The Precautionary Principle in the Information Society

The Precautionary Principle aims to anticipate and minimize potentially serious or irreversible risks under conditions of uncertainty. Thus it preserves the potential for future developments. It has been incorporated into many international treaties and pieces of national legislation for environmental protection and sustainable development. However the Precautionary Principle has not yet been applied systematically to novel Information and Communication Technologies (ICTs) and their potential environmental, social, and health effects. In this article we argue that precaution is necessary in this field and show how the general principle of precaution can be put in concrete terms in the context of the information society. We advocate precautionary measures directed towards pervasive applications of ICT (Pervasive Computing) because of their inestimable potential impacts on society.     

The regional distribution of manganese in the normal human brain

The concentration of manganese per gram dry tissue weight was determined in samples from 39 areas of 8 normal human brains. Manganese was shown to be unevenly distributed with the largest concentrations in the pineal gland and the olfactory bulb. The gray matter yielded a higher content of manganese than the white matter. Significant differences between individuals were found for identical areas of the gray and white matter of the cerebral cortex. Higher levels of manganese were demonstrated in the tail of the caudate nucleus than in the body and the head of the same structure. No significant correlation was shown between the amount of manganese in brain and age.     

Phagocytosis by rat peritoneal mast cells: independence of IgG Fc-mediated and C3-mediated signals

Phagocytosis of sheep erythrocytes (E) bearing rabbit immunoglobulin and rat C3 by rat peritoneal mast cells was quantitated by using 51Cr-labeled E and was confirmed by electron microscopy. The relative importance of IgG Fc receptor interaction in C3-mediated phagocytosis was assessed. Removal of any traces of IgG antibody by absorption of IgM antibody with protein A-Sepharose and absorption of the other reagents with sheep E had no effect on the phagocytosis of C3b- and C3bi-coated cells. IgG antibody enhanced the phagocytosis of intermediates prepared with IgM, purified components and rat C3 (EaIgMClgp4hu oxy2hu3brat) with a graded dose response, but was only additive and not synergistic with C3. The independence of the C3- and Fc-mediated signals was confirmed by using chemically produced polymers of rabbit IgG to inhibit phagocytosis. These polymers, especially tetramers and higher aggregates, completely blocked ingestion of EAIgG, but not that of EAIgMC1423b or -3bi. When IgG was substituted for IgM in the C3b intermediate, the IgG polymers inhibited about 50% of the phagocytosis. Cumulatively, the data demonstrated that in the case of rat mast cells, the stimuli to phagocytosis induced by C3 and IgG are independent; either is sufficient by itself.     

Topology of diphtheria toxin in lipid vesicle membranes: a proteolysis study

The diphtheria toxin (DT) membrane topology was investigated by proteolysis experiments. Diphtheria toxin was incubated with asolectin liposomes at pH 5 in order to promote its membrane insertion, and the protein domains located outside the lipid vesicles were digested with proteinase K (which is a non-specific protease). The protected peptides were separated by electrophoresis and identified by microsequence analysis. Their orientation with respect to the lipid bilayer and their accessibility to the aqueous phase were determined by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR). These data, combined with those provided by proteolytic cleavage with a specific protease (endoproteinase Glu-C), led us to propose a topological model of the N-terminal part of the diphtheria toxin B fragment inserted into the lipid membrane. In this model, two a-helices adopt a transmembrane orientation, with their axes parallel to the lipid acyl chains, while a third o-helix could adopt a transmembrane topology only in a small proportion of DT molecules.     

Degradation of human anaphylatoxin C3a by rat peritoneal mast cells: a role for the secretory granule enzyme chymase and heparin proteoglycan

Purified human C3a was iodinated (125I-C3a) and used to study the interaction of labeled peptide with rat peritoneal mast cells (RMC). Cellular binding of 125I-C3a occurred within 30 sec, followed by a rapid dissociation from the cell. Both the binding of 125I-C3a and the rate of dissociation from the cell were temperature dependent. At 0 degrees C, the binding of 125I-C3a was increased and the rate of dissociation reduced, as compared with 37 degrees C. Once 125I-C3a was exposed to RMC, it lost the ability to rebind to a second batch of RMC. Analysis of the supernatants by trichloroacetic acid (TCA) precipitation and electrophoresis in sodium dodecyl sulfate polyacrylamide gels (SDS PAGE) revealed a decrease in the fraction of 125I precipitable by TCA and the appearance of 125I-C3a cleavage fragments. Pretreatment of RMC with enzyme inhibitors specific for chymotrypsin, but not trypsin, abrogated the degradation of 125I-C3a. Treatment of RMC bearing 125I-C3a with bis (sulfosuccinimidyl) suberate (BS3) covalently cross-linked the 125I-C3a to chymase, the predominant enzyme found in the secretory granules. Antiserum directed against chymase precipitated 125I-C3a from extracts of RMC treated with BS3. Indirect immunofluorescence of RMC by using the IgG fraction of goat anti-rat chymase showed that chymase is present on the surface of unstimulated cells. Neither purified chymase nor heparin proteoglycan alone had any appreciable effect on 125I-C3a, but together they resulted in prompt degradation of the 125I-C3a. Immunoabsorption of RMC sonicates with specific antibody for chymase completely abrogated the ability of these sonicates to degrade 125I-C3a. The results indicate that 125I-C3a binds to RMC and is promptly degraded by chymase in the presence of heparin proteoglycan.     

