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PubMed1987

On the overdispersed molecular clock.

Rates of molecular evolution at some loci are more irregular than described by simple Poisson processes. Three situations under which molecular evolution would not follow simple Poisson processes are reevaluated from the viewpoint of the neutrality hypothesis: concomitant or multiple substitutions in a gene, fluctuating substitution rates in time caused by coupled effects of deleterious mutations and bottlenecks, and changes in the degree of selective constraints against a gene (neutral space) caused by successive substitutions. The common underlying assumption that these causes are lineage nonspecific excludes the case where mutation rates themselves change systematically among lineages or taxonomic groups, and severely limits the extent of variation in the number of substitutions among lineages. Even under this stringent condition, however, the third hypothesis, the fluctuating neutral space model, can generate fairly large variation. This is described by a time-dependent renewal process, which does not exhibit any episodic nature of molecular evolution. It is argued that the observed elevated variances in the number of nucleotide or amino acid substitutions do not immediately call for positive Darwinian selection in molecular evolution.

Animals↗
PubMedDate not supplied

A molecular dynamics simulation of the (dG)6 . (dC)6 minihelix including counterions and water.

The results of a 60 ps molecular dynamics (MD) simulation of (dG)6.(dC)6 including 10 Na+ counterions and 292 water molecules are presented. All backbone angles and helix parameters for the hexamer are reported in this paper along with trajectory plots of selected angles. Hydrogen bonding between the bases along the helical axis was observed to fluctuate with time, showing the dynamic nature of the base-pairing interaction. These fluctuations gave rise to unusual hydrogen-bonding patterns. Good intrastrand base stacking and no interstrand base stacking were also observed. The hexamer minihelix retains an essentially B-DNA conformation throughout the entire simulation even though some helix parameters and backbone angles do not have strict B-DNA values. The most striking feature obtained from the simulation was a high propeller twist, which resulted in a narrow minor groove for the minihelix. It is proposed that (dG)n.(dC)n sequences are resistant to DNAase I because of this narrow minor groove in dilute aqueous solution.

Base Sequence↗
PubMed1981

Isolation and preliminary characterization of bleomycin-resistant mutants from Chinese hamster ovary cells.

Stable mutants resistant to an anticancer antibiotic, bleomycin-A2, were selected in Chinese hamster ovary (CHO) cell either spontaneously or after ethylmethane sulfonate mutagenesis. Fluctuation analysis showed that bleomycin resistance occurs in CHO at a rate of 6.50--6.58 x 10(-7) mutations per cell per generation. Bleomycin-A2-resistant cell lines exhibited increased resistance to bleomycin analogs--bleomycin-A5, -B2, -B4, and pepleomycin. Colchicine, mitomycin C, and ultraviolet light irradiation inhibited colony formation equally in CHO cells and in bleomycin-resistant mutants. Cell-cell hybridization tests showed that bleomycin-resistance behaves as a dominant trait. Bleomycin-inactivating activity in the mutant cell extracts was three to fourfold higher than that in extracts of the parental CHO cell.

Animals↗
PubMed2001

Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors.

Ampakines are small benzamide compounds that allosterically produce the positive modulation of AMPA receptors and improve performance on a variety of behavioral tasks. To test if the native synaptic membrane is necessary for the effects of such positive modulators, the mechanism of action of the Ampakine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (CX509) was investigated in isolated rat brain AMPA receptors reconstituted in lipid bilayers. The drug increased the open time of AMPA-induced single channel current fluctuations with an EC(50) of 4 microM. The action of CX509 was highly selective since it had no effect on the amplitude or close time of channel events. The open time effect had a maximum enhancement of 70-fold and the modulated currents were blocked by CNQX. It is concluded that the synaptic membrane environment is not necessary for Ampakine effects. In fact, CX509 was about 100 times more potent on the reconstituted AMPA receptors than on receptors in their native membrane. These findings indicate that centrally active Ampakines modulate specific kinetic properties of AMPA currents. They also raise the possibility that AMPA receptors are regulated by factors present in situ, thus explaining the more efficient modulatory effects of CX509 when acting on receptors removed from their synaptic location.

