Ciba Foundation symposium最新文献

The vertebrate body plan is determined by a variety of morphoregulatory genes that are highly conserved throughout evolution. This review presents a phylogenetic analysis of selected molecular and morphological features in vertebrates with particular emphasis upon the phylogeny of tooth morphogenesis and enamel formation. Three lines of evidence support our hypothesis that the agnathans (e.g. hagfishes) are the most primitive extant vertebrates and that enamel gene products are highly conserved during vertebrate evolution. First, an antibody raised against the polypeptide produced by exon 4 of the mouse amelogenin gene recognizes proteins in hagfish, sharks, reptiles and mammals. Second, electron photomicrographic evidence suggests heterochronic shifts in the relative time and rate of enamel formation during vertebrate tooth evolution. Third, mRNA phenotyping suggests significant homology between amelogenin transcripts expressed in species of various vertebrate phyla including agnathans and mammals. These three lines of evidence indicate that amelogenin gene products are expressed in agnathan, reptilian and mammalian teeth.

Bone and dentine extracellular matrix proteins are similar, consisting primarily of type I collagen, acidic proteins and proteoglycans. Although collagen forms the lattice for deposition of calcium and phosphate for formation of carbonate apatite, the non-collagenous proteins are believed to control initiation and growth of the crystals. Despite this similarity, dentine contains three unique proteins apparently absent from bone and other tissue: dentine phosphophoryn (DPP), dentine matrix protein 1 (DMP1) and dentine sialoprotein (DSP). DPP and DMP1 are acidic phosphoproteins probably involved in the control of mineralization processes. DPP may localize in gap regions of collagen and initiate apatite crystal formation by binding large quantities of calcium in a conformation that promotes this process. Extensive studies have been conducted in our laboratory on the nature, biosynthesis, localization and gene structure of DSP. Immunolocalization studies showed that rat DSP, a 53 kDa sialic acid-rich glycoprotein, was synthesized by young and mature odontoblasts, and by dental pulp cells and pre-ameloblasts, but not by ameloblasts, osteoblasts, chondrocytes or other cell types. The cDNA sequence indicated that DSP was a 366-residue protein with several potential N-glycosylation sites, as well as phosphorylation sites, but that the amino acid sequence was dissimilar to that of other known proteins. Northern blot analysis detected several mRNA species near 4.6 and 1.5 kb, indicative of alternative splicing events. Evidence for two DSP genes was obtained, further complicating this picture. Recent in situ hybridization studies utilizing rat and mouse molars and incisors indicated that DSP mRNA was expressed by young odontoblasts and odontoblasts in animals of all ages. Transcripts were also observed in pre-ameloblasts. The expression of DSP mRNA ceased when these cells matured to become secretory ameloblasts. DSP transcripts were not detected in osteoblasts or other cell types. The transient expression in pre-ameloblasts suggests a role of epithelial-mesenchymal interactions in the formation of the tooth.

In Gram-negative pathogens, multiple antibiotic resistance is common and many of the known resistance genes are contained in mobile gene cassettes. Cassettes can be integrated into or deleted from their receptor elements, the integrons, or infrequently may be integrated at other locations via site-specific recombination catalysed by an integron-encoded recombinase. As a consequence, arrays of several different antibiotic resistance genes can be created. Over 40 gene cassettes and three distinct classes of integrons have been identified to date. Cassette-associated genes conferring resistance to beta-lactams, aminoglycosides, trimethoprim, chloramphenicol, streptothricin and quaternary ammonium compounds used as antiseptics and disinfectants have been found. In addition, most members of the commonest family of integrons (class 1) include a sulfonamide resistance determinant in the backbone structure. Integrons are themselves translocatable, though most are defective transposon derivatives. Integron movement allows transfer of the cassette-associated resistance genes from one replicon to another or into another active transposon which facilitates spread of integrons that are transposition defective. Horizontal transfer of the resistance genes can be achieved when an integron containing one or more such genes is incorporated into a broad-host-range plasmid. Likewise, single cassettes integrated at secondary sites in a broad-host-range plasmid can also move across species boundaries.

Occupational asthma-asthma induced by an agent inhaled at work-provides a valid model for the examination of the more general environmental causes of asthma. In many instances, definable populations exposed to a novel allergen in the workplace at concentrations that are relatively easily measured develop IgE-associated asthma and characteristic eosinophilic bronchitis. Carefully designed epidemiological studies suggest that the incidence of IgE antibody and asthma is highest in the first one to two years of exposure; and that the risk is directly related to the intensity of airborne allergen exposure. The relationship between exposure and outcome is modified both by concurrent cigarette smoking and by genotype, although the details of this latter interaction remain unclear. Symptoms, airway hyper-responsiveness and airway inflammation may persist for several years after avoidance of exposure to the initiating agent. If the relevance of the model is accepted then these insights require testing and further investigation, both within the field of occupational asthma and, by extension, in the wider field of asthma in the general environment.