Monoclonal antibody to human IgG Fc receptors. Cross-linking of receptors induces lysosomal enzyme release and superoxide generation by neutrophils

The monoclonal antibody KuFc79 binds to a determinant on the Fc receptors (Fc gamma R) of human leukocytes. We examined the biologic effects of the interaction of this antibody with Fc gamma R on human neutrophils (PMNL). The univalent Fab fragment of KuFc79 inhibits the formation of rosettes with IgG-sensitized sheep erythrocytes by as much as 91.7%. In other experiments in which PMNL were washed after exposure to Fab of KuFc79, phagocytosis of IgG-sensitized sheep erythrocytes was inhibited by 36%. Fab fragments of other mouse IgG2b monoclonal proteins did not have these effects. When PMNL are exposed to coverslips coated with univalent Fab fragments of this antibody, the Fc gamma R are removed from the surface of the PMNL. Under these conditions, rosetting could be inhibited by 85.4%. We examined cross-linking of receptor bound monoclonal antibody or its Fab fragment by either Protein A or F(ab')2 of an anti-mouse Ig. As much as 31.7% of beta-glucuronidase, a marker for lysosomal enzymes, is specifically released by cross-linking the Fc gamma R on PMNL. The generation of O2- is also induced by specifically cross-linking Fc gamma R with Fab and anti-Fab. The data constitute the first formal demonstration that cross-linking of Fc gamma R on PMNL leads to enzyme release and superoxide generation.     

Implicit and Explicit Timing in Oculomotor Control

The passage of time can be estimated either explicitly, e.g. before leaving home in the morning, or implicitly, e.g. when catching a flying ball. In the present study, the latency of saccadic eye movements was used to evaluate differences between implicit and explicit timing. Humans were required to make a saccade between a central and a peripheral position on a computer screen. The delay between the extinction of a central target and the appearance of an eccentric target was the independent variable that could take one out of four different values (400, 900, 1400 or 1900 ms). In target trials, the delay period lasted for one of the four durations randomly. At the end of the delay, a saccade was initiated by the appearance of an eccentric target. Cue&target trials were similar to target trials but the duration of the delay was visually cued. In probe trials, the duration of the upcoming delay was cued, but there was no eccentric target and subjects had to internally generate a saccade at the estimated end of the delay. In target and cue&target trials, the mean and variance of latency distributions decreased as delay duration increased. In cue&target trials latencies were shorter. In probe trials, the variance increased with increasing delay duration and scalar variability was observed. The major differences in saccadic latency distributions were observed between visually-guided (target and cue&target trials) and internally-generated saccades (probe trials). In target and cue&target trials the timing of the response was implicit. In probe trials, the timing of the response was internally-generated and explicitly based on the duration of the visual cue. Scalar timing was observed only during probe trials. This study supports the hypothesis that there is no ubiquitous timing system in the brain but independent timing processes active depending on task demands.     

Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers

Presenilin is the enzymatic component of gamma-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for gamma-tubulin in the pathway.     

Exercise training in normobaric hypoxia in endurance runners. II. Improvement of mitochondrial properties in skeletal muscle.

This study investigates whether adaptations of mitochondrial function accompany the improvement of endurance performance capacity observed in well-trained athletes after an intermittent hypoxic training program. Fifteen endurance-trained athletes performed two weekly training sessions on treadmill at the velocity associated with the second ventilatory threshold (VT2) with inspired O2 fraction = 14.5% [hypoxic group (Hyp), n = 8] or with inspired O2 fraction = 21% [normoxic group (Nor), n = 7], integrated into their usual training, for 6 wk. Before and after training, oxygen uptake (VO2) and speed at VT2, maximal VO2 (VO2 max), and time to exhaustion at velocity of VO2 max (minimal speed associated with VO2 max) were measured, and muscle biopsies of vastus lateralis were harvested. Muscle oxidative capacities and sensitivity of mitochondrial respiration to ADP (Km) were evaluated on permeabilized muscle fibers. Time to exhaustion, VO2 at VT2, and VO2 max were significantly improved in Hyp (+42, +8, and +5%, respectively) but not in Nor. No increase in muscle oxidative capacity was obtained with either training protocol. However, mitochondrial regulation shifted to a more oxidative profile in Hyp only as shown by the increased Km for ADP (Nor: before 476 +/- 63, after 524 +/- 62 microM, not significant; Hyp: before 441 +/- 59, after 694 +/- 51 microM, P < 0.05). Thus including hypoxia sessions into the usual training of athletes qualitatively ameliorates mitochondrial function by increasing the respiratory control by creatine, providing a tighter integration between ATP demand and supply.