Comptes rendus des seances de la Societe de biologie et de ses filiales最新文献

Some toxins from scorpion venoms, much more toxic to insects than to other animal classes, possess high affinity to Na+ channels. These anti-insect scorpion toxins have been divided into: 1) alpha toxins which lack strict selectivity for insects, do not compete with following groups of anti-insect toxins, resemble other alpha scorpion toxins by their structure and their ability, as alpha anemone toxins, to prolong insect axonal action potential durations through a drastic slowing down of the Na+ current inactivation, 2) excitatory insect selective scorpion toxins which induce in blowfly larvae an immediate fast paralysis; in isolated cockroach axons, they depolarize and induce a sustained repetitive activity of short (normal) action potentials through a shift of Na+ activation mechanism towards more negative potentials and some decrease of inactivation at these potential values, 3) depressant insect selective neurotoxins which cause a slow progressive flaccid paralysis of larvae, depolarize insect axons and reduce or even suppress evoked action potentials; resting depolarizations which are antagonized by a post-application of TTX, are due to the opening of sodium channels at very negative potential values and to the suppression of their inactivation mechanism. The decrease of the maximal Na+ conductance following flaccid toxin action may be understood if toxin-modified channels opened at very negative potentials values remain open (or re-open) for much longer times than in control conditions and pass by substate less conductant states. Anti-insect scorpion toxins become of major interest into insect neurophysiology and also into insect pest control, due to their specific target sites and to the recent constructions of insecticidal baculovirus expressions of several of these toxins.

The focus of the present review is to present recent studies of the mammalian circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The main questions in circadian neuroscience are: how many oscillators are implicated, how are their daily oscillations generated and synchronized to the external environment and how does the central clock send timed signals to the whole organism. The review is introduced by a presentation of circadian system properties and by a description of the responses to manipulations of the main entraining factor, i.e. the light-dark cycle. The anatomy of the SCN and its major afferents from the retina (glutamate, Substance P), raphe (serotonin) and intergeniculate leaflet (neuropeptide Y) of the thalamus are presented with a special emphasis on the interaction of these inputs with the circadian timekeeping mechanism. The arguments related to the issue of whether the retina contain an endogenous oscillator are exposed. What is known of the endogenous mechanism(s) of this small structure containing 10,000 or so "self-oscillating neurons" is reviewed through: i) the anatomical distribution and functional significance of clock-peptides (VIP, PHI, GRP, VP or SS), ii) the putative involvement of the SCN astrocytic population in coordinating neuronal activities, iii) the various aspects of cellular activity (electrical activity, energy metabolism, protein or peptide synthesis) and iv) the participation of immediate early genes in light-driven phase shifts. The present understanding of molecular timekeeping mechanism is exposed in light of the growing list of candidate clock-genes described within the SCN as well as in peripheral tissues of mammals and also in the clock-systems of phylogenetically lower species. Efferents from the SCN are also discussed with an interest toward understanding how the central circadian information is transmitted to the rest of the brain in order to impulse or/and coordinate the numerous rhythmic activities of the organism. Finally, cellular disturbances in peptide expression or content, reduction in the amplitude of a given functional index or even astrocytic proliferation are viewed along the line of pathologies observed with aging.

Glucose, that Claude Bernard has demonstrated in 1850 to be synthesized and secreted by the liver, is an important regulator of gene transcription in all types of organisms. In vertebrates, it especially regulates transcription of metabolic genes in the liver and fat tissue, activating genes encoding enzymes and regulators of the glycolytic and lipogenic pathways. Working with the L-type pyruvate kinase gene we have found that in hepatocytes glucose-dependent gene regulation requires: Presence of the GLUT2 glucose transporter, necessary to allow for an effective depletion in glucose 6-phosphate (G-6P) under gluconeogenic conditions. Phosphorylation of glucose to G-6P assured either by insulin-dependent glucokinase or by another hexokinase isoform. Most likely, entry of G-6P in the pentose phosphate pathway. Modulation of a kinase/phosphatase cascade, in particular inhibition of the 5'AMP-activated protein kinase. Signalling through a glucose response complex assembled onto a glucose-response element (GIRE) located in regulatory regions of glucose-responsive genes. The activators USF belong to the complex, and are required for a normal gene activation by glucose, as evidenced from the phenotype of knock-out mice deficient in USF. The study of USF-defective knock-out mice suggest that USF could be involved in nutritional activation of a whole class of genes regulated by glucose, and not by insulin itself. In particular, lipogenic genes and the ob gene, encoding the leptin satiety hormone, are abnormally responsive to diet in USF-/- mice. The transactivation potential of USF would be modulated by a glucose sensor system implying the COUP-TFII transcription inhibitor. The main role of insulin in the glucose response of genes like the L-PK gene is to induce the glucokinase gene. Glucagon, through cyclic AMP, inhibits L-PK gene transcription mainly through activation of PKA. The PKA catalytic subunit could act by phosphorylating member(s) of the glucose-response complex, or of contiguous transcription factor, e.g. HNF4. In conclusion, through a pluridisciplinary approach ranging from Claude Bernard-derived biology to modern molecular biology, important progress have been made during the last years on the mechanisms of the regulation of gene transcription by glucose in vertebrates.

