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.     

Advanced carcinoma of the prostate: treatment with a gonadotrophin releasing hormone agonist.

Ten patients with advanced progressive adenocarcinoma of the prostate were treated with a long acting analogue of gonadotrophin releasing hormone. Eight of these patients responded to treatment in terms of pain relief and clinical regression of tumour. Serum gonadotrophin and testosterone concentrations were significantly suppressed by the end of the second week of treatment, testosterone concentrations being comparable with those achieved by castration. The two patients who failed to respond had both relapsed previously when receiving conventional treatment, and neither showed any endocrine response to the analogue. Superagonists of gonadotrophin releasing hormone may be the treatment of choice in adenocarcinoma of the prostate, but further trials are required to establish long term safety and efficacy.