Genes,agents and the institution of responsible action

The concern of this paper is with how the accounts of human beings and their behaviour now emerging from genetics, genomics and the new human biotechnology should be related to traditional accounts in which we identify ourselves as responsible agents, capable of choice, who normally act freely and voluntarily. The paper addresses these apparently competing accounts in terms of their functions and modes of use, and thereby arrives at a general solution to this current version of the ancient problem of free will and determinism. The causal scientific discourse of genetics and the everyday discourse of responsibility and choice do different things for us, it suggests, and should not be regarded as articulating conflicting theories. Whilst the former is oriented to the task of naturalistic explanation, the latter is predominantly, if not entirely, a medium of communication through which we affect each other and thereby mutually regulate our conduct. If this is indeed the case, then interesting implications follow concerning the proper relationship of the two kinds of account, which need no longer be regarded as incompatible with each other. And insights emerge into both the limitations and the profound importance of the contribution that genetics and genomics seem destined to make to the understanding of human behaviour.     

Phencyclidine-induced depressions of cerebellar purkinje neurons

Local administration of phencyclidine (PCP) by pressure ejection elicited a dose-dependent slowing of the spontaneous discharge of cerebellar Purkinje neurons. Ketamine also depressed firing and was much less potent than PCP. Effects of both PCP and ketamine were antagonized by local or parenteral administration of antipsychotic drugs. The similarities between the electrophysiological and behavioral actions of phencyclidine suggest that alterations in neuronal discharge may underlie its psychotomimetic properties.     

Rapid determination of substrate specificity of Clostridium histolyticum beta-collagenase using an immobilized peptide library.

The molecular basis of the substrate specificity of Clostridium histolyticum beta-collagenase was investigated using a combinatorial method. An immobilized positional peptide library, which contains 24,000 sequences, was constructed with a 7-hydroxycoumarin-4-propanoyl (Cop) fluorescent group attached at the N terminus of each sequence. This immobilized peptide library was incubated with C. histolyticum beta-collagenase, releasing fluorogenic fragments in the solution phase. The relative substrate specificity (k(cat)/K(m)) for each member of the library was determined by measuring fluorescence intensity in the solution phase. Edman sequencing was used to assign structure to subsites of active substrate mixtures. Collectively, the substrate preference for subsites (P(3)-P(4)') of C. histolyticum beta-collagenase was determined. The last position on the C-terminal side in which the identity of the amino acids affects the activity of the enzyme is P(4)', and an aromatic side chain is preferred in this position. The optimal P(1)'-P(3)' extended substrate sequence is P(1)'-Gly/Ala, P(2)'-Pro/Xaa, and P(3)'-Lys/Arg/Pro/Thr/Ser. The Cop group in either the P(2) or P(3) position is required for a high substrate activity with C. histolyticum beta-collagenase. S(2) and S(3) sites of the protease play a dominant role in fixing the substrate specificity. The immobilized peptide library proved to be a powerful approach for assessing the substrate specificity of C. histolyticum beta-collagenase, so it may be applied to the study of other proteases of interest.     

Isoleucine and Valine Metabolism in Escherichia coli XVIII. Induction of Acetohydroxy Acid Isomeroreductase

The regulation by substrate induction of the acetohydroxy acid isomeroreductase was studied in Escherichia coli. Induction was inhibited by chloramphenicol and rifampin. The addition of rifampin resulted in a decay of the capacity to form isomeroreductase. This was attributed to the breakdown of the isomeroreductase messenger, which had a half-life of about 45 sec at 37 C. Induction of isomeroreductase was enhanced by including glucose in the medium. This effect was shown to be due in part to the lowering of the pH of the medium, which presumably made inducer entry more rapid.     

Superoxide perturbation of the organization of vascular endothelial cell membranes

Cultured porcine thoracic aorta endothelial cells were covalently labeled with 4-maleimido-2,2,6,6-tetramethylpiperidinooxyl. Electron paramagnetic resonance spectrometry revealed two major binding environments representing strongly and weakly immobilized species. The disorder parameter of weak/strong, determined from the respective peak amplitudes, was irreversibly elevated following incubation of endothelial cells with a superoxide-generating system, indicating increased membrane fluidity. The rate of increase in membrane disorder was dependent upon superoxide generation rates. Incorporation of the spin-label at concentrations less than 250 microM had no effect on cell viability. The cellular proteins reacting with the spin-label were predominantly membrane proteins, characterized by immunoblotting using a rabbit anti-4-maleimido-2,2,6,6-tetramethylpiperidinooxyl IgG, following sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrophorectic transfer to nitrocellulose.     

On the fisher and the cubic-polynomial equations for the propagation of species properties

For precise boundary conditions of biological relevance, it is proved that the steadily propagating plane-wave solution to the Fisher equation requires the unique (eigenvalue) velocity of advance 2(Df)^1/2, whereD is the diffusivity of the mutant species andf is the frequency of selection in favor of the mutant. This rigorous result shows that a so-called “wrong equation”, i.e. one which differs from Fisher's by a term that is seemingly inconsequential for certain initial conditions, cannot be employed readily to obtain approximate solutions to Fisher's, for the two equations will often have qualitatively different manifolds of exact solutions. It is noted that the Fisher equation itself may be inappropriate in certain biological contexts owing to the manifest instability of the lowerconcentration uniform equilibrium state (UES). Depicting the persistence of a mutantdeficient spatial pocket, an exact steady-state solution to the Fisher equation is presented. As an alternative and perhaps more faithful model equation for the propagation of certain species properties through a homogeneous population, we consider a reaction-diffusion equation that features a cubic-polynomial rate expression in the species concentration, with two stable UES and one intermediate unstable UES. This equation admits a remarkably simple exact analytical solution to the steadily propagating plane-wave eigenvalue problem. In the latter solution, the sign of the eigenvelocity is such that the wave propagates to yield the “preferred” stable UES (namely, the one further removed from the unstable intermediate UES) at all spatial points ast→∞. The cubic-polynomial equation also admits an exact steady-state solution for a mutant-deficient or mutant-isolated spatial pocket. Finally, the perpetuating growth of a mutant population from an arbitrary localized initial distribution, a mathematical problem analogous to that for ignition in laminar flame theory, is studied by applying differential inequality analysis, and rigorous sufficient conditions for extinction are derived here.