Abstract: The operational model of agonism assumes that the maximum effect a particular receptor system can achieve (the Em parameter) is fixed. Em estimates are above but close to the asymptotic maximum effects of endogenous agonists. The concept of Em is contradicted by superagonists and those positive allosteric modulators that significantly increase the maximum effect of endogenous agonists. An extension of the operational model is proposed that assumes that the Em parameter does not necessarily have a single value for a receptor system but has multiple values associated to multiple active receptor conformations. The model provides a mechanistic link between active receptor conformation and agonist efficacy, which can be useful for the analysis of agonist response under different receptor scenarios.

Abstract: Deep understanding of myocardial structure linking morphology and function of the heart would unravel crucial knowledge for medical and surgical clinical procedures and studies. Several conceptual models of myocardial fiber organization have been proposed but the lack of an automatic and objective methodology prevented an agreement. We sought to deepen in this knowledge through advanced computer graphic representations of the myocardial fiber architecture by diffusion tensor magnetic resonance imaging (DT-MRI).
We performed automatic tractography reconstruction of unsegmented DT-MRI canine heart datasets coming from the public database of the Johns Hopkins University. Full scale tractographies have been build with 200 seeds and are composed by streamlines computed on the vectorial field of primary eigenvectors given at the diffusion tensor volumes. Also, we introduced a novel multi-scale visualization technique in order to obtain a simplified tractography. This methodology allowed to keep the main geometric features of the fiber tracts, making easier to decipher the main properties of the architectural organization of the heart.
On the analysis of the output from our tractographic representations we found exact correlation with low-level details of myocardial architecture, but also with the more abstract conceptualization of a continuous helical ventricular myocardial fiber array.
Objective analysis of myocardial architecture by an automated method, including the entire myocardium and using several 3D levels of complexity, reveals a continuous helical myocardial fiber arrangement of both right and left ventricles, supporting the anatomical model of the helical ventricular myocardial band described by Torrent-Guasp.

Abstract: Empirical and mechanistic models differ in their approaches to the analysis of pharmacological effect. Whereas the parameters of the former are not physical constants those of the latter embody the nature, often complex, of biology. Empirical models are exclusively used for curve fitting, merely to characterize the shape of the E/[A] curves. Mechanistic models, on the contrary, enable the examination of mechanistic hypotheses by parameter simulation. Regretfully, the many parameters that mechanistic models may include can represent a great difficulty for curve fitting, representing, thus, a challenge for computational method development. In the present study some empirical and mechanistic models are shown and the connections, which may appear in a number of cases between them, are analyzed from the curves they yield. It may be concluded that systematic and careful curve shape analysis can be extremely useful for the understanding of receptor function, ligand classification and drug discovery, thus providing a common language for the communication between pharmacologists and medicinal chemists.