Animals↗
PubMed1994

Nuclear Ca2+: physiological regulation and role in apoptosis.

The last decade has seen the rapid development of research investigating the molecular mechanisms whereby hormones, peptide growth factors and cytokines regulate cell metabolism, differentiation and proliferation. One general signalling mechanism used to transfer the information delivered by agonists into appropriate intracellular compartments involves the rapid Ca2+ redistribution throughout the cell, which results in transient elevations of the cytosolic free Ca2+ concentration. Ca2+ signals are required for a number of cellular processes including the activation of nuclear processes such as gene transcription and cell cycle events. The latter require that appropriate Ca2+ signals elicited in response to agonists be transduced across the nuclear envelope. It has generally been assumed that small molecules, metabolites and ions could freely diffuse across the nuclear envelope. Nevertheless several findings during the past few years have suggested that nuclear pore permeability can be regulated and that ion transport systems and ion-selective channels may exist on the nuclear membranes and regulate intranuclear processes. Intranuclear Ca2+ fluctuations can affect chromatin organization, induce gene expression and also activate cleavage of nuclear DNA by nucleases during programmed cell death or apoptosis. The possible mechanisms involved in nuclear Ca2+ transport and the control of nuclear Ca(2+)-dependent enzymes in apoptosis is discussed below.

Animals↗
PubMed2005

Stochasticity or the fatal 'imperfection' of cloning.

The concept of clone is analysed with the aim of exploring the limits to which a phenotype can be said to be determined geneticaly. First of all, mutations that result from the replication, topological manipulation or lesion of DNA introduce a source of heritable variation in an otherwise identical genetic background. But more important, stochastic effects in many biological processes may superimpose a phenotypic variation which is not encoded in the genome. The source of stochasticity ranges from the random selection of alleles or whole chromosomes to be expressed in small cell populations, to fluctuations in processes such as gene expression, due to limiting amounts of the players involved. The picture emerging is that the term clone is a statistical over-simplification representing a series of individuals having essentially the same genome but capable of exhibiting wide phenotypic variation. Finally, to what extent fluctuations in biological processes, usually thought of as noise, are in fact signal is also discussed.

Animals↗
PubMed1994

Nuclear calcium transport and the role of calcium in apoptosis.

The last decade has been the rapid development of research investigating the molecular mechanisms whereby hormones, peptide growth factors and cytokines regulate cell metabolism, differentiation and proliferation. One general signalling mechanism used to transfer the information delivered by agonists into appropriate intracellular compartments involves the rapid Ca2+ redistribution throughout the cell, which results in transient elevations of the cytosolic free Ca2+ concentration. Ca2+ signals are required for a number of cellular functions, including the activation of nuclear processes such as gene transcription and cell cycle events. The latter requires that appropriate Ca2+ signals elicited in response to agonists be transduced across the nuclear envelope. It has generally been assumed that small molecules, metabolites and ions could diffuse freely across the nuclear envelope. Nevertheless, several findings during the past few years have suggested that nuclear pore permeability can be regulated and that ion transport systems and ion-selective channels may exist in the nuclear membranes and regulate intranuclear processes. Intranuclear Ca2+ fluctuations can affect chromatin organization, induce gene expression and also activate cleavage of nuclear DNA by nucleases during programmed cell death or apoptosis. The possible mechanisms involved in nuclear Ca2+ transport and the regulation of nuclear Ca(2+)-dependent enzymes in apoptosis are discussed in the following sections.

Animals↗
PubMed1994

Immune modulating effects of intravenous immunoglobulin (IVIg) in autoimmune diseases.

