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PubMed2006

Separation of time scales, fixation probabilities and convergence to evolutionarily stable states under isolation by distance.

To a first order of approximation, selection is frequency independent in a wide range of family structured models and in populations following an island model of dispersal, provided the number of families or demes is large and the population is haploid or diploid but allelic effects on phenotype are semidominant. This result underlies the way the evolutionary stability of traits is computed in games with continuous strategy sets. In this paper similar results are derived under isolation by distance. The first-order effect on expected change in allele frequency is given in terms of a measure of local genetic diversity, and of measures of genetic structure which are almost independent of allele frequency in the total population when the number of demes is large. Hence, when the number of demes increases the response to selection becomes of constant sign. This result holds because the relevant neutral measures of population structure converge to equilibrium at a rate faster than the rate of allele frequency changes in the total population. In the same conditions and in the absence of demographic fluctuations, the results also provide a simple way to compute the fixation probability of mutants affecting various ecological traits, such as sex ratio, dispersal, life-history, or cooperation, under isolation by distance. This result is illustrated and tested against simulations for mutants affecting the dispersal probability under a stepping-stone model.

Ecology↗

PubMed2006

Separation of time scales, fixation probabilities and convergence to evolutionary stable states under isolation by distance.

Ecology↗

PubMedDate not supplied

[The sex and corticosteroid hormones of rats selected for estrous-cycle reaction to constant illumination].

Two substrains of rats selected for the high (ESTH) and low (ESTL) ability to develop permanent oestrus under constant illumination were produced. The concentration of estradiol, testosterone in blood and 11-OCS in blood and adrenals was studied in rats of the 29 th generation under normal day (14L : 10D) and constant illumination (CL). The concentration of estradiol in blood of control rats in proestrus was 61.6 +/- 4.1 pg/ml and did not differ from substrain ESTH (59.6 +/- 4.5 pg/ml) and ESTL (58.8 +/- 4.8 pg/ml); in oestrus, the minimal concentration of estradiol was noted in control-(46.5 +/- 3.1 pg/ml), maximal one-in rats of substrain ESTL (63.3 +/- 6.2 pg/ml), in ESTH-55.8 +/- 1.7 pg/ml. The maintenance of rats in condition of CL brought about the tendency to decrease the level of estradiol in blood of rats selected in proestrus and to increase it in oestrus in comparison to control. The level of testosterone in blood of control rats in proestrus-oestrus changed in parallel to concentration of estradiol. The concentration of testosterone in blood of selected rats was higher in proestrus-oestrus as compared to control. In condition of CL, the testosterone level in proestrus did not differ from control, in oestrus it was higher than in control. The level of 11-OCS in adrenals of selected substrain was higher than in control as well in condition of 14L : 10D as in CL. The exception was substrain ESTH-in proestrus the concentration of 11-OCS in condition of CL was lower than in control. CL drastically changed direction of cyclic shifts in level of 11-OCS from higher value in proestrus under condition of 14L : 10D to low one in condition of CL. The fluctuation of 11-OCS level in blood in groups of experimental rats usually was parallel to that in adrenals.

Adrenal Glands↗

PubMed2000

Nonlinear time series analysis of normal and pathological human walking.

