The normativity of artefacts

Part of the distinction between artefacts, objects made by humans for particular purposes, and natural objects is that artefacts are subject to normative judgements. A drill, say, can be a good drill or a poor drill, it can function well or correctly or it can malfunction. In this paper I investigate how such judgements fit into the domain of the normative in general and what the grounds for their normativity are. Taking as a starting point a general characterization of normativity proposed by Dancy, I argue how statements such as ‘this is a good drill’ or ‘this drill is malfunctioning’ can be seen to express normative facts, or the content of normative statements. What they say is that a user who has a desire to achieve a particular relevant outcome has a reason to use, or not to use, the artefact in question. Next this analysis is extended to show that not just statements that say that an artefact performs its function well or poorly, but all statements that ascribe a function to an artefact can be seen as expressing a normative fact. On this approach the normativity of artefacts is analyzed in terms of reasons on grounds of practical, and to a lesser extent theoretical, rationality. I close by investigating briefly to what extent reasons on moral grounds are, in the analysis adopted here, involved in the normativity of artefacts.     

Little effect of dimethyl sulfoxide on blood-brain barrier to dopamine

Summary Rats were treated with dimethyl sulfoxide (DMSO) intraperitoneally or intravenously, and simultaneously with dopamine (DA). The presence of DMSO resulted in small or no increases in brain levels of DA or its metabolites.Acknowledgments. Supported in part by the Parkinson's Disease Foundation and by a Peggy Engl Fellowship to Dr Walters.     

Anticonidiogenic effect of hydroxyurea on Neurospora crassa]

Conidiation induced in a low sugar-ammonium medium (or by other means such as full starvation or heat shock) is almost fully prevented by hydroxyurea. In a parallel manner the DNA/RNA and DNA/protein ratios are prevented from increasing.     

Biochemical events associated with rapid cellular damage during the oxygen- and calcium-paradoxes of the mammalian heart

The O2- and Ca2(+)-paradoxes have a number of features in common and it is suggested that release of cytosolic proteins in both paradoxes is initiated by the activation of a sarcolemma NAD(P)H dehydrogenase which can generate a transmembrane flow of H+ and e- and also oxygen radicals or redox cycling which damage ion channels and membrane proteins (phase I). Entry of Ca2+ through the damaged ion channels then exacerbates the damage by further activating this system, either directly or indirectly, and the redox cycling and/or oxygen radicals cause further damage to integral and cytoskeletal proteins of the sarcolemma resulting in microdamage to the integrity of the membrane (phase II) and the consequent release or exocytosis of cytoplasmic proteins and, under specialised conditions, the blebbing of the sarcolemma. The system may be primed either by removal of extracellular Ca2+ or by raising [Ca2+]i by a variety of measures, these two actions being synergistic. The system is initially activated in the Ca2(+)-paradox by the membrane perturbation associated with removal of extracellular Ca2+; prolonged anoxia in the metabolically active cardiac muscle causes a depletion of the ATP supply, particularly in the absence of glucose, and hence a rise in [Ca2+]i in phase I of the oxygen paradox with the consequent activation of the NAD(P)H oxidase at the sarcolemma. Oxygen radicals are probably generated in both paradoxes and may have a partial role in the genesis of damage, but are not essential in the Ca2(+)-paradox which continues under anoxia. Massive entry of Ca2+ also activates an intracellularly localised dehydrogenase (probably at the SR) which produces myofilament damage by redox cycling.     

Role of intracellular calcium in promoting muscle damage: a strategy for controlling the dystrophic condition.

It is suggested that various muscle diseases and examples of experimentally-induced muscle damage arise because of a high calcium level in the myoplasm. When [Ca2+]i is raised experimentally in amphibian or mammaliam muscle by treatment with A23187 or caffeine, myofilament degradation follows quickly. Such a rapid action suggests the involvement of a sequence of proteolytic activity that is stimulated by a rise in [Ca2+]i. Ca2+ might either trigger protease activity directly or indirectly, or promote the release of lysosomal enzymes. A high [Ca2+]i in dystrophic muscle is believed to be the resultant of a sequence of events that is summarized in the figure. Suggestions are presented for different ways in which the steady-state position of [Ca2+]i might ultimately be controlled for the clinical amelioration of some dystrophic conditions.     

