A rational fraction polynomials model to study vertical dynamic wheel-rail interaction

This paper presents a model designed to study vertical interactions between wheel and rail when the wheel moves over a rail welding. The model focuses on the spatial domain, and is drawn up in a simple fashion from track receptances. The paper obtains the receptances from a full track model in the frequency domain already developed by the authors, which includes deformation of the rail section and propagation of bending, elongation and torsional waves along an infinite track. Transformation between domains was secured by applying a modified rational fraction polynomials method. This obtains a track model with very few degrees of freedom, and thus with minimum time consumption for integration, with a good match to the original model over a sufficiently broad range of frequencies. Wheel-rail interaction is modelled on a non-linear Hertzian spring, and consideration is given to parametric excitation caused by the wheel moving over a sleeper, since this is a moving wheel model and not a moving irregularity model. The model is used to study the dynamic loads and displacements emerging at the wheel-rail contact passing over a welding defect at different speeds.

Calpain-Mediated Processing of Adenylate Cyclase Toxin Generates a Cytosolic Soluble Catalytically Active N-Terminal Domain

Bordetella pertussis, the whooping cough pathogen, secretes several virulence factors among which adenylate cyclase toxin (ACT) is essential for establishment of the disease in the respiratory tract. ACT weakens host defenses by suppressing important bactericidal activities of the phagocytic cells. Up to now, it was believed that cell intoxication by ACT was a consequence of the accumulation of abnormally high levels of cAMP, generated exclusively beneath the host plasma membrane by the toxin N-terminal catalytic adenylate cyclase (AC) domain, upon its direct translocation across the lipid bilayer. Here we show that host calpain, a calcium-dependent Cys-protease, is activated into the phagocytes by a toxin-triggered calcium rise, resulting in the proteolytic cleavage of the toxin N-terminal domain that releases a catalytically active "soluble AC''. The calpain-mediated ACT processing allows trafficking of the "soluble AC'' domain into subcellular organella. At least two strategic advantages arise from this singular toxin cleavage, enhancing the specificity of action, and simultaneously preventing an indiscriminate activation of cAMP effectors throughout the cell. The present study provides novel insights into the toxin mechanism of action, as the calpain-mediated toxin processing would confer ACT the capacity for a space- and time-coordinated production of different cAMP "pools'', which would play different roles in the cell pathophysiology.