Administration of intravenous immunoglobulins (IVIg) have now been reported to be beneficial in a large number of autoimmune diseases, whether mediated by autoantibodies or by T cells. We have proposed that the immunoregulatory effect of IVIg in autoimmune diseases is dependent on the selection of recipient's immune repertoires by variable (V) regions of infused immunoglobulins. Thus: (a) IVIg contains antibodies reactive with idiotypes of natural and disease-related autoantibodies and surface immunoglobulins of B cells; IVIg also contains antibodies reactive with idiotype, framework and constant regions of the beta chain of the alpha beta T cell receptor; (b) infusion of IVIg results in transient or long-lasting suppression of specific autoantibody clones in vivo and in stimulation of a distinct subset of B cells reactive with F(ab')2 fragments of IVIg; (c) infusion of IVIg alters the general "architecture" of the network as assessed by studying the kinetic patterns of spontaneous fluctuations of natural autoantibodies in serum; (d) infusion of normal mouse Ig in healthy adult mice selects expressed immune repertoire by removing late pre-B and B cells in the bone marrow, mostly those expressing D proximal VH genes, and by activating distinct subsets of B cells and CD4+ T cells in the spleen; and (e) infusion of IVIg results in a modulation of synthesis and release of cytokines. Although dependent on the V-region reactivities (composition) or injected preparations, these effects probably also require that the infused immunoglobulin contains an intact Fc moiety. This review focuses on autoimmune and inflammatory diseases in which IVIg therapy has been beneficial. Recent recommendations from a committee of experts for IVIg therapy have been pointed out.

Adjuvants, Immunologic↗
PubMed2005

Increased sensitivity of the serotonergic system during the breeding season in free-living American tree sparrows.

In order to understand the physiological role of serotonin in regulating aggressive behaviour it is important to understand how this neuromodulator acts within the context of a naturally fluctuating social and physical environment. To accomplish this, we examined the effect of the selective serotonin reuptake inhibitor fluoxetine during the breeding season in free-living male American tree sparrows (Spizella arborea) in Northern Alaska. During this time period males are maximally aggressive towards territorial intruders. Male, territorial sparrows were injected with either vehicle or a 10 mg/kg dose of fluoxetine. One hour later, aggression was measured using a simulated territorial intrusion. Depending upon when birds were sampled, the aggression scores for vehicle and fluoxetine treatments were grouped according to the number of days after territorial behaviour was initiated. The three groups were: early, days 1-5; middle, days 6-10; and late, days 11-15. There was a significant overall difference between groups (F(5,36)=5.18, P<0.0015). Post hoc analysis demonstrated that the level of aggression did not differ between the three groups of saline injected birds. However, fluoxetine injected birds showed a time dependent decrease in aggression. When compared to control birds the middle and late fluoxetine groups had significantly less aggression. Furthermore, the late group of fluoxetine treated birds were significantly less aggressive than the early group of fluoxetine birds. This demonstrates that free-living male ATSPs show a rapid change in their behavioural response to fluoxetine across the first 2 weeks of the breeding season. The rapidity of the change in responsiveness suggests a dynamic sensitivity of the serotonergic system.

Aggression↗
PubMed2000

Singular subsets of locus coeruleus neurons may recover tyrosine hydroxylase phenotype transiently expressed during development.

The number of tyrosine hydroxylase (TH)-expressing neurons appears to be precisely determined in basal conditions within the noradrenergic pontine nucleus locus coeruleus (LC). However, additional neurons exhibiting TH phenotype have been observed in the adult rat LC following a single administration of RU 24722, a potent inducer of TH expression specific to the LC. The neurons acquiring TH phenotype following treatment had a topographical localization similar to that of the neurons, which transiently expressed TH during postnatal development and lost TH phenotype during the third postnatal week. The idea that the fluctuation of TH phenotype in singular subsets of LC neurons during development may be selectively restored in adults is of particular interest. The present study attempted to determine whether the cells in which TH expression was repressed during the third postnatal week could correspond to those which exhibited TH phenotype in response to RU 24722 treatment in adults. We first verified that no massive cell death occurred in the LC during the period ranging from days 13 to 30. Then, we observed that both cell populations exhibited the same altered steady-state concentration of TH-mRNA as compared to cells that permanently expressed TH. Finally, we demonstrated the presence of TH-negative neurons expressing the homeodomain transcription factor Phox2a, specific for the determination of noradrenergic phenotype, providing further evidence that "resting-noradrenergic" neurons exist in the adult rat LC under basal conditions. These neurons provide interesting prospective for gain of noradrenergic function when classical noradrenergic LC neurons are impaired.

Aging↗
PubMed1995

Autistic regression and disintegrative disorder: how important the role of epilepsy?

