Sulfide salts are known to promote the release of nitric oxide (NO) from S-nitrosothiols and potentiate their vasorelaxant activity, but much of the cross-talk between hydrogen sulfide and NO is believed to occur via functional interactions of cell regulatory elements such as phosphodiesterases. Using RFL-6 cells as an NO reporter system we sought to investigate whether sulfide can also modulate nitrosothiol-mediated soluble guanylyl cyclase (sGC) activation following direct chemical interaction. We find a U-shaped dose response relationship where low sulfide concentrations attenuate sGC stimulation by S-nitrosopenicillamine (SNAP) and cyclic GMP levels are restored at equimolar ratios. Similar results are observed when intracellular sulfide levels are raised by pre-incubation with the sulfide donor, GYY4137. The outcome of direct sulfide/nitrosothiol interactions also critically depends on molar reactant ratios and is accompanied by oxygen consumption. With sulfide in excess, a ‘yellow compound’ accumulates that is indistinguishable from the product of solid-phase transnitrosation of either hydrosulfide or hydrodisulfide and assigned to be nitrosopersulfide (perthionitrite, SSNO−; λmax 412 nm in aqueous buffers, pH 7.4; 448 nm in DMF). Time-resolved chemiluminescence and UV–visible spectroscopy analyses suggest that its generation is preceded by formation of the short-lived NO-donor, thionitrite (SNO−). In contrast to the latter, SSNO− is rather stable at physiological pH and generates both NO and polysulfides on decomposition, resulting in sustained potentiation of SNAP-induced sGC stimulation. Thus, sulfide reacts with nitrosothiols to form multiple bioactive products; SSNO− rather than SNO− may account for some of the longer-lived effects of nitrosothiols and contribute to sulfide and NO signaling.

A unified numerical approach to evaluate the endurance limit for general multiaxial fatigue loading, under proportional or nonproportional loading, is presented. A minimum circumscribed ellipsoid approach is proposed for computing the amplitude and mean value of the equivalent shear stress, and an efficient numerical algorithm is developed for solving the min-max problem by using a constrained optimization method. The approach is general and efficient, especially suitable for computer-aided design and optimization. With this approach, nonproportional loading effects can be taken into account, overcoming limitations of many other multiaxial fatigue criteria. Experimental results collected from the literature are compared with results predicted by the numerical approach proposed in this paper. The comparison shows that the predictions agree well with experiments for both proportional and nonproportional loading situations.

SUMMARYA unified approach is presented for design sensitivity analysis of non-linear structural systems that include truss, beam, plane elastic solid and plate components. Both geometric and material non-linearities are treated. Sizing design variables, such as thickness and cross-sectional areas of components of individual members and built-up structures, are considered. A distributed parameter structural design sensitivity analysis approach is used that retains the continuum elasticity formulation throughout the derivation of design sensitivity analysis results. Using this approach and an adjoint variable method, expressions for design sensitivity in terms of design variations are derived in the continuous setting which can be evaluated numerically using analysis results of finite element analysis. Both total Lagrangian and updated Lagrangian formulations in non-linear analysis of solid mechanics are used for design sensitivity analysis. Numerical implementation of design sensitivity analysis results using existing finite element code will be presented in Part I1 of this paper.

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