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PubMed2001

The quantitative genetics of fluctuating asymmetry.

Fluctuating asymmetry (subtle departures from identical expression of a trait across an axis of symmetry) in many taxa is under stabilizing selection for reduced asymmetry. However, lack of reliable estimates of genetic parameters for asymmetry variation hampers our ability to predict the evolutionary outcome of this selection. Here we report on a study, based on analysis of variation within and between isofemale lines and of generation means (line-cross analysis), designed to dissect in detail the quantitative genetics of positional fluctuating asymmetry (PFA) in bristle number in natural populations of Drosophila falleni. PFA is defined as the difference between the two sides of the body in the placement or position of components of a meristic trait. Heritability (measured at 25 degrees C) of two related measures of PFA were 13% and 21%, both of which differed significantly from zero. In contrast, heritability estimates for fluctuating asymmetry in the total number of anterior (0.7%) and transverse (2.4%) sternopleural bristles were smaller, not significant, and in quantitative agreement with previously published estimates. Heritabilities for bristle number (trait size) were considerably greater than that for any asymmetry measure. The experimental design controlled for the potentially confounding effects of common familial environment, and repeated testing revealed that PFA differences between lines were genetically stable for up to 16 generations in the laboratory at 25 degrees C. We performed line cross analysis between strains at the extremes of the PFA distribution (highest and lowest values); parental strains, F1, F1r (reciprocal), F2, backcross, and backcross reciprocal generations were represented. The inheritance of PFA was described best by additive and dominance effects localized to the X-chromosomes, whereas autosomal dominance effects were also detected. Epistatic, maternal, and cytoplasmic effects were not detected. The inheritance of trait size was notably more complex and involved significant autosomal additive, dominance, and epistatic effects; maternal dominance effects; and additive and dominance effects localized to the X-chromosomes. The additive genetic correlation between PFA and its associated measure of trait size was negative (-0.049), but not statistically significant, indicating that the loci contributing additive genetic effects to these traits are probably different. It is suggested that PFA may be a sensitive measure of developmental instability because PFA taps the ability of an organism to integrate interconnected developmental pathways.

Animals↗
PubMed1981

A computer model of the evolution of specific maximum lifespan.

To answer the question of why organisms have evolved finite and specific maximum lifespans, I have built and experimentally studied a discrete-event simulation model of the evolution of lifespan. Through natural selection, the model evolves an apparent plateau in maximum lifespan, the height of which is a decreasing function of both the intensity of niche fluctuations and specific fecundity. Evolved lifespan is therefore finite (small and essentially constant over accessible time intervals) and specific. Experiments demonstrate that the plateau is not due to group selection. Instead, it occurs because the rate of increase of maximum lifespan by natural selection - in an environment presenting a finite probability that death will occur prior to reaching the genetically specified maximum - is a decreasing function of maximum lifespan itself and asymptotically approaches zero. This supports in part a class of existing hypotheses that finite lifespan is due to an equilibrium between weak selection, as in the model, and various lifespan-decreasing processes, which however were not simulated in the present experiments. Although the model shows that such counter processes are not strictly necessary for the evolution of finite and specific maximum lifespan, my interpretation of the model's correspondence to organic evolution does imply a counter process, a bias in random genetic drift toward shorter lifespan, that is more general than those previously hypothesized.

Biological Evolution↗
PubMed1980

Adenosine triphosphatase activity and its sensitivity to ruthenium red oscillate during the cell cycle of Escherichia coli K12.

