Prenatal hypoxic stress: physiological and biochemical consequences,correction by regulator peptides

The review is devoted to the problem of prenatal hypoxia influence on central and vegetative nervous system, cardio-vascular and respiratory systems, cell metabolism. It is shown that perinatal hypoxia is often resulted in severe non-reversal functional disorders of postnatal development based on significant morphological changes. Regulatory peptide pretreatment is discussed as one of the methods for correction of pre- and postnatal hypoxic consequences.     

Causes and consequences of stress

Stress involves real or perceived changes within an organismin the environment that activate an organism's attempts to copeby means of evolutionarily ancient neural and endocrine mechanisms.Responses to acute stressors involve catecholamines releasedin varying proportion at different sites in the sympatheticand central nervous systems. These responses may interact withand be complemented by intrinsic rythms and responses to chronicor intermittent stressors involving the hypothalamic-pituitary-adrenalaxis. Varying patterns of responses to stressors are also affectedby an animal's assessment of their prospects for successfulcoping. Subsequent central and systemic consequences of thestress response include apparent changes in affect, motivation,and cognition that can result in an altered relationship toenvironmental and social stimuli. This review will summarizerecent developments in our understanding of the causes and consequencesof stress. Special problems that need to be explored involvethe manner in which ensembles of adaptive responses are assembled,how autonomic and neurohormonal reflexes of the stress responsecome under the influence of environmental stimuli, and how somespecific aspects of the stress response may be integrated intothe life history of a species.     

Genetic and evolutionary consequences of symbiosis

Permanent stable symbioses, primarily microbial, are analyzed as parasexual phenomena from the evolutionary point of view. Such associations bring together in single individuals heritable traits of high selective advantage in certain environments. By convergent evolution several types of associations have repeatedly arisen: motile photosynthetic forms, nitrogen fixing and wood digesting complexes, and so forth. Many examples are discussed from the point of view of the number of originally independent genomes that comprise the recognizable individuals.The level of partner integration in many associations is analyzed. Examples of many levels: genic, gene product, metabolite, behavioral, and the methods by which they can be distinguished are discussed.The literature concerning a large number of associations is reviewed: Methanobacillus; predatory and consortia bacteria; blue green algal sheath dwelling bacteria; anaerobic worm-bacterial; algal, and foreign chloroplast retention by heterotrophic eukaryotes (ciliates, coelenterates, mollusks); the double nucleated photosynthetic dinoflagellate (Peridinium balticum); hindgut microbes in termites and woodroaches (Pyrsonympha, Barbulanympha and their associated spirochetes and other bacteria); sand dwelling and other ciliates and their associated bacteria; and so forth. The status of observations and artificial systems claiming evidence for transfer of genes between very distantly related organisms is critically discussed.A continuum from nearly completely autonomous partners (e.g., zoochlorellae in invertebrate animals) to nearly unrecognizable merged components (e.g., gamma particles in Blastocladiella) is found to exist among examples of extant organisms. The diversity and prevalence of such associations support the concept that there are many precedents for the steps hypothesized in the serial endosymbiotic theory of the origin of eukaryotic cells.     

Adverse biochemical and clinical consequences of furosemide administration.

Nurse monitors collected clinical and laboratory data from 204 hospitalized patients receiving furosemide (122 men and 82 women; mean age 69.6 years). Biochemical abnormalities and clinical problems definitely or probably induced by any drug occurred in 70.6% and 49.0% respectively of the patients, and were attributed to furosemide in 81.3% and 13.0% respectively of these patients. The most important clinical events were dehydration and hypotension. Furosemide-induced hypochloremia, hypokalemia and hyponatremia occurred in 35.8%, 25.0% and 24.5% of the patients respectively. Most of the biochemical changes were slight, and only 3.9% of the patients had a furosemide-induced decrease in the serum potassium concentration to less than 3.0 mmol/L. Surprisingly, 24.5% of the patients also manifested drug-induced hyperkalemia. Administration potassium supplements or spironolactone, or both, concurrently with furosemide was responsible in most cases for the development of hyperkalemia. The occurrence of drug-induced adverse effects after 2 weeks of hospitalization was significantly associated (P less than 0.05) with subsequent prolongation of hospitalization. The high frequency of drug-induced events warrants careful monitoring of all patients receiving furosemide in spite of the low frequency of serious toxic effects produced by the drug.     

