Studies of the dose-effect relation

Dose-effect relations and, specifically, cell survival curves are surveyed with emphasis on the interplay of the random factors--biological variability, stochastic reaction of the cell, and the statistics of energy deposition--that co-determine their shape. The global parameters mean inactivation dose, D, and coefficient of variance, V, represent this interplay better than conventional parameters. Mechanisms such as lesion interaction, misrepair, repair overload, or repair depletion have been invoked to explain sigmoid dose dependencies, but these notions are partly synonymous and are largely undistinguishable on the basis of observed dose dependencies. All dose dependencies reflect, to varying degree, the microdosimetric fluctuations of energy deposition, and these have certain implications, e.g. the linearity of the dose dependence at small doses, that apply regardless of unresolved molecular mechanisms of cellular radiation action.     

Interaction of extrinic fluoresence probes with E. coli glutamine synthetase

Summary Binding of 2-p-toluidinylnaphthalene-6-sulfonate (TNS) to adenylylated glutamine synthetase is cooperative and time-dependent, with 3 dye sites per subunit. In fluorescence polarization experiments TNS and pyrene butyrate give normalized Perrin plots that indicate a symmetrical arrangement of dye excited state dipoles, relative to the rotational axis of the oblate ellipsoid of the dodecameric native enzyme.Acknowledgment. Drs G. Weber and L. Brand are thanked for helpful comments on this work. — Supported in part by grants from the National Science Foundation (BMS 72-02165 and GU-3182). Portions of this work were presented in preliminary form at the 9th International Congress of Biochemistry, Stockholm, Sweden, July 1973.     

Hashish VI1: Conversion of (-)-Δ 1(6)-Tetrahydrocannabinol to (-)-Δ 1(7)-Tetrahydrocannabinol. Stability of (-)-Δ 1 and (-)-Δ 1(6)-Tetrahydrocannabinols

Zusammenfassung Die Synthese von (—)-¹⁽⁷⁾-Tetrahydrocannabinol (THC) auf (—)-¹⁽⁶⁾ wird beschrieben. Das Hauptprodukt der oxidativen Zerstörung von (—)-¹-THC ist Cannabinol. Beschleunigte Versuche der Luftoxidation von (—)-¹-THC und (—)-¹⁽⁶⁾-THC haben gezeigt, dass das letztere beständiger ist. Dieser Unterschied kann mit der Reaktivität des C₃-benzylisch-allylischen Wasserstoffes in (—)-¹-THC erklärt werden.     

Dynamic laser light scattering studies of the effects of pyrophosphate on cyclic motions of cross-bridges in isolated thick myofilaments fromLimulus striated muscle

Pyrophosphate (PP_i) is a non-hydrolyzable ATP analogue known to affect the binding between myosin heads and actin. By using a dynamic laser light scattering method, we have shown that 1–2 mM PP_i enhances the increase in values induced by Ca²⁺ in isolated thick myofilaments fromLimulus striated muscle. However, similar treatment has no effect on the values of filaments suspended in either relaxing solution or ATP-free solution. is the average linewidth of the photoelectron count autocorrelation function of the light scattered. PP_i had no effect on the increase of values by Sr²⁺ but it substantially increased the values of the thick myofilaments suspended in Ba²⁺-substituted Ca²⁺ activating solution. The results show that PP_i also affects the energy-requiring cyclic cross-bridge motions.     

Reduced deformability of erythrocytes exposed to hypercapnia

Summary The effect of hypercapnia on the deformability of erythrocytes was studied by means of a nuclepore membrane filter method. A decrement of the deformability by 20–40% was observed when was increased from 50 mm Hg to 200 mm Hg, accompanied with an increment of 5% in hematocrit value.     

Immunocytochemical localization of hyperglycemic hormone (HGH) in the neurosecretory system of the eyestalk of the crayfishAstacu leptodactylus

Summary Hyperglycemic hormone (HGH) fromAstacus leptodactylus can be visualized by an immunocytochemical procedure using a specific antiserum against HGH and the peroxidase-anti-peroxidase (PAP) method. HGH containing cells are localized in the most distal portion of the x-organ in the medulla terminalis. Their cell diameter is about 47±7 m; the nucleus measures about 22±2 m. They form a subgroup of neurosecretory cell type 1, already described for the crayfish. A large amount of this HGH material is homogeneously stored in the sinus gland. A group of fibres in the x-organ — sinus gland — tractus can be followed, due to their positive reaction with the PAP-reagent.     