A procedure has been developed for the large-scale fractionation into size and age classes of bacteria from exponentially growing cultures of Escherichia coli K12 by centrifugation through an equivolumetric gradient of sucrose in a zonal rotor. The resolution attained is superior to that in methods of this type that have been described previously. The activity of adenosine triphosphatase (ATPase) was assayed in extracts from bacteria separated into size classes by this method and from synchronous cultures prepared by size selection. Activity approximately doubled during a cell cycle, but the experimental data did not fit models of either continuously or exponentially increasing activity during the cycle. It is suggested that ATPase activity oscillates during the cell cycle with maxima at about 0.37 and 0.80 of a cycle. The fluctuations in activity greatly exceed the variations due to experimental error and, in the case of synchronous cultures, do not arise from perturbations in growth behaviour following zonal gradient selection. Sensitivity of ATPase activity to 75 micrometer-Ruthenium Red also fluctuates during the cell cycle, with maximum inhibition (60 to 80%) occurring near the middle of the cycle, a time that does not coincide with maximum enzyme activity.

Adenosine Triphosphatases↗
PubMed2006

Bond fluctuation of S/Se anchoring observed in single-molecule conductance measurements using the point contact method with scanning tunneling microscopy.

Conductance was measured for the single molecules with S/Se anchoring on a Au surface using the point contact method with scanning tunneling microscopy that enables us to selectively perform a repeated analysis of a chosen target molecule. Apparent conductance changes observed in sequential measurements suggest the existence of bond fluctuation among the adsorption sites.

Journal Article↗
PubMed2006

Redox-reactive autoantibodies: detection and physiological relevance.

We recently described a hitherto unrecognized family of autoantibodies that become unmasked (detectable) subsequent to oxidation-reduction (redox) reactions. These masked redox-reactive autoantibodies are not detectable by using conventional immunoassays. Additional experimentation has demonstrated that autoantibodies in the blood of patients with autoimmune diseases can be masked (become undetectable) by exposure to oxidizing agents. Simultaneous masking and unmasking of different autoantibodies in a given patient's serum or plasma is evidence that immune complexes are not the source of redox-reactive autoantibodies. We propose that a mechanism responsible for unmasking-masking antibody specificities requires nitrosylation of tyrosine residues in the hypervariable or complementarity determining regions of the antibodies' antigen-binding sites. Other laboratories, selected by us for their respective expertise, have studied our redox-reacted and control serum and/or antibody preparations and have found an expanding array of autoantibody specificities. The gathering data suggest that certain autoimmune diseases may involve redox disorders rather than a failure to deplete, suppress, tolerate or divert self-directed B cell activity. The persistence and fluctuation of redox-reactive autoantibodies suggest that they are manifestations of an as yet undefined natural selective pressure on the evolution of the immunological system. We propose that they are the "contrivances" suggested by Paul Ehrlich more than a hundred years ago, and that these antibodies perform important physiological and pathophysiological functions.

Animals↗
PubMed2006

Ligand-induced conformational changes in the acetylcholine-binding protein analyzed by hydrogen-deuterium exchange mass spectrometry.

Recent x-ray crystallographic studies of the acetylcholine-binding protein (AChBP) suggest that loop C, found at the circumference of the pentameric molecule, shows distinctive conformational changes upon antagonist and agonist occupation. We have employed hydrogen-deuterium exchange mass spectrometry to examine the influence of bound ligands on solvent exposure of AChBP. Quantitative measurements of deuterium incorporation are possible for approximately 56% of the Lymnaea AChBP sequence, covering primarily the outer surface of AChBP. In the apoprotein, two regions flanking the ligand occupation site at the subunit interface, loop C (residues 175-193) and loop F (residues 164-171), show greater extents of solvent exchange than other regions of the protein including the N- and C-terminal regions. Occupation by nicotinic agonists, epibatidine and lobeline, and nicotinic antagonists, methyllycaconitine, alpha-bungarotoxin, and alpha-cobratoxin, markedly restricts the exchange of loop C amide protons, influencing both the rates and degrees of exchange. Solvent exposure of loop C and its protection by ligand suggest that in the apoprotein, loop C exhibits rapid fluctuations in an open conformation. Bound agonists restrict solvent exposure through loop closure, whereas the larger antagonists restrict solvent exposure largely through occlusion of solvent. Loop F, found on the complementary subunit surface at the interface, also reveals ligand selective changes in amide proton exchange rates. Agonists do not affect solvent accessibility of loop F, whereas certain antagonists cause subtle accessibility changes. These results reveal dynamic states and fluctuating movements in the vicinity of the binding site for unligated AChBP that can be influenced selectively by ligands.

