Michael J Lew | PubMed Health

PubMed2006

Principles: when there should be no difference--how to fail to reject the null hypothesis.

It is common to perform experiments in which a 'success' is claimed when the null hypothesis is discarded. However, there is a category of experiment that has become important in which a success is when the null hypothesis is not rejected. Failing to discard the null hypothesis is different from proving it to be valid, a distinction that is particularly important in experiments in which any inadequacy of experimental design or implementation enhances the likelihood of a success. The appropriate analysis of such experiments tests for evidence of the validity of the null hypothesis rather than simply failing to find evidence against it.

Confidence Intervals↗

PubMed2004

The two-state model of antagonist-AT1 receptor interaction: an hypothesis defended but not tested.

A correlation between insurmountable antagonism and slow dissociation has been observed for the non-peptidic AT1 receptor antagonists. This commentary examines the validity of conclusions regarding a two stage binding mechanism that has been proposed in order to account for both the slow dissociation and insurmountable antagonism. Support for that hypothetical mechanism is in the form of the goodness of fit between experimental data and modelled data in a number of papers from the same laboratory. We challenge the idea that a simple match of model and data is an adequate test of an hypothesis by showing that a simpler model matches the data equally well. We conclude that two stage binding is not necessary to explain the behaviour of AT1 receptor antagonists.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2002

Side-chain substitutions within angiotensin II reveal different requirements for signaling, internalization, and phosphorylation of type 1A angiotensin receptors.

Binding of the peptide hormone angiotensin II (AngII) to the type 1 (AT(1A)) receptor and the subsequent activation of phospholipase C-mediated signaling, involves specific determinants within the AngII peptide sequence. In contrast, the contribution of such determinants to AT(1A) receptor internalization, phosphorylation and activation of mitogen-activated protein kinase (MAPK) signaling is not known. In this study, the internalization of an enhanced green fluorescent protein-tagged AT(1A) receptor (AT(1A)-EGFP), in response to AngII and a series of substituted analogs, was visualized and quantified using confocal microscopy. AngII-stimulation resulted in a rapid, concentration-dependent internalization of the chimeric receptor, which was prevented by pretreatment with the nonpeptide AT(1) receptor antagonist EXP3174. Remarkably, AT(1A) receptor internalization was unaffected by substitution of AngII side chains, including single and double substitutions of Tyr(4) and Phe(8) that abolish phospholipase C signaling through the receptor. AngII-induced receptor phosphorylation was significantly inhibited by several substitutions at Phe(8) as well as alanine replacement of Asp(1). The activation of MAPK was only significantly inhibited by substitutions at position eight in the peptide and specific substitutions did not equally inhibit inositol phosphate production, receptor phosphorylation and MAPK activation. These results indicate that separate, yet overlapping, contacts made between the AngII peptide and the AT(1A) receptor select/induce distinct receptor conformations that preferentially affect particular receptor outcomes. The requirements for AT(1A) receptor internalization seem to be less stringent than receptor activation and signaling, suggesting an inherent bias toward receptor deactivation.

Angiotensin II↗