Allosteric proteins after thirty years: The binding and state functions of the neuronalα7 nicotinic acetylcholine receptors

A key statement of the 1965 Monod-Wyman-Changeux (MWC) model for allosteric proteins concerns the distinction between the ligand-binding function ( ) and the relevant state function ( ). Sequential models predict overlapping behavior of the two functions. In contrast, a straightforward experimental consequence of the MWC model is that for an oligomeric protein the parameters which characterize the two functions should differ significantly. Two situations, where \bar Y$$ " align="middle" border="0"> and the system ishyper-responsive or where and the system ishypo-responsive, have been encountered. Indeed, the hyper-responsive pattern was first observed for the enzyme aspartate transcarbamoylase, by comparing with monitored by a change in sedimentation. Extensions of the theory to ligand-gated channels led to the suggestion that, on the one hand, hyper-responsive properties also occur with high-affinity mutants. On the other hand, native channels of the acetylcholine neuronal7 receptor and low-affinity mutants of the glycine receptor can be interpreted in terms of the hypo-responsive pattern. For the ligand-gated channels, whereas is detected directly by ion flux, ligand binding has rarely been measured and the formation of desensitized states may complicate the analysis. However, stochastic models incorporating both binding and channel opening for single molecules predict differences that should be measurable with new experimental approaches, particularly fluorescence correlation spectroscopy.     

Effects of DL-propranolol on exercise heart rate and maximal rates of oxygen consumption inScaphiopus intermontanus

Summary Lymphatic injection of propranolol (0.2–10 g) into toads decreased exercise heart rate in a dose-dependent manner. There was a significant linear corrleation between exercise heart rate and maximal oxygen consumption rates . These data are consistent with the hypothesis that blood oxygen transport is the limiting process for max in anuran amphibians.This work was supported by a grant from the National Science Foundation (PCM-8021808). I am grateful to Dr P.C. Withers for logistical support and Dr S. Yokota for the initial idea.     

Proton-induced dismutation of superoxide in aprotic media by bile pigments

Summary Cyclic voltammetry of molecular oxygen in aprotic media (dimethylformamide) and in the presence of bilirubin and other bile pigments shows that superoxide anion ( ) undergoes proton-induced dismutation. Lactam hydrogens of bile pigments are sufficiently acid to induce disproportionation to O₂ and H₂O₂. Because of its characteristic lipophilic behavior, a biological role for natural bilirubin similar to that of other non-enzymatic lipophilic scavengers of is suggested.     

Lack of pressor effect of dopamine in the pentobarbital-anesthetized rat

Summary The blood pressure and heart rate responses to intravenous dopamine infusion at 2.5, 5.0 and 10.0 g·min^–1·100 g^–1 were studied in conscious and pentobarbital-anesthetized Sprague — Dawley rats. In the conscious rats, dopamine caused a significant dose-related increase in the mean arterial blood pressure which was abolished in the anesthetized rats. The heart rate increased significantly only at the highest dose infused. The responses to equipressor doses of noradrenaline (40 ng·min^–1·100 g^–1) and phenylephrine (1.0 g·min^–1·100 g^–1) were also suppressed in the anesthetized rats. The results suggest that pentobarbital anesthesia depresses the blood pressure response to dopamine infusion in the rat through a depression of activation of alpha-adrenoceptors.16 June 1986     

Effects of water acidification on the distribution pattern and the reproductive success of amphibians

Summary Nine amphibian species were encountered in poorly buffered waters of The Netherlands (alkalinity 1 meq·l^–1). These soft water systems are highly sensitive to acidifying precipitation. The number of species as well as the percentage of waters which harbour amphibian populations are strongly reduced in the extremely acid pH-class . The reproductive success of amphibians is negatively affected by low pH. The eggs become heavily infested with fungi (Saprolegniaceae). In acidifying systems many physico-chemical parameters are significantly correlated with the pH of the water. Strongly acidified waters are characterized by low alkalinity, conductivity and ionic content but high acidity and high concentrations of (heavy) metals and ammonium and a high relative sulphate concentration. Culture experiments with eggs and larvae ofRana arvalis. Rana esculenta, Rana temporaria andBufo bufo show that apart from the pH, elevated aluminium, cadmium and ammonium contents may also affect the reproductive success of amphibians.     

Superoxide anion scavenging effect and superoxide dismutase activity ofGinkgo biloba extract

Summary Ginkgo biloba extract is known to be efficient in diseases associated with free radical generation. The purpose of this work was to study, under in vitro conditions, the action ofGinkgo biloba extract (Gbe) against superoxide anion ( ), which is directly or indirectly implicated in cell damage.Gbe appears to have both an scavenging effect and also a superoxide dismutase activity. Its antiradical effect was demonstrated by low temperature electron spin resonance and in a non-enzymatic system (phenazine methosulfate-NADH), and its enzymatic activity was shown by polarographic determination.     

Reaction time of the topminnowAplocheilus lineatus to surface waves determined by video- and electromyogram recordings

Summary Evoked muscle potentials during a localizing response for a wave center occur inAplocheilus lineatus 30±1.5 msec ( ) earlier than the simultaneously monitored body movements. Considering this time, only the first 8–10 wave cycles of a total wave signal are utilized to identify and localize a wave source.This study was supported by the Deutsche Forschungsgemeinschaft.     

The absolute configuration of valeroidine

Zusammenfassung Auf Grund der Laktonregel vonHudson konnte dem (—) 3·6-Dihydroxy-tropan und (—) Valeroidin eine absolute Konfiguration zugeschrieben werden.     

Mitochondrial DNA mutators

In this article we review our current knowledge of the mechanisms by which point mutations arise in the mitochondrial DNA (mtDNA) of Saccharomyces cerevisiae and discuss to what extent these mechanisms operate in human mtDNA mutagenesis. The 3–5 exonuclease proofreading activity of Pol ensures accuracy of mtDNA replication in both yeast and humans, while the role of base excision repair in mtDNA error avoidance remains debated. The mitochondrial mismatch repair Msh1 protein, which removes transitions in yeast, is absent in humans, a particularity that might cause accumulation of transitions, while the most frequent substitution in yeast mtDNA is A:T to T:A transversion. Proofreading-deficient mutator human cell lines and knockin mice have been created. They will be useful for studying the mechanisms by which mtDNA mutations accumulate in diseases, ageing, malignancy and drug therapy.Received 25 May 2004; received after revision 21 June 2004; accepted 7 July 2004     

Cadmium in the atmosphere

Summary Cadmium is present naturally in the air mainly as a result of volcanic emissions and release by vegetation. Anthropogenic sources, which overall give rise to emissions one order of magnitude greater than natural sources, are largely primary non-ferrous metals production and waste incineration. Measured concentrations of airborne cadmium are typically < 1 ng m^–3 at remote sites, 0.1–10 ng m^–3 at rural sites and 1–100 ng m^–3 at urban and industrial sites, dependent upon the nature and proximity of local sources. Particle sizes are generally <2 m, and often considerably smaller, consistent with an anthropogenic source and a long atmospheric life-time. Cadmium deposition to the land occurs with fluxes varying from 0.05 ng cm^–2 month^–1 in Greenland to circa 1000 ng cm^–2 month^–1 in the vicinity of major industrial sources. The possible significance of a motor vehicular source of airborne cadmium is also reviewed.     

Increase in the survival time of mice exposed to ionizing radiation by a new class of free radical scavengers

Summary N-acyl dehydroalanines react with and scavenge mainly superoxide radical and hydroxyl radical (HO^.). The ortho-methoxyphenylacetyl dehydroalanine derivative, indexed as AD-20, protects mice against damage resulting from total body X-irradiation, as measured by the increase in their survival time. AD-20 increases the LD₅₀ at 30 days from 6.1 to 7.3 Gy in animals exposed to a wide range of X-rays (6 to 10 Gy). The dose reduction factor (D R F) of AD-20 is 1.20. We postulate that such radioprotective effect may result from its free radical scavenging activity.     

Ginkgo biloba extract inhibits oxygen species production generated by phorbol myristate acetate stimulated human leukocytes

Summary A Ginkgo biloba extract (Gbe) containing flavonoids, among other compounds, was tested for the release of activated oxygen species ( , H₂O₂, OH^.) during the stimulation of human neutrophils (PMNs) by a soluble agonist. The extract slows down O₂-consumption (respiratory burst) of stimulated cells by its inhibitory action on NADPH-oxidase, the enzyme responsible for the reduction of O₂ to . Consequently, superoxide anion ( ) and hydrogen peroxide (H₂O₂) production is significantly decreased when the PMNs stimulation is done in the presence of the extract at concentrations of 500, 250 and 125 g/ml. Moreover, the hydroxyl radical generation (OH^.) is very much decreased at concentrations as low as 15.6 g Gbe/ml, which indicates that the extract also has free radical scavenging activity. Gbe is able at least to reduce very severel the activity of myeloperoxidase contained in neutrophils. This enzyme, secreted into the intra and extracellular medium, catalyzes the oxidation of chloride (Cl^–) by H₂O₂ to yield strong oxidants (HOCl, chloramines) which are implicated in inflammatory processes     

Goitrin — a nitrosatable constituent of plant foodstuffs

Summary N-nitrosamides are known as direct-acting carcinogens at the site of their formation; they do not need any metabolic activation in vivo. The conditions leading to their formation in the stomach, and also their genotoxicity, have been thoroughly studied with some model compounds^{1, 2}. Several reports link this type of compound to the induction of gastric cancer in human^{3, 4}. However, only limited data are presently available about possible precursors of N-nitrosamides in foods. In the present study we found that goitrin — a naturally occurring compound in cruciferous vegetables and rape—could be easily nitrosated by treatment with nitrite under stomach conditions, yielding with loss of sulfur the N-nitroso-oxazolidone4 (fig.). This product has a mutagenicity pattern and potency similar to that of N-nitroso-N-methyl-N-nitroguanidine (MNNG) in the Ames Salmonella/mammalian microsome test.