No abstract

Mathematical modelling of kinetic processes with different time scales allows a reduction of the governing equations using quasi-steady-state approximations (QSSA). A QSSA theorem is applied to a mathematical model of the influence that Raf kinase inhibitor protein (RKIP) has on the ERK signalling pathway. On the basis of previously published parameter values, the system of 11 ordinary differential equations is rewritten in a form suitable for model reduction. In accordance with the terminology of the QSSA theorem, it is established that four of the protein and protein-complex concentrations are 'fast varying', such that the corresponding kinetic equations form an attached system. Another concentration is 'medium varying' such that the corresponding equation is reduced with respect to the four fast ones. The other six concentrations are 'slow varying', which means the corresponding kinetic equations also present a reduced system with respect to the others. Analytical solutions, relating the steady-state values of the fast varying protein concentrations and the slow varying ones, are derived and interpreted as restrictions on the regulatory role of RKIP on ERK-pathway.

Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis animal model. EAE mice typically develop motor deficits in a caudal-to-rostral pattern when inflammatory lesions have already developed. However, to monitor more subtle behavioral deficits during lesion development (i.e., pre-clinical phase), more sophisticated methods are needed. Here, we investigated whether high speed ventral plane videography can be applied to monitor early motor deficits during ‘pre-clinical’ EAE. For this purpose, EAE was induced in C57BL/6 mice and gait abnormalities were quantified using the DigiGait™ apparatus. Gait deficits were related to histopathological changes. 10 out of 10 control (100%), and 14 out of 18 (77.8%) pre-clinical EAE mice could be evaluated using DigiGait™. EAE severity was not influenced by DigiGait™-related mice handlings. Most gait parameters recorded from day 6 post-immunization until the end of the experiment were found to be stable in control mice. During the pre-clinical phase, when conventional EAE scorings failed to detect any functional impairment, EAE mice showed an increased Swing Time, increased %Swing Stride, decreased %Stance Stride, decreased Stance/Swing, and an increased Absolute Paw Angle. In summary, DigiGait™ is more sensitive than conventional scoring approaches to study motor deficits during the EAE pre-clinical phase.