At least a third of autistic toddlers regress in language, sociability, play, and often cognition. Many fewer children undergo a similar, unexplained regression after language is fully developed (disintegrative disorder [DD]). Epilepsy or a paroxysmal electroencephalogram (EEG) with/without clinical seizures, including electrical status epilepticus in slow wave sleep (ESES), may be associated, in occasional children, with either selective loss of language (Landau-Kleffner syndrome [LKS]) or with pervasive autistic regression. Fluctuation in language and behavior deficits should raise the suspicion of epilepsy. Review of the literature and of the author's experience suggests that epilepsy probably plays a relatively minor, although non-negligible, pathogenetic role in autistic regression. Multidisciplinary, possibly multi-institutional, longitudinal studies that encompass the regression are needed to sharpen diagnostic criteria to devise more effective therapies.

Autistic Disorder↗
PubMed1986

Effect of sodium on amiloride- and triamterene-induced current fluctuations in isolated frog skin.

The apparent association constants of two agents, amiloride and triamterene, that block the Na-selective channel of apical membrane of frog skin are shown to decrease as the Na concentration is increased in the apical bathing solution in isolated skin of the frog, Rana temporaria, Rana esculenta, and Rana pipiens. These results were obtained in "normally polarized" skins. These effects were independent of the anion used (chloride or methylsulfate) or the cation used as the Na substitute (Tris, DDA, or K ion). When NaCl was replaced with mannitol, the Na effect on the amiloride association rate constant persisted, which shows that ionic strength was not critically involved. The amiloride corner frequency was unaffected when the clamp potential was altered from +100 to -60 mV. The Na dependence was greatly attenuated or absent when the serosal surface was bathed in 120 mM K Ringer's, an effect that appears to be attributable to some pharmacological effect of high serosal K. A previously described three-state model is used to analyze the inhibitory effect of Na on the blocker association rate constant.

Amiloride↗
PubMed1993

The influence of DNA topology on the environmental regulation of a pH-regulated locus in Salmonella typhimurium.

Salmonella typhimurium is exposed to major shifts in H+ concentration both in its natural and pathogenic environments. The organism undergoes extensive changes in gene expression in response to these pH fluctuations. A current question of regulatory biology is how a change in external pH selectively modulates transcription. We have analysed the expression of one such pH-regulated locus, aniG, and found it is controlled by several additional environmental conditions including osmolarity and oxygen. For factors such as osmolarity and anaerobiosis, an environmentally triggered change in DNA supercoiling has been suggested as a means for controlling gene expression. Thus, environmentally induced changes in DNA topology were explored as a possible common means for establishing the multiple controls on aniG. The involvement of DNA supercoiling in the genetic response of S. typhimurium to external pH has not previously been defined. This report establishes that alkaline environments lower the linking number of reporter plasmids when compared to acidic environments. A consistent pattern was then established whereby conditions or mutations leading to either increased or decreased negative supercoiling were associated with altered expression of aniG. A similar relationship was observed for another environmentally regulated locus, proU. The DNA topology effects on aniG expression were dependent on the presence of EarA, the negative regulator of aniG. These data can be explained by a model in which repressor-operator interactions are very sensitive to changes in operator conformation. These environmentally induced topological influences on operator DNA structure contribute to the magnitude of pH control exerted upon aniG.

Amino Acid Transport Systems↗
PubMed2004

Life history implications of rRNA gene copy number in Escherichia coli.

The role of the rRNA gene copy number as a central component of bacterial life histories was studied by using strains of Escherichia coli in which one or two of the seven rRNA operons (rrnA and/or rrnB) were deleted. The relative fitness of these strains was determined in competition experiments in both batch and chemostat cultures. In batch cultures, the decrease in relative fitness corresponded to the number of rRNA operons deleted, which could be accounted for completely by increased lag times and decreased growth rates. The magnitude of the deleterious effect varied with the environment in which fitness was measured: the negative consequences of rRNA operon deletions increased under culture conditions permitting more-rapid growth. The rRNA operon deletion strains were not more effective competitors under the regimen of constant, limited resources provided in chemostat cultures. Enhanced fitness in chemostat cultures would have suggested a simple tradeoff in which deletion strains grew faster (due to more efficient resource utilization) under resource limitation. The contributions of growth rate, lag time, Ks, and death rate to the fitness of each strain were verified through mathematical simulation of competition experiments. These data support the hypothesis that multiple rRNA operons are a component of bacterial life history and that they confer a selective advantage permitting microbes to respond quickly and grow rapidly in environments characterized by fluctuations in resource availability.

