside. At 1.2 mmol l-1 Ca2+, an increase in K+ from 2.4 to 12 mmol l-1 required tenfold higher concentrations of dihydro-ouabain to produce equal inotropic effects. This factor was reduced to four at 3.2 mmol l-1 Ca2+. The same change in K+ concentration, at 1.2 mmol l-1 Ca2+, diminished the inotropic effect of ouabain on rested-state contractions by a factor of six. The positive inotropic effect of Ca2+ was also antagonized by K+ (1.2-12 mmol l-1). Reduction of Na+ from 140 to 70 mmol l-1 abolished the antagonistic action of K+ (1.2-8.0 mmol l-1). Moreover the inotropic effect of Ca2+ was enhanced. Reduction of Na+, from 140 to 70 mmol l-1, antagonized the positive inotropic effect of dihydro-ouabain more at low (2.4 mmol l-1) than at high (8.0 mmol l-1) K+. Accordingly, the extent of the dihydro-ouabain-K+ antagonism was reduced. When the K+ concentration was increased from 2.4 to 12 mmol l-1, [3H]-ouabain binding was reduced by a factor of three. This is less than the reduction in the inotropic effectiveness of ouabain or dihydro-ouabain. Reduction of stimulation frequency from 1 to 0.1215 Hz did not significantly alter the antagonistic effect of K+. Diminution of Vmax of the action potential was observed only at K+ concentrations greater than 5.9 mmol l-1, whereas the resting membrane potential was continuously depolarized over the entire range of K+ concentrations. The results support the view that the reduction in receptor affinity cannot be the sole cause of the antagonism between the glycoside and K+. Impairment of passive Na+ influx during diastole, due to the K+-dependent depolarization of the resting membrane potential, contributed to about one half of the glycoside-K+ antagonism.