Enhancement of the cytogenetic efficacy of the antitumor agent bleomycin by the calcium and calmodulin antagonist fendiline

Summary The induction of chromosome aberrations (dicentric and ring chromosomes) in human lymphocytes by the antitumor agent bleomycin is synergistically enhanced when bleomycin is applied together with the calcium antagonist fendiline (Sensit^®).     

The cytogenetic efficiency of the antitumor agents bleomycin and peplomycin is enhanced by the heart drug verapamil (isoptin)

Summary The induction of 2-break chromosome aberrations (dicentrics and ring chromosomes) in human lymphocytes by the antitumor agents bleomycin and peplomycin is strongly enhanced when those agents are applied together with the heart drug verapamil (isoptin).We thank Heinrich Mack Nachf./Illertissen (Germany) for generously supplying both the bleomycin and the peplomycin and Dr P. Engel, Illertissen, for valuable informations.     

The cytogenetic efficiency of the antitumor agents bleomycin and peplomycin is enhanced by the heart drug verapamil (isoptin)

The induction of 2-break chromosome aberrations (dicentrics and ring chromosomes) in human lymphocytes by the antitumor agents bleomycin and peplomycin is strongly enhanced when those agents are applied together with the heart drug verapamil (isoptin).     

Sensitivity of human lymphocytes to bleomycin increases with age

Summary The sensitivity of human peripheral blood lymphocytes to bleomycin and mitomycin-C was assessed by measuring the inhibition of phytohemagglutinin stimulated proliferation. The sensitivity to bleomycin, and not to mitomycin-C, increased with the age.We thank Miss L. Bailey for excellent technical assistance and the Bristol-Myers Company for supply of bleomycin. This work was supported by the National Health and Medical Research Council of Australia and the Anti-Cancer Council of Adelaide University, South Australia.     

Sensitivity of human lymphocytes to bleomycin increases with age.

The sensitivity of human peripheral blood lymphocytes to bleomycin and mitomycin-C was assessed by measuring the inhibition of phytohemagglutinin stimulated proliferation. The sensitivity to bleomycin, and not to mitomycin-C, increased with the age.     

Paradoxical effect of 1-β-D-arabinofuranosyl cytosine triphosphate on bleomycin-induced unscheduled DNA synthesis in permeable sarcoma cells

Summary 1--D-Arabinofuranosyl cytosine-5-triphosphate (araCTP), an inhibitor of DNA synthesis, paradoxically enhanced unscheduled DNA synthesis (USD) induced by bleomycin in permeable mouse sarcoma cells. A greater enhancing effect of araCTP on bleomycin-induced USD was observed with lower concentrations of dCTP in the assay mixture. USD measured without bleomycin in nuclei isolated from mouse sarcoma cells was not enhanced, but inhibited by araCTP.Acknowledgments. The authors wish to thank Nippon Kayaku Co. (Tokyo, Japan) for providing copper-free bleomycin A₂. This research was supported in part by a grant from the Japan Ministry of Education, Science and Culture.     

Soluble polysialylated NCAM: a novel player of the innate immune system in the lung

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing “neutrophil extracellular traps”, which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.     

Sea urchin embryo as a model for analysis of the signaling pathways linking DNA damage checkpoint,DNA repair and apoptosis

DNA integrity checkpoint control was studied in the sea urchin early embryo. Treatment of the embryos with genotoxic agents such as methyl methanesulfonate (MMS) or bleomycin induced the activation of a cell cycle checkpoint as evidenced by the occurrence of a delay or an arrest in the division of the embryos and an inhibition of CDK1/cyclin B activating dephosphorylation. The genotoxic treatment was shown to induce DNA damage that depended on the genotoxic concentration and was correlated with the observed cell cycle delay. At low genotoxic concentrations, embryos were able to repair the DNA damage and recover from checkpoint arrest, whereas at high doses they underwent morphological and biochemical changes characteristic of apoptosis. Finally, extracts prepared from embryos were found to be capable of supporting DNA repair in vitro upon incubation with oligonucleotides mimicking damage. Taken together, our results demonstrate that sea urchin early embryos contain fully functional and activatable DNA damage checkpoints. Sea urchin embryos are discussed as a promising model to study the signaling pathways of cell cycle checkpoint, DNA repair and apoptosis, which upon deregulation play a significant role in the origin of cancer. Received 10 April 2007; accepted 23 April 2007     

Differential sensitivity to ethidium bromide of replicative DNA synthesis and bleomycin-induced unscheduled DNA synthesis in permeable mouse sarcoma cells1

Summary Replicative DNA synthesis in permeable mouse sarcoma cells was more sensitive to ethidium bromide (EtBr) than bleomycin-induced unscheduled DNA synthesis (UDS). A similar difference in sensitivity to EtBr was observed between DNA polymerases and . The difference in sensitivity to EtBr of replicative DNA synthesis and UDS in the present system seems to reflect mainly the sensitivity difference between DNA polymerases and .Acknowledgments. The authors wish to thank Nippon Kayaku Co. (Tokyo, Japan) for providing copper-free bleomycin A₂. This research was supported in part by a grant from the Japan Ministry of Education, Science and Culture.     