Genetic and evolutionary consequences of metapopulation structure

Extinction and recolonization of populations may have various effects on the degree and distribution of genetic variation, but turnover is generally associated with low levels of among-population variation, in both 'classical' and other types of metapopulation. Therefore, adaptive evolution is unlikely to be promoted by selection among populations. Whether adaptation is promoted or slowed by population subdivision, with or without turnover, remains a subject of theoretical debate.     

Genetic and phylogenetic consequences of island biogeography

Abstract.— Island biogeography theory predicts that the number of species on an island should increase with island size and decrease with island distance to the mainland. These predictions are generally well supported in comparative and experimental studies. These ecological, equilibrium predictions arise as a result of colonization and extinction processes. Because colonization and extinction are also important processes in evolution, we develop methods to test evolutionary predictions of island biogeography. We derive a population genetic model of island biogeography that incorporates island colonization, migration of individuals from the mainland, and extinction of island populations. The model provides a means of estimating the rates of migration and extinction from population genetic data. This model predicts that within an island population the distribution of genetic divergences with respect to the mainland source population should be bimodal, with much of the divergence dating to the colonization event. Across islands, this model predicts that populations on large islands should be on average more genetically divergent from mainland source populations than those on small islands. Likewise, populations on distant islands should be more divergent than those on close islands. Published observations of a larger proportion of endemic species on large and distant islands support these predictions.     

DNA repair and the genetic effects of thymidylate stress in yeast

Folate antagonists, such as aminopterin, methotrexate and various sulfonamides, block de novo thymidylate biosynthesis in Saccharomyces cerevisiae. The resulting starvation for thymine nucleotides is lethal and recombinagenic in RAD wild-type strains. In this paper we report our studies of these effects in repair-deficient yeast. Antifolate treatment of various rad mutants revealed that repair defects influence the killing and recombination caused by thymidylate deprivation. Compared to a RAD wild-type strain, diploids homozygous for rad3, rad6 or rad18 were more resistant to cell killing. Thus, contrary to findings with conventional DNA-damaging agents, the lethal effects of thymidylate starvation appear to be ameliorated by certain DNA repair deficiencies. On the other hand, a rad50 strain was extremely sensitive to the antifolates. Within this series of diploids, increasing sensitivity to thymidylate starvation was accompanied by an increase in recombination frequencies. The degrees of lethality and recombination, induced by thymidylate depletion, were correlated with the severity of DNA-strand breakage in the RAD and rad50 strains. Experiments with diploids homozygous for rad52, rad54 or rad57 suggested that aborted recombination events, provoked by thymidylate deprivation, caused chromosome loss. Furthermore, the repair defects in these mutants indicated that double-strand breaks are among the lethal lesions induced by thymine nucleotide starvation. Finally, we discuss the possibility that the recombinagenicity of thymidylate stress may account for one type of acquired resistance to methotrexate in mammalian cells.     

Genetic system for analyzing Escherichia coli thymidylate synthase.

Random in vitro mutagenesis of the thyA gene is being used to delineate its regulatory elements as well as the functional domains of its product, thymidylate synthase (EC 2.1.1.45). Streamlined procedures have been developed for the isolation and characterization of the mutants. Positive selection for synthase-deficient thyA Escherichia coli permitted the isolation of 400 mutants, which are being categorized by phenotypic and genetic criteria. An in situ 5-fluorodeoxyuridylate binding assay was devised to rapidly probe the substrate binding domain, whereas facile mapping procedures, based on pBR322- or M13-borne thyA deletion derivatives, were developed to localize mutations. The sequence changes of one amber mutation and another mutation that abolishes catalysis while maintaining substrate binding activity are presented. The orientation of the thyA gene on the E. coli chromosome was established.     

Genetic damage during thymidylate starvation in Saccharomyces cerevisiae.

