The fundamentals of clinical discovery

There is a widespread view that clinical research is failing to advance appropriately, particularly in comparison with other aspects of biomedical science. I argue that this is due in part to an inadequate understanding of how medical advance occurs. The common usage of such terms as basic or fundamental, or the uncritical use of the term model is unhelpful--unhelpful, in that such terms tend to presuppose a certain model of clinical advance that is unusual, and furthermore, because they tend to exaggerate the importance of research in subjects such as biochemistry and genetics at the expense of other areas. I suggest that much medical research is best viewed as a form of engineering rather than science, and that the knowledge base and research funding for the amelioration of disease needs to be much more broadly based than at present.     

Old soldiers never die ....

An ancestral supersoldier phenotype of Pheidole ants can be recovered when selection for supersoldiers re-emerges, indicating that the developmental potential for caste pathways is retained.     

To build an enzyme....

The structural components that lead to enzyme function are discussed for one simple enzyme-catalysed reaction: that mediated by triosephosphate isomerase. First, the recognition and binding of the substrates' phospho group is seen to involve four main-chain-NH-hydrogen bonds, two of which are positioned at the positive end of a short alpha-helix aimed precisely at the phospho group and interact with the three peripheral phospho group oxygens. Second, the chemical steps (of substrate enolization) are shown to require both base and general acid catalysis. The identity and the positioning of the base, a carboxylate group, nicely fulfils the expectations both of mechanistic economy and of stereoelectronics. The identity of the general acid is shown by Fourier transform infrared and by 15N nuclear magnetic resonance (NMR) to be a neutral imidazole group, lying between the two substrate oxygens. The positioning of the ring is ideal, but its protonation state is unexpected. Thus the pKa of this histidine side-chain is less than 4.5, lowered from 6.5 (the value in the denatured protein) by its position at the positive end of another well-aimed alpha-helix. Third, the need for enzymes to provide kinetic barriers to the loss of reaction intermediates from the active site is emphasized. Triosephosphate isomerase achieves this sequestration of the reaction intermediate by using a flexible loop of the protein, and thus improves the efficiency of the catalysed transformation.     

Stickiness--some fundamentals of adhesion

We review some adhesion mechanisms that have been understoodin the field of synthetic adhesives, and more precisely foradhesives that adhere instantaneously (a property named tackiness)and whose adhesive strength usually depends on the applied pressure(pressure-sensitive adhesives). The discussion includes effectsof surface roughness, elasticity, cavitation, viscous and elasticfingering, substrate flexibility.