Altered or increased transfer-RNA methylation in the course of Interferon action on cells in culture?

Summary The induction of the antiviral state by Interferon might reflect the decrease of the rate of biosynthesis, the degradation or the alteration of one or several tRNAs. This could result in rate-limiting concentrations for codons common in viral RNA but rare in host mRNA. Altered methylation of tRNA could be the basis of such a phenomenon. However, we could not find an altered extent of methylation of total tRNA or an altered pattern of methylation, if mixed tRNAs were chromatographed on MAK- or BD-cellulose columns, despite a large range of conditions of pretreatment of chick embryo fibroblast cultures with interferon.Work supported by the Swiss National Science Foundation, grants 3.1050 and 3.540.     

The identification of chemical intermediates in enzyme catalysis by the rapid quench-flow technique

Traditionally, enzyme transient kinetics have been studied by the stopped-flow and rapid quench-flow (QF) methods. Whereas stopped-flow is the more convenient, it suffers from two weaknesses: optically silent systems cannot be studied, and when there is a signal it cannot always be assigned to a particular step in the reaction pathway. QF is a chemical sampling method; reaction mixtures are aged for a few milliseconds or longer, ‘stopped’ by a quenching agent and the product or the intermediate is measured by a specific analytical method. Here we show that by exploiting the array of current analytical methods and different quenching agents, the QF method is a key technique for identifying, and for characterising kinetically, intermediates in enzyme reaction pathways and for determining the order by which bonds are formed or cleaved by enzymes acting on polymer substrates such as DNA. Received 24 May 2006; received after revision: 3 July 2006; accepted 19 July 2006     

Zur entwicklungsphysiologischen Wirkungsanalyse von antimitotischen Stoffen

Summary The cleavage mitoses of eggs of the fresh-water oligochete Tubifex may be irreversibly blocked, if treated during a relatively short time by solutions of certain antimitotic substances (benzoquinone, naphthoquinone or colchicine). It is also possible to inhibit tail regeneration in tadpoles of Rana or Xenopus by a single colchicine treatment during only 30 to 60 minutes. It is discussed whether this is due to irreversible loss of regeneration capacity or simply to an inhibition of the first regeneration processes.     

Effect of pectin and cellulose on formation and regression of gallstones in hamsters

Summary Male Syrian hamsters were fed a lithogenic diet containing 7% cellulose or 4.2% pectin. After 50 days, pectin was 76% and cellulose 64% less lithogenic than the control diet. Hamsters fed the control diet for 50 days were maintained on that diet for another 50 days or fed diets containing cellulose or pectin. These was a 52% increase in gallstone incidence in hamsters continued on the control diet and a 9% increase in those on cellulose. Pectin promoted regression of gallstones (by 52%).Acknowledgments. This work was supported, in part, by a grant (HL-03299) and a Research Career Award (HL-00734) from the National Institutes of Health, and by funds from Mary L. Smith and the Commonwealth of Pennsylvania.     

Role of serum components in the binding and phagocytosis of oxidatively damaged erythrocytes by autologous mouse macrophages

To investigate the role of autologous serum components in the recognition of damaged cells by macrophages, we examined the binding and phagocytosis of damage oxidatively damaged red blood cells with Cu2+ and ascorbate (oxRBCs) by autologous resident mouse peritoneal macrophages. The binding of oxRBCs by macrophages was independent of the presence of serum. However, phagocytosis by macrophages increased with serum concentration, and macrophages showed little ingestion of oxRBCs in a serum-free medium. Macrophages neither bound nor appreciably ingested native RBCs (before oxidation) in either the absence or presence of autologous serum. Mouse macrophages ingested significantly more native as well as oxRBCs in the presence of heat-inactivated fetal calf serum than in the presence of heat-inactivated mouse serum. Pretreated oxRBCs with normal serum were rarely ingested by macrophages in a serum-free medium. Phagocytosis of oxRBCs was significantly inhibited by depletion of IgG or calcium from serum, by heat inactivation of complement, or by antiserum against mouse C3. These results demonstrate that serum components such as IgG, C3, and calcium are involved in phagocytosis of oxRBCs by autologous macrophages.     