Amino Acid Sequence↗
PubMed1984

[Genetic characteristics of Chinese hamster cell resistance to colchicine, actinomycin D and ethidium bromide].

We have tried to study genetics of Chinese hamster cellular drug resistance to colchicine, actinomycin D and ethidium bromide. Resistant variants arising at a frequency 10(-5) to 10(-7) were selected from a sensitive population. Pretreatment with MNNG increased this frequency 106, 9-15, 12-26 times for colchicine, actinomycin D and ethidium bromide, respectively. Fluctuation test analysis allows to suppose that phenotypic expression of drug resistance is genetically determined and resulted from random genetical events. Significant values of particular correlation coefficients for selecting resistant variants in a set of independently originated subpopulations suggest the genetical identity of the majority of variants selected by colchicine and actinomycin D. At the same time, the significant portion of colchicine-resistant cells may be selected using ethidium bromide. It is not unlikely that under above experimental conditions, each selective agent reveals genetically different resistant variants. The possible genetic mechanisms of resistance to the drugs used are discussed.

Animals↗
PubMed2000

Annual fluctuation in amplitudes of daily variations of electrical signals measured in the trunk of a standing tree.

Electrical potential differences between electrodes inserted in eight selected sites of the trunk of a Turkey oak (Quercus cerris) and the ground have been recorded continuously since November 1997. The mean amplitudes of daily electric variations were determined for time intervals when the meteorological and atmospheric electricity conditions were undisturbed. It was found that the mean daily amplitudes show a characteristic annual fluctuation. Both in 1998 and in 1999 two peaks were observed: the first maximum appears suddenly about the end of March, and the second one was seen in late June, July. Between November and March the mean amplitudes were smaller by about one order of magnitude.

Circadian Rhythm↗
PubMed1993

The visual field indices in primary open-angle glaucoma.

PURPOSE: The distribution of sensitivity across the visual field, as determined by automated threshold static perimetry, can be summarized in terms of visual field indices. Such indices can be weighted for the variation in threshold at each eccentricity. The aims of this study were to determine the influence of the weighting factor, the relationship between the unweighted indices derived from Programs 30-2 and 24-2, and the relationship between the number of double determinations of threshold and the magnitude of the short-term fluctuation. METHODS: One visual field derived by Program 30-2 of the Humphrey Field Analyzer was selected from each of 60 consecutive patients with primary open-angle glaucoma. The first two fields from each individual patient were avoided. Unweighted visual field indices were calculated and compared with the Program 30-2 weighted indices using an assessment of agreement evaluated with respect to the 95% confidence limits of the population. RESULTS: The weighting function had no influence on the mean deviation, but it caused a slight reduction in the short-term fluctuation and an elevation in the pattern and corrected pattern standard deviations. There was little difference between the indices generated by Programs 30-2 and 24-2. The short-term fluctuation increased with an increase in the number of double determinations of threshold. CONCLUSIONS: The weighting function had little clinical influence on the visual field indices. The indices derived from Programs 30-2 and 24-2 were similar, and the short-term fluctuation would better reflect the intratest variability if all available double determinations of threshold were used to calculate the index.

Aged↗
PubMedDate not supplied

Immunoglobulins and the regulation of autoimmunity through the immune network.

Beneficial effects of the administration of intravenous immunoglobulins (IVIg) have now been reported in a large number of autoimmune diseases, whether mediated by autoantibodies or by autoaggressive T cells. We have proposed that the immunoregulatory effect of IVIg in autoimmune disease is dependent on the selection of the recipient's immune repertoires by the variable (V) region reactivities of infused immunoglobulins. Thus IVIg contains antibodies reactive with idiotypes of natural and disease-related autoantibodies and surface immunoglobulins of B cells; IVIg also contains antibodies reactive with the idiotype, framework and constant regions of the beta chain of the alpha beta T cell receptor. 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 the F(ab')2 fragments of IVIg 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. 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. 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. If one considers the effect of IVIg on the structure, function and dynamics of the immune network IVIg may be viewed as a substitutive therapy for the quantitative/qualitative defects in network regulation that are associated with autoimmune diseases.