There is now increasing evidence that maternal factors may play a role in the development of asthma and asthma-related syndromes in children. For years it has been known that younger mothers are more likely to have children who develop wheezing illnesses in early life. It has been suggested that the development of the lung may differ in children of younger mothers compared to that in children of older mothers, but the biology of this association is not well understood. Recent data suggest that there is a much stronger association of allergic conditions in early life with allergic disease in the mother than in the father. Maternal asthma is more strongly associated with childhood asthma than is paternal asthma. The influence of the pattern of immune responsiveness in the mother on the ontogeny of the immune system in children needs further exploration, and it may offer new clues as to the factors determining the development of asthma and allergy in children.

Micro-organisms play important roles in the environmental fate of radionuclides in both aquatic and terrestrial ecosystems, with a multiplicity of physico-chemical and biological mechanisms effecting changes in mobility and speciation. Physico-chemical mechanisms of removal, which may be encompassed by the general term 'biosorption', include adsorption, ion exchange and entrapment. These are features of living and dead organisms as well as their derived products. In living cells biosorptive processes can be directly and indirectly influenced by metabolism, and may be reversible and affected by changing environmental conditions. Metabolism-dependent mechanisms of radionuclide immobilization include metal precipitation as sulfides, sequestration by metal-binding proteins and peptides, and transport and intracellular compartmentation. Chemical transformations of radionuclide species, particularly by reduction, can result in immobilization. Microbial processes involved in solubilization include autotrophic and heterotrophic leaching, complexation by siderophores and other metabolites, and chemical transformations. Such mechanisms are important components of natural biogeochemical cycles for radionuclides and should be considered in any analyses of environmental radionuclide contamination. Several micro-organism-based biotechnologies, e.g. those based on biosorption or precipitation, are of potential use for the treatment of radionuclide contamination.

The consumption of food is an important pathway involved in the internal contamination of humans. The site-related critical foodstuffs can be grouped into three main categories: dairy products; aquatic animals, such as fish, molluscs and crustaceans; and other typical foods. The concentration factor plays a more important role than the amount of a certain food consumed. Semi-natural and natural ecosystems are of special interest in this context because they can provide critical pathways for radionuclide transfer to humans, and they can also act as temporary sinks or long-term sources for radionuclides deposited from the atmosphere. From the viewpoint of population health, another important role is played by the countermeasures. The reference values commonly adopted in radiation protection are conservative and they have been established for planning practices that could provide future sources of irradiation. After a large release of radionuclides, the evaluation of the problem must be as realistic as possible, otherwise the countermeasures will imply consequences worse than those produced by the accident itself (without any further intervention). This criterion was clearly stated by the International Commission on Radiological Protection but it was frequently neglected after the Chernobyl accident. The results of a survey on the number of induced abortions following this incident are reported. These suggest that moral and ethical problems are involved above and beyond any economical implications.

The purpose of radioecological models is to make realistic estimates of doses to the public after accidental releases of radionuclides into the environment. Important physical, chemical and biological processes involved in the dispersion and transport of radioactive substances in the atmosphere and along the food-chains are presented. The results of the EURAD (EURopean Acid Deposition) model, predicting the deposition patterns of 131I and 137Cs in Belarus and Ukraine after the Chernobyl accident, are discussed. An overview of the most important ecological processes--such as deposition, interception and translocation, weathering, transfers from soil to plants and from plants to animal/animal products, and seasonality in agricultural environments--is given. Examples corresponding to these individual processes, mainly experimental results after the Chernobyl accident and related to radiocaesium and radioiodine, are shown and discussed.

The partition coefficient (Kd) and the water retention rate (RR) are fundamental components of dynamic, mass-balance models, not just for radionuclides in fresh water but also for contaminants in all aquatic ecosystems. Kd may be regarded as an 'entry gate' and RR an 'exit gate'. Uncertainties in Kd and RR cause uncertainties in model predictions. Uncertainties in important rates for processes within ecosystems (such as sedimentation, diffusion, advection, bio-uptake and excretion) cannot be adequately evaluated when uncertainties exist for Kd and RR. Empirical data show that there may be a variation in Kd of two orders of magnitude with environmental factors such as pH. This is important because Kd regulates the amount of radionuclides in dissolved and particulate phases, and hence also pelagic and benthic transport. Pelagic transport is directly linked to the outflow and retention of substances in the water mass, and thus also to concentrations and ecological effects. There are many approaches for sub-models of Kd and RR. Which provide the best predictive power? This chapter gives a brief overview and discussion of the benefits and drawbacks of different alternatives for Kd and RR within the framework of a lake model for radiocaesium.

Synthetic oligonucleotides offer interesting perspectives for the regulation of gene expression in normal and pathological situations. Poor uptake in many cell types, inadequate intracellular compartmentalization, often fragmentary knowledge of intracellular behaviour and mechanism of action, and lack of specificity remain major challenges. These limitations strongly urge the design of new oligonucleotide analogues and more efficient antisense strategies. Present achievements and perspectives for further developments will be discussed with emphasis on cell delivery and intracellular fate.