Characterizing locomotor dynamics is essential for understanding the neuromuscular control of locomotion. In particular, quantifying dynamic stability during walking is important for assessing people who have a greater risk of falling. However, traditional biomechanical methods of defining stability have not quantified the resistance of the neuromuscular system to perturbations, suggesting that more precise definitions are required. For the present study, average maximum finite-time Lyapunov exponents were estimated to quantify the local dynamic stability of human walking kinematics. Local scaling exponents, defined as the local slopes of the correlation sum curves, were also calculated to quantify the local scaling structure of each embedded time series. Comparisons were made between overground and motorized treadmill walking in young healthy subjects and between diabetic neuropathic (NP) patients and healthy controls (CO) during overground walking. A modification of the method of surrogate data was developed to examine the stochastic nature of the fluctuations overlying the nominally periodic patterns in these data sets. Results demonstrated that having subjects walk on a motorized treadmill artificially stabilized their natural locomotor kinematics by small but statistically significant amounts. Furthermore, a paradox previously present in the biomechanical literature that resulted from mistakenly equating variability with dynamic stability was resolved. By slowing their self-selected walking speeds, NP patients adopted more locally stable gait patterns, even though they simultaneously exhibited greater kinematic variability than CO subjects. Additionally, the loss of peripheral sensation in NP patients was associated with statistically significant differences in the local scaling structure of their walking kinematics at those length scales where it was anticipated that sensory feedback would play the greatest role. Lastly, stride-to-stride fluctuations in the walking patterns of all three subject groups were clearly distinguishable from linearly autocorrelated Gaussian noise. As a collateral benefit of the methodological approach taken in this study, some of the first steps at characterizing the underlying structure of human locomotor dynamics have been taken. Implications for understanding the neuromuscular control of locomotion are discussed. (c) 2000 American Institute of Physics.

Journal Article↗

PubMed1996

A selective phenomenology of the seismicity of Southern California.

Predictions of earthquakes that are based on observations of precursory seismicity cannot depend on the average properties of the seismicity, such as the Gutenberg-Richter (G-R) distribution. Instead it must depend on the fluctuations in seismicity. We summarize the observational data of the fluctuations of seismicity in space, in time, and in a coupled space-time regime over the past 60 yr in Southern California, to provide a basis for determining whether these fluctuations are correlated with the times and locations of future strong earthquakes in an appropriate time- and space-scale. The simple extrapolation of the G-R distribution must lead to an overestimate of the risk due to large earthquakes. There may be two classes of earthquakes: the small earthquakes that satisfy the G-R law and the larger and large ones. Most observations of fluctuations of seismicity are of the rate of occurrence of smaller earthquakes. Large earthquakes are observed to be preceded by significant quiescence on the faults on which they occur and by an intensification of activity at distance. It is likely that the fluctuations are due to the nature of fractures on individual faults of the network of faults. There are significant inhomogeneities on these faults, which we assume will have an important influence on the nature of self-organization of seismicity. The principal source of the inhomogeneity on the large scale is the influence of geometry--i.e., of the nonplanarity of faults and the system of faults.

Journal Article↗

PubMed1990

Switches in species-specific codon preferences: the influence of mutation biases.

A model of synonymous codon usage is developed in which the most frequent codons are selectively advantageous because of their coadaptation with tRNA abundances. Random drift opposes the progress of this coevolution by pushing codon frequencies in the direction of the frequency that would result from mutation in the absence of selection. It is predicted that, within a certain range, an increased mutation bias away from an advantageous codon has little influence on its usage in highly expressed genes. However, a subsequent small increase in mutation bias over a critical range leads to a large reduction in the frequency of the codon. The switch in preference from one synonym to another is a sharp transition, with no stable intermediate state in which neither codon is advantageous. Codon usage patterns were compared among three related bacterial species of differing genomic G & C contents, Escherichia coli, Serratia marcescens, and Proteus vulgaris. It was found that although changes in mutation biases do not always result in switches in codon preferences, some switches have occurred in the direction of species-specific mutation biases. Fluctuating mutation biases may therefore be the main cause of differences between species in their codon preferences.

Amino Acids↗

PubMed1997

A kappa opioid antagonist blocks sensitization in a rodent model of Parkinson's disease.

Treatment of Parkinson's disease with levodopa is associated with fluctuations in motor function and dyskinesias, which may in part depend upon the mode of levodopa treatment. In rats with unilateral 6-hydroxydopamine lesions, intermittent levodopa results in sensitization to apomorphine-induced rotation, associated with massive ipsilateral increases in nigral dynorphin. We assessed the effects of nigral infusion of the selective kappa opioid antagonist nor-binaltorphomine (nor-BNI) in this model. Nor-BNI reduced apomorphine-induced rotation in animals receiving intermittent levodopa to a level comparable with that seen in animals treated with continuous levodopa or with saline. These data suggest that behavioural sensitization arising from intermittent levodopa therapy in a rodent model of parkinsonism depends upon increased expression of dynorphin in the striatonigral pathway and provides further insight into the mechanisms underlying motor fluctuations which develop during the treatment of Parkinson's disease.