Animals↗
PubMed1988

Fluctuations of CD4+ T-cell subsets in remitting-relapsing multiple sclerosis.

Patients with multiple sclerosis (MS) frequently have selective depletion of the CD45R+CD4+ T-cell subset during active phases of disease. To study the relationship between changes in this subset and the onset of objective clinical exacerbations of disease, a longitudinal study was undertaken. Two CD4+ T-cell subsets and two CD8+ T-cell subsets were monitored by two-color immunofluorescence using a fluorescence-activated cell sorter. These subsets of peripheral blood lymphocytes were monitored monthly for one year in a group of 9 patients with remitting-relapsing MS and in 11 healthy age-matched control subjects. Significant changes in the ratio of two CD4+ T-cell subsets (CD45R-/CD45R+) were detected in 7 of 9 patients with MS, but not in any of the control subjects. Of those 7 persons, 4 suffered major clinical relapses substantiated by alterations in the neurological examination. The other 3 suffered minor relapses with subjective clinical abnormalities. All 7 had increased CD4+ T-cell subset ratios (%CD4+CD45R-/%CD4+CD45R+) within the month that new symptoms were reported. Most such increases resulted from a simultaneous depletion in the number of CD45R+CD4+ T cells and an increase in the number of CD45R-CD4+ T cells. One patient suffered a major relapse with no change in the ratio of CD4+ subsets but had a depletion of all CD4+ T cells. There were no consistent changes in any of the other subsets measured. These results indicate that a subgroup of patients with MS have abnormal fluctuations of two CD4+ T-cell subsets, which may correlate with increased disease activity.

Adult↗
PubMed2005

Statistical analysis of systematic errors in high-throughput screening.

High-throughput screening (HTS) is an efficient technology for drug discovery. It allows for screening of more than 100,000 compounds a day per screen and requires effective procedures for quality control. The authors have developed a method for evaluating a background surface of an HTS assay; it can be used to correct raw HTS data. This correction is necessary to take into account systematic errors that may affect the procedure of hit selection. The described method allows one to analyze experimental HTS data and determine trends and local fluctuations of the corresponding background surfaces. For an assay with a large number of plates, the deviations of the background surface from a plane are caused by systematic errors. Their influence can be minimized by the subtraction of the systematic background from the raw data. Two experimental HTS assays from the ChemBank database are examined in this article. The systematic error present in these data was estimated and removed from them. It enabled the authors to correct the hit selection procedure for both assays.

Algorithms↗
PubMed2005

Ageing and the extinction of large animals.

In the modulation of longevity by natural selection there is a trade-off between the investment of resources in the maintenance of the body, or soma, and the investment in reproduction. There is accumulating evidence that long-lived mammalian species have much more efficient maintenance than short-lived ones. It is also clear that short-lived ground-living mammalian species reproduce very much more quickly than larger long-lived species, and in all mammals there is an inverse relationship between maximum reproductive potential and maximum longevity. These features of life-history strategies very strongly support the disposable soma theory of the evolution of ageing. Slow development and large size are associated with delayed ageing. If the environment changes, for whatever reason, small rapidly breeding species are able to adapt and survive much more easily that large slow breeding species. This can explain the very well documented extinction of many large mammalian species during the Pleistocene. In an environment which remains constant for a long period of time, selection favours the evolution of larger species, but these are put at risk if the environment becomes less favorable. Fluctuating environments are more likely to promote the evolution of small short-lived species with high fecundity.

Aging↗
PubMed2001

Sexual selection of multiple handicaps in the red-collared widowbird: female choice of tail length but not carotenoid display.