Summary Thymidylate starvation in a yeast mutant auxotrophic for dTMP caused cell death and the induction of mutations in the mitochondrial genome. After 24 h of starvation almost all surviving cells were respiratory deficient petites. In addition, shorter episodes of dTMP starvation induced chloramphenicol and erythromycin resistant mutants, indicating the occurrence of mitochondrial point mutations. Suboptimal concentrations of exogenous thymidylate were also found to induce petites and a decline in cell viability and the magnitude of these effects was acutely dependent upon the dTMP concentration. Cesium chloride gradient analysis of DNA from cells undergoing thymineless incubation revealed a progressive loss of mitochondrial DNA, and a decrease in the molecular weight of nuclear DNA.     

Secondary biochemical and morphological consequences in lysosomal storage diseases

More than 50 hereditary lysosomal storage disorders (LSDs) are currently described. Most of these disorders are due to a deficiency of certain hydrolases/glycosidases and subsequent accumulation of nonhydrolyzable carbohydrate-containing compounds in lysosomes. Such accumulation causing hypertrophy of the lysosomal compartment is a characteristic feature of affected cells in LSDs. The investigation of biochemical and cellular parameters is of particular interest for understanding “life” of lysosomes in the normal state and in LSDs. This review highlights the wide spectrum of biochemical and morphological changes during developing LSDs that are extremely critical for many metabolic processes inside the various cells and tissues of affected persons. The data presented will help establish new complex strategies for metabolic correction of LSDs.     

Genetic and biochemical analyses of protein II

We compared the structure of P.II proteins of gonococcal strain FA1090 by N-terminal sequence analysis of purified proteins and by DNA sequencing of cloned P.II genes. Regulation of P.II gene expression does not involve major DNA rearrangements, but may involve generation of frame-shifts in unexpressed P.II genes. There are probably 8 or 9 P.II genes, each possessing a common leader sequence, in the gonococcal chromosome.     

Genetic consequences of local population extinction and recolonization

Theoretical results have shown that a pattern of local extinction and recolonization can have significant consequences for the genetic structure of subdivided populations; consequences that are relevant to issues in both evolutionary and conservation biology. The nature of those consequences depends largely on the mode of colony formation. Extinction and recolonization can either increase or decrease the genetic differentiation of local populations and can lead to a loss of the genetic diversity stored in an array of populations. Recent ecological studies of two insect species have revealed population structures resembling, in part, that considered in the models. They serve to illustrate the potential complexity of the processes of extinction and recolonizatiion in nature.     

Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences

In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, a number of enzymic and nonenzymic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins. Whereas random, global modification of many different amino acid residues and extensive fragmentation occurs when proteins are exposed to oxygen radicals produced by high energy radiation, only one or a few amino acid residues are modified and relatively little peptide bond cleavage occurs when proteins are exposed to metal-catalyzed oxidation (MCO) systems. The available evidence indicates that the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 and that these products react at metal-binding sites on the protein to produce active oxygen (free radical?) species (viz; OH, ferryl ion) which attack the side chains of amino acid residues at the metal-binding site. Among other modifications, carbonyl derivatives of some amino acid residues are formed; prolyl and arginyl residues are converted to glutamylsemialdehyde residues, lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues; histidyl residues are converted to asparagine and/or aspartyl residues; prolyl residues are converted to glutamyl or pyroglutamyl residues; methionyl residues are converted to methionylsulfoxide residues; and cysteinyl residues to mixed-disulfide derivatives. The biological significance of these metal ion-catalyzed reactions is highlighted by the demonstration: (i) that oxidative modification of proteins "marks" them for degradation by most common proteases and especially by the cytosolic multicatalytic proteinase from mammalian cells; (ii) protein oxidation contributes substantially to the intracellular pool of catalytically inactive and less active, thermolabile forms of enzymes which accumulate in cells during aging, oxidative stress, and in various pathological states, including premature aging diseases (progeria, Werner's syndrome), muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-reperfusion. Furthermore, the metal ion-catalyzed protein oxidation is the basis of biological mechanisms for regulating changes in enzyme levels in response to shifts from anaerobic to aerobic metabolism, and probably from one nutritional state to another. It is also involved in the killing of bacteria by neutrophils and in the loss of neutrophil function following repeated cycles of respiratory burst activity.