Animals↗

PubMed1997

Thermodynamics of a reverse turn motif. Solvent effects and side-chain packing.

The linear pentapeptide, Ala-Tyr-cis-Pro-Tyr-Asp-NMA (AYPYD) is known to have a significant population of type VI turn conformers in aqueous solvent. We have carried out theoretical studies of the conformational energetics of this peptide using a potential of mean force (PMF) consisting of the AMBER/OPLS empirical potential energy function, a macroscopic electrostatic model of polar solvation, and a surface area-based model of non-polar solvation. Conformers were taken from molecular dynamics simulations reported elsewhere, or generated by a random search method reported here. The chain entropy of folding was calculated by a systematic search of accessible dihedral angle space. The intra-peptide component was found to strongly favor folding and was nearly cancelled by the polar solvation term which disfavored folding. The non-polar solvation term had little effect. Fluctuations about the average value of the PMF were small and in accord with estimates from a simple harmonic model. When applied to conformers generated by a random search, the PMF selected a conformer close to the NMR-determined structure as the lowest energy conformer. The conformer with the second-lowest energy was extended, but was found to fold rapidly to the turn state in a subsequent molecular dynamics study, and may be an important state on the folding-unfolding pathway. Averages of the PMF were combined with the entropy estimates to provide an estimate of the free energy of folding that is in reasonable agreement with experimental results. In terms of the interplay between backbone electrostatic interactions and the packing of apolar side-chains, this peptide provides a model for the energetics of protein folding, and therefore makes a useful test case for calculations.

Entropy↗

PubMed1998

Environmental enrichment alters organizational features of the forepaw representation in the primary somatosensory cortex of adult rats.

The cortical forepaw area of young adult rats was mapped by recording the response properties of small clusters of neurons in layer IV of the primary somatosensory (SI) cortex. First we quantitatively analyzed the somatotopic organizational features of the cortical forepaw representation in terms of areal extent and topography, receptive field (RF) sensory modality, size, and location. We also assessed the influence of environmental enrichment, known to induce structural alterations in cortical connectivity, on the representational characteristics of the forepaw maps. Long-Evans rats were housed in environments (standard, SE; enriched, EE) promoting differential tactile experience for 71-113 days from weaning. Within the SI, we found a single and complete topographic map of the cutaneous surfaces of the forepaw consisting of a rostrolateral-caudomedial sequence of digit and pad representational zones. Small islets of noncutaneous responses (NCR; high-threshold, deep-receptor input) within the boundaries of the cutaneous maps were a conspicuous feature of the forepaw map for SE rats. These islets created discontinuities in the representation of contiguous skin territories. In the SE rats, about 79% of the cortical sites activated by light tactile stimulation had a single cutaneous RF, whereas about 21% exhibited multiple RFs. Most single-digit RFs we delineated in the SE rats extended across two or three phalanges. As a result, the representations of the phalangeal skin surfaces were not segregated but formed an overlapping continuum. Moreover, within these regions, as the electrode was displaced in regular steps across the mediolateral axis, RFs did not shift across the digit skin surface in an orderly manner, suggesting a lack of internal topography in the finger representation zones. Tactile experience promoted by environmental enrichment induced alterations in the representational features of the SI cutaneous map of the forepaw. In EE rats, the areal extent of the forepaw cutaneous representation was 1.5 times larger than in SE rats. Indeed, the cutaneous map extended into NCR cortical sectors along its external margins and also into NCR islets found in the forepaw area. Consequently, in EE rats there were fewer representational discontinuities. The areal enlargement was due to a selective increase in the areal extent of the glabrous but not the hairy skin surface representations. Furthermore, protuberant glabrous skin (digit tips, palmar pads) was represented over larger cortical regions than were other glabrous skin territories less likely to be stimulated during object palpation and manipulation. Maps from