Although sexual selection through female choice explains exaggerated male ornaments in many species, the evolution of the multicomponent nature of most sexual displays remains poorly understood. Theoretical models suggest that handicap signaling should converge on a single most informative quality indicator, whereas additional signals are more likely to be arbitrary Fisherian traits, amplifiers, or exploitations of receiver psychology. Male nuptial plumage in the highly polygynous red-collared widowbird (Euplectes ardens) comprises two of the commonly advocated quality advertisements (handicaps) in birds: a long graduated tail and red carotenoid coloration. Here we use multivariate selection analysis to investigate female choice in relation to male tail length, color (reflectance) of the collar, other aspects of morphology, ectoparasite load, display rate, and territory quality. The order and total number of active nests obtained are used as measures of male reproductive success. We demonstrate a strong female preference and net sexual selection for long tails, but marginal or no effects of color, morphology, or territory quality. Tail length explained 47% of male reproductive success, an unusually strong fitness effect of natural ornament variation. Fluctuating tail asymmetry was unrelated to tail length, and had no impact on mating success. For the red collar, there was negative net selection on collar area, presumably via its negative relationship with tail length. None of the color variables (hue, chroma, and brightness) had significant selection differentials, but a partial effect (selection gradient) of chroma might represent a color preference when tail length is controlled for. We suggest that the red collar functions in male agonistic interactions, which has been strongly supported by subsequent work. Thus, female choice targets only one handicap, extreme tail elongation, disregarding or even selecting against the carotenoid display. We discuss whether long tails might be better indicators of genetic quality than carotenoid pigmentation. As regards the evolution of multiple ornaments, we propose that multiple handicap signaling is stable not because of multiple messages but because of multiple receivers, in this case females and males.

Animals↗
PubMed1993

High rate of multilocus deletion in a human tumor cell line.

The nature of recessive mutations at the autosomal locus encoding the purine salvage enzyme adenine phosphoribosyl transferase (APRT) was analyzed in a highly malignant human tumor cell line (the colorectal carcinoma line SW620). Mutant strains resistant to the purine analog 8-azaadenine were obtained in two steps. The first step selection for partial drug resistance produced strains hemizygous for APRT as a result of high frequency loss of one allele. In the second step selection, low frequency base substitutions, small deletions, or insertions produced complete azaadenine resistance. Luria-Delbruck fluctuation analysis of each step of this process indicated that the rate of mutation resulting from allele loss was over 100-fold greater than the rate of mutation resulting from base substitution. There was no reproducible difference in the rate of loss of either of the two APRT alleles even though one maps to a rearranged chromosome. Similarly base substitution rates for the two alleles were not significantly different. Polymorphic loci surrounding APRT on chromosome 16 band q24 were lost together with the selected gene in all isolates while polymorphic loci on the short arm of the chromosome were retained. Thus the high frequency loss of APRT in SW620 appears to be the result of multilocus deletions. SW620 derivatives behaving as heterozygotes were also obtained in the first step selections, but these constituted only 5% of isolates.

Adenine↗
PubMed1975

Fitness of allozyme variants in Drosophila pseudoobscura. I. Selection at the PGM-1 and Me-2 loci.

We have studied in Drosophila pseudoobscura the effect of allozyme variation on seven fitness components: female fecundity, egg hatchability, egg-to-adult survival under near-optimal and under competitive conditions, rate of development under near-optimal and under competitive conditions, and mating capacity of males. Three genotypes at each of two loci, Pgm-1 and Me-2, have been studied in various combinations. These two loci are highly polymorphic in natural populations of D. pseudoobscura. Statistically significant differences involving one or more genotypes exist for all components of fitness. No single genotype is best for all fitness components; rather the relative fitnesses of genotypes are reversed when different parameters are considered, or when they are studied in different environmental conditions. Also, the average egg-to-adult survival and rate of development are better when different genotypes are reared together than when they occur in pure culture. Four different modes of selection have been uncovered by our experiments. These forms of selection may account for the persistence of the two allozyme polymorphisms in nature, and for previously observed seasonal fluctuations of the allelic frequencies in natural populations.