Culture Media↗
PubMed2004

Stochastic processes influence stationary-phase decisions in Bacillus subtilis.

It has recently been proposed that phenotypic variation in clonal populations of bacterial species results from intracellular "noise," i.e., random fluctuations in levels of cellular molecules, which would be predicted to be insensitive to selective pressure. To test this notion, we propagated five populations of Bacillus subtilis for 5,000 generations with selection for one phenotype: the decision to sporulate. In support of the noise hypothesis, we report that none of the populations responded to selection by improving their efficiency of sporulation, indicating that intracellular noise is independent of heritable genotype.

Bacillus subtilis↗
PubMed2002

Hearing asymmetry and auditory acuity in the Australian bushcricket Requena verticalis (Listroscelidinae; Tettigoniidae; Orthoptera).

Fluctuating asymmetry in bilaterally placed sensory structures of insects may be considered maladaptive; natural selection should favour a symmetrical system. Among bushcrickets or katydids, threshold hearing sensitivity is, in part, dependent on the size of the auditory spiracle in the prothorax. We tested the degree of natural asymmetry in the hearing system of the ensiferan orthopteran Requena verticalis by measuring the size of the auditory spiracle of females. Naturally occurring asymmetry approached 8%, which translates to a hearing bias at a threshold of only 0.8 dB. Auditory asymmetry of females was experimentally exaggerated by packing cotton wool into either the right or left auditory spiracle. We made neurophysiological recordings from the ascending auditory T-fibre in the neck connective and found that the left-right bias created by this operation approximated 5 dB; this is greater than that found in nature. For these experiments, sound was delivered to the operated side of the insect from a speaker placed at either 90 degrees or 30 degrees to the long-body axis. To test the influence of this induced auditory bias, free-moving females were allowed to orient towards a speaker emitting male calls at near-natural call intensities of 51 and 82 dB (SPL), 80 cm from the speaker on a flat arena. There was no variation in angle or vector between experimental and control insects, and there was no difference in acuity between intensity. We discuss the relevance of threshold measurements of bushcricket hearing systems in regard to sound localisation and, from these experiments question any role of asymmetry.

Animals↗
PubMed2003

Spatial resolution enhancement of fiber-optic scanning white-light interferometer by use of a Vernier principle.

A Vernier principle is employed to improve the spatial resolution of a fiber-optic white-light interferometer to the accuracy of 0.2 microm. The Vernier principle is implemented by combination of interference fringes itself and a virtual fringe that is generated by means of software tracing the scanning mirror. Two rulers are read with respect to each other. This design is insensitive to intensity fluctuation of the interference fringe. The applications, submicrometer estimation for the quadrature-locking selection and the tolerance of the relative measurement, demonstrate its effectiveness.

Journal Article↗
PubMed1998

A retrospective cohort study on retirement and mortality for male employees of a local government of Japan.

This retrospective cohort study describes the mortality pattern after retirement and examines associations of the last job position and work status immediately after retirement with the mortality for male employees who retired from Kochi prefectural government. The subjects include 514 retirees over the 1977-1981 period, who were followed for 9.8 years after retirement, and 721 retirees over the 1982-1986 period, who were followed for 5.8-9.8 years. All subjects were hypothesized to have retired at a normal retirement age. Mortality risk was stable through the follow-up period subdivided into two-year intervals in both cohorts of retirees. In both cohorts, men who did not work immediately after retirement had increased mortality within the first two years of retirement compared with those who worked immediately after retirement. This finding is consistent with the mortality pattern explained by health related selection into working after retirement. The present study does not show a meaningful mortality fluctuation over the post-retirement period among male employees of the local government. Lack of information on ages and health status at retirement of individual subjects hampers discussion about causality of observed associations between two study variables concerning pre- and post-retirement characteristics and post-retirement mortality.

Aged↗