The concept of interrelationships between the central nervous system and the periphery aimed at maintaining normal body weight homeostasis has been strengthened by the discovery of hypothalamic neuropeptide Y (NPY) and adipose tissue leptin. NPY, when infused intracerebroventricularly in normal animals produces hyperphagia and hormono-metabolic changes (hyperinsulinemia, hypercorticism) channeling nutrients preferentially toward lipogenesis and storage in adipose tissue and away from their utilization by muscles (muscle insulin resistance). Storage in NPY-infused rats is further favored by the observed decrease in the expression of uncoupling proteins. NPY-induced hyperinsulinemia and hypercorticosteronemia also promote leptin over-secretion. Released leptin, acting within the hypothalamus, decreases hypothalamic NPY levels (probably those of other hypothalamic neuropeptides as well), food intake, insulinemia, insulin sensitivity of white adipose tissue, while increasing that of muscles. Leptin acting centrally additionally favors the expression of uncoupling protein 1, 2, and 3, in keeping with an eflect on energy dissipating mechanisms. The respective hormono-metabolic eflects of NPY and leptin maintain a normal body homeostasis. In most obesity syndromes, the functional relationships between NPY and leptin are altered. Due to hypothalamic leptin receptor mutations or dysfunctions, leptin cannot exert its eflects: NPY levels (possibly those of other neuropeptides) remain elevated, maintaining excess storage, insulin as well as leptin resistance.

This study was devoted to the continued search for an explanation of the neurodegeneration found in a severely TPI deficient Hungarian patient whose brother with genomically completely identical TPI defect was completely free of neurological disorders. The changes found in the molecular species composition of the major PL subclasses and the decrease in PE plasmalogens explain the earlier round increase in membrane fluidity interfering thereby with the physiological function of membrane enzymes, receptors, signal transduction, protein-protein interactions and vesicle fusion. Plasmalogens have also the capacity to protect against oxidative stress, that is deemed to contribute to neurodegenerative processes. The presence of chronic oxidative stress was well reflected in the decreased levels of GSH and alpha-tocopherol in the affected brothers. Decrease in plasmalogens have been described recently in Zellweger's syndrome, in other peroxisomal neurodegenerative disorders, in demyelinating processes and in Alzheimer's disease. The brain in normal individuals is highly enriched in plasmalogens. The pathological decrease found in TPI deficient lymphocytes will presumably be more pronounced in excitatory tissues. The recently described role of expanding nucleotide triplets in the development of neurodegeneration is suggested to result through the selective binding via their polyglutamine repeats to GAPDH. The role of GAPDH in TPI deficiency may be of crucial help in the elucidation of the development of neurodegeneration, since the enzymatic defect of TPI can be partially bypassed by means of the HMP shunt which generates GAP via GAPDH without the participation of TPI. Considering the results found in TPI deficiency in comparison to the new literary findings in different neurodegenerative diseases the following pathomechanism may be proposed. The protein products of the defective genes due to their abnormal steric structure bind GAPDH in a different manner or in differing quantity than their normal counterparts. The PL composition and the resulting differences in the biophysical properties of the cell membranes have crucial impact on these protein-protein interactions and on the activity of enzymes and membrane transport functions. The plasmalogen decrease impairs the protection against oxidative stress with consecutive worsening of the neurodegenerative process. The final common pathway to neuronal death leads through destabilization of intracellular Ca2+ homeostasis via elevation of intracellular Ca2+ to apoptosis. The most important conclusion is that lipids are not an inert environment of membrane proteins. Unravelling of the pathogenesis of neurodegeneration needs more concerted investigation of the interactions between genetic changes with biophysical and biochemical cell membrane lipid alterations.

The yeast Saccharomyces cerevisiae was a powerful tool in the identification of the structural genes involved in sterol biosynthesis in eucaryotes. Among 20 genes, 16 were isolated by genetic techniques using either complementation of mutants or overexpression strategy using specific inhibitors. In spite of this good knowledge concerning the genes of the pathway, little is known about the regulation of the isoprenoid/steroid biosynthetic pathway. However, the existence of two genes encoding HMG-CoA reductase in yeast genome suggests strongly that this enzyme could play a fundamental function in regulation, such as in plants and mammals. The regulation mechanisms could also involve sterol trafficking and storage. Indeed, one enzyme in the pathway, the sterol-C24-methyl transferase is localized in lipid particles that correspond to the storage form of steryl esters. Yeast cells are impermeable towards exogenous sterols in aerobiosis and become permeable in anaerobiosis when ergosterol synthesis is precluded by the absence of molecular oxygen. This phenomenon called aerobic sterol exclusion is dependent on the hem status of the cell. One gene, named SUT1 was identified that directs aerobic sterol uptake in yeast SUT1 gene and his partner SUT2 present strong features common to yeast transcription factors and could regulate the expression of genes involved in sterol uptake or intracellular trafficking.

The measurement of osmotic fragility of erythrocytes has been applied to the diagnosis of hemolytic diseases, studies of membrane permeability and alternations leading to destruction of erythrocytes. Almost 30 years have gone by since the coil planet centrifuge system was devised for measuring the osmotic fragility of erythrocytes. Many excellent studies by means of this centrifuge system have been published. Prominent investigations are reviewed as follows: in relation to the osmotic fragility, various liver diseases, angina pectoris, trapping the aged erythrocytes, tumor, lactic acid, unsaturated fatty acids, free cholesterol, exercise and lead exposure level were examined.