Biological weapons

Bioterrorism is defined by the intentional or threatened of microorganisms or toxins derived from living organisms to cause death or diseases in humans, animals or plants on which we depend. The other major point is to generate fear in the population. More than 180 pathogens have been reported to be potential agents for bioterrorism. The following is an overview of several agents that could be involved in a biological attack.     

Dopaminergic mechanisms in thiophene-2-aldoxime tremor

Summary Tremor induced by thiophene-2-aldoxime is enhanced or reduced in intensity and duration by agents which respectively interfere with or promote dopaminergic tone.This project was supported by a grant from the Lebanese National Research Council. We thank the following companies for the indicated drugs: Abbott (pargyline), Specia (chlorpromazine), Squibb (cinanserin).     

Hsp70: a carrier molecule with built-in adjuvanticity

One problem associated with the development of subunit vaccines is their limited immunogenicity, due to their physico-chemical structure, their inability to encounter the correct MHC restriction element, or the need for strong adjuvants to be delivered along with them. These problems are usually solved by conjugating target epitopes (peptides or oligosaccharides) with carrier proteins which provide a source of T-cell epitopes recognised by a large proportion of the vaccinated individuals. We have shown that mycobacterial hsp65 and hsp70 exert a strong helper effect in vivo when conjugated to synthetic peptides or oligosaccharides. Interestingly, this helper effect did not require the need for any adjuvant, either in mice or in monkeys. The helper effect mediated by the hsp65 required that animals were previously primed with either live BCG or the hsp65 alone; on the other hand, such a priming was not required when the hsp70 was used in the conjugates. Similar results were obtained with HSP molecules fromEscherichia coli. This may suggest that the adjuvant-free helper effect observed applies not only to mycobacterial HSP, but also to HSP from other prokaryotes. These findings suggest that microbial hsp70 could be considered for the design of conjugated vaccine constructs for eventual human use.     

Role of plasminogen activator-plasmin system in tumor angiogenesis

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.     

Maturation of the pineal melatonin rhythm in long- and short-day reared Djungarian hamsters

Summary Male Djungarian hamsters, reared under long (16L/8D) or short (10L/14D) days, were sacrificed at various ages during the day or night, or at night following a 30-min light pulse. The pineal melatonin rhythm matured similarly under long and short days by 20 days of age. The results are discussed in context of the hypothesis that melatonin mediates the photoperiod effects which forestall puberty in short-day reared hamsters.Supported by NIH research grant HD-05481.     

Interaction of chlorpromazine with organic solvents and fatty acids as studied by UV-spectrophotometry

Summary The magnitude of the UV-spectral change of chlorpromazine increases in the presence of increasing concentrations of alcohols or fatty acids and with increasing chain length. A maximum is reached with 14.0- or 16.0-fatty acids. The difference spectrum is still larger with unsaturated fatty acids, a maximum effect being obtained with one cis-double bond. The spectral change is abolished by chaotropic and enhanced by antichaotropic agents.Supported by a grant of the Swiss National Science Foundation.     

Altered or increased transfer-RNA methylation in the course of Interferon action on cells in culture?

The induction of the antiviral state by Interferon might reflect the decrease of the rate of biosynthesis, the degradation or the alteration of one or several tRNAs. This could result in rate-limiting concentrations for codons common in viral RNA but rare in host mRNA. Altered methylation of tRNA could be the basis of such a phenomenon. However, we could not find an altered extent of methylation of total tRNA or an altered pattern of methylation, if mixed tRNAs were chromatographed on MAK- or BD-cellulose columns, despite a large range of conditions of pretreatment of chick embryo fibroblast cultures with interferon.