Animals↗
PubMed2005

Dopamine-dependent and dopamine-independent actions of cocaine as revealed by brain thermorecording in freely moving rats.

Brain temperature fluctuates biphasically in response to repeated, intravenous (i.v.) cocaine injections, perhaps reflecting cocaine's inhibiting effect on both dopamine (DA) transporters and Na+ channels. By using a DA receptor blockade, one could separate these actions and determine the role of DA-dependent and DA-independent mechanisms in mediating this temperature fluctuation. Rats were chronically implanted with thermocouple probes in the brain, a non-locomotor head muscle and subcutaneously. Temperature fluctuations associated with ten repeated i.v. cocaine injections (1 mg/kg with 8-min inter-injection intervals) were examined after a combined, systemic administration of selective D1-like and D2-like receptor blockers (SCH-23390 and eticlopride) at doses that effectively inhibit DA transmission. In contrast to the initial temperature increases and subsequent biphasic fluctuations (decreases followed by increases) seen with repeated cocaine injections in saline-treated control, brain and muscle temperatures during DA receptor blockade decreased with each repeated cocaine injection. DA receptor blockade had no effects on skin temperature, which tonically decreased and biphasically fluctuated (decreases followed by increases) during repeated cocaine injections in both conditions. DA receptor blockade by itself slightly increased brain and muscle temperatures, with no evident effect on skin temperature. DA antagonists also strongly decreased spontaneous movement activity and completely blocked the locomotor activation normally induced by repeated cocaine injections. Although our data confirm that cocaine's inhibitory action on presynaptic DA uptake is essential for its ability to induce metabolic and behavioral activation, they also suggest that the physiological effects of this drug cannot be explained through this system alone. The continued hypothermic effect of cocaine points to its action on other central systems (particularly blockade of Na+ channels) that may be important for the development of cocaine abuse and adverse effects of this drug.

Animals↗
PubMed2000

Auditory thalamus neurons during sleep: changes in frequency selectivity, threshold, and receptive field size.

The present study describes how the frequency receptive fields (RF) of auditory thalamus neurons are modified when the state of vigilance of an unanesthetized animal naturally fluctuates among wakefulness (W), slow-wave sleep (SWS), and paradoxical sleep (PS). Systematic quantification of several RF parameters-including strength of the evoked responses, response latency, acoustic threshold, shape of rate-level function, frequency selectivity, and RF size-was performed while undrugged, restrained guinea pigs presented spontaneous alternances of W, SWS, and PS. Data are from 102 cells recorded during W and SWS and from 53 cells recorded during W, SWS, and PS. During SWS, thalamic cells behaved as an homogeneous population: as compared with W, most of them (97/102 cells) exhibited decreased evoked spike rates. The frequency selectivity was enhanced and the RF size was reduced. In contrast during PS, two populations of cells were identified: one (32/53 cells) showed the same pattern of changes as during SWS, whereas the other (21/53 cells) expressed values of evoked spike rates and RF properties that did not significantly differ from those in W. These two populations were equally distributed in the different anatomical divisions of the auditory thalamus. Last, during both SWS and PS, the responses latency was longer and the acoustic threshold was higher than in W but the proportion of monotonic versus nonmonotonic rate-level functions was unchanged. During both SWS and PS, no relationship was found between the changes in burst percentage and the changes of the RF properties. These results point out the dual aspect of sensory processing during sleep. On the one hand, they show that the auditory messages sent by thalamic cells to cortical neurons are reduced both in terms of firing rate at a given frequency and in terms of frequency range. On the other hand, the fact that the frequency selectivity and the rate-level function are preserved suggests that the messages sent to cortical cells are not deprived of informative content, and that the analysis of complex acoustic sounds should remain possible. This can explain why, although attenuated, reactivity to biologically relevant stimuli is possible during sleep.

Acoustic Stimulation↗