益气化瘀化痰法对肺纤维化大鼠肺组织结构及血清MMP-9、TIMP-1的影响

目的 观察益气化瘀化痰法(YHH)对肺纤维化大鼠肺组织结构、血清基质金属蛋白酶-9(MMPO)和金属蛋白酶组织抑制物-1(TIMP-1)水平的影响,探讨其防治肺纤维化的可能机制.方法 健康SD大鼠采用博来霉素建立肺纤维化模型,随机分成7组:正常对照组(Z组)、模型组(M组)、氢化可的松组(QK组)、益气组(YQ组)、化瘀组(HY组)、化痰组(HT组)、益气化瘀化痰组(YHH组).HE、Masson染色光镜观察肺组织病理形态变化;电镜观察肺组织超微结构变化;酶联免疫吸附法(ELISA)检测血清MMP-9、TIMP-1含量.结果 1)与M组比较,各治疗组均能减少肺间质胶原沉积,减轻肺纤维化程度,尤以YHH组较为明显2)与Z组比较,M组血清MMP-9水平有所升高,TIMP-1水平显著升高,MMP-9/TIMP-1比值降低(P＜0.05);与M组比较,各治疗组均能升高血清MMP-9水平,降低TIMP-1水平,升高MMP-9/TIMP-1比值,以YHH组作用更显著(P＜0.05).结论 益气化瘀化痰法可能在一定程度上通过调整MMP-9/TIMP-1的比值,使其趋于平衡,从而延缓肺纤维化的进程.     

On the genesis of the soil mantle of the region of Manaus,Central Amazonia,Brazil

Summary The dynamics of the forest to the north of Manaus is tightly linked to that of the soil. The latosol that covers the plateau, which supports a dense forest, consists from top to bottom of: (a) a brown, clayey organic horizon (0.3 m), (b) a yellow horizon, very rich in clay but permeable (from 0.3 to 4 m), (c) a nodular horizon rich in Al and Fe oxides (from 4 to 9 m), and (d) a horizon which still preserves the sedimentary structures of the parent sandstone, where quartz is intensely dissolved and kaolinite crystallizes in pores. In perfectly flat areas, the clay of the organic horizon is destroyed by acidocomplexolysis, and the dissolved Al is transported vertically by the drainage water. A part of this Al is used to make the gibbsite nodules of horizon (c), and the rest is used to make kaolinite in horizon (d). Because aluminum is thus conserved within any vertical prism, the rate of destruction of horizon (a) is equivalent to the rate of advance of the kaolinization zone into the sediment: the latosol is said to be in equilibrium, the surface remains perfectly flat as it slowly sinks, the quantity of kaolinite increases with time, and the silica released by quartz dissolution in the whole profile is exported by drainage water to the water table. In contrast, near drainage axes, however small initially, the drainage becomes inclined toward the axis. Part of the Al released by acidocomplexolysis of horizon (a) is now exported to rivers, and Al is no longer conserved within any given prism. The rate of advance of the kaolinization zone (d) into the sediment now becomes less than the rate of destruction of horizon (a) and the surface sinks faster than that of the surrounding plateau. After this differential podzolization has gone on long enough, it creates a network of geochemical valleys characterized by convex slopes and bounded by sandy soils (campinas). The vegetation becomes sparser and sparser. At the end, only some bushes and lichens survive on the white sand.Acknowledgments. The authors are indebted to Dr E. Merino (Dept. of Geology, Indiana University) for helpful criticisms and suggestions. This research was carried out in I.N.P.A. (Instituto Nacional de Pesquisas da Amazonia) and was financially supported by the CNPq-CNRS/ORSTOM conv.     

Development of the innervation of the urogenital complex in the fetal mouse

The developing urogenital complex of the fetal mouse was studied by means of silver impregnation and electron microscopy. These studies showed that: 1) the mesonephric field is innervated during prenatal stages (Wolffian nerve); 2) nerve penetration precedes the differentiation of the gonads and related ducts; and 3) the Wolffian nerve arises during the earliest stages from the first pair of abdominal rami communicantes. The identity between the fetal Wolffian nerve and the nerve of the suspensory ligament (higher pathway) of the adult is discussed.     

Development of the innervation of the urogenital complex in the fetal mouse

Summary The developing urogenital complex of the fetal mouse was studied by means of silver impregnation and electron microscopy. These studies showed that: 1) the mesonephric field is innervated during prenatal stages (Wolffian nerve); 2) nerve penetration precedes the differentiation of the gonads and related ducts; and 3) the Wolffian nerve arises during the earliest stages from the first pair of abdominal rami communicantes. The identity between the fetal Wolffian nerve and the nerve of the suspensory ligament (higher pathway) of the adult is discussed.     

Effect of diabetes on the enzymes of the cholinergic system of the rat brain

Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were determined in several brain regions of normal and streptozotocin-induced diabetic rats. The diabetic rats exhibited significant increase in ChAT activity (p less than 0.05) in all brain regions studied except for the cortex and the midbrain. Meanwhile, the diabetes condition was associated with significant increase (p less than 0.05) in AChE activity of the bulbus olfactorius, medulla oblongata and cerebellum. These data suggest that uncontrolled diabetes is associated with significant alterations in the brain cholinergic systems.     

Effect of diabetes on the enzymes of the cholinergic system of the rat brain

Summary Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were determined in several brain regions of normal and streptozotocin-induced diabetic rats. The diabetic rats exhibited significant increase in ChAT activity (p<0.05) in all brain regions studied except for the cortex and the midbrain. Meanwhile, the diabetes condition was associated with significant increase (p<0.05) in AChE activity of the bulbus olfactorius, medulla oblongata and cerebellum. These data suggest that uncontrolled diabetes is associated with significant alterations in the brain cholinergic systems.To whom requests of reprints should be addressed.This work was supported by grants from the National Aeronautics and Space Administration (NSG 2183 and NAG-2-411), a grant from the National Institutes of Health (NIH Grant RR0811) and a grant from the Division of Research Resources, National Institutes of Health (NIH Grant RR03020).     

Correlations between the neurobiology of colour vision and the psycholinguistics of colour naming

Summary Neurobiological experiments demonstrate that colour sensation is perceived by the brain by processes which, in principle, follow the opponent colour pairs scheme proposed by Hering in 1874. Tests on colour naming in various European, Asian and Central American languages have shown that the opponent scheme is also reflected in psycholinguistics. The linguistic evolution of colour terms proposed by Berlin and Kay (1969) is correlated directly with the ontogenetic development of language in children as elucidated by Jakobson (1941). Colour vision is therefore a suitable field for interdisciplinary investigations of brain processes and linguistics.Dedicated to Prof. Roman Jakobson, Cambridge, Mass.Acknowledgment. I thank Prof. Roman Jakobson, Harvard University and M.I.T., Cambridge (Mass.) and Prof. Elmar Holenstein, Ruhr-Universität, Bochum, Germany (formerly University of Zurich, Switzerland) for many stimulating discussions.     

The accuracy of aminoacylation--ensuring the fidelity of the genetic code

The fidelity of protein biosynthesis rests not only on the proper interaction of the messenger RNA codon with the anticodon of the tRNA, but also on the correct attachment of amino acids to their corresponding (cognate) transfer RNA (tRNA) species. This process is catalyzed by the aminoacyl-tRNA synthetases which discriminate with remarkable selectivity amongst many structurally similar tRNAs. The basis for this highly specific recognition of tRNA by these enzymes (also referred to as 'tRNA identity') is currently being elucidated by genetic, biochemical and biophysical techniques. At least two factors are important in determining the accuracy of aminoacylation: a) 'identity elements' in tRNA denote nucleotides in certain positions crucial for protein interactions determining specificity, and b) the occurrence in vivo of competition between synthetases for a particular tRNA which may have ambiguous identity.     

On the epistemological foundations of the law of the lever

In this paper I challenge Paolo Palmieri’s reading of the Mach—Vailati debate on Archimedes’ proof of the law of the lever. I argue that the actual import of the debate concerns the possible epistemic (as opposed to merely pragmatic) role of mathematical arguments in empirical physics, and that construed in this light Vailati carries the upper hand. This claim is defended by showing that Archimedes’ proof of the law of the lever is not a way of appealing to a non-empirical source of information, but a way of explicating the mathematical structure that can represent the empirical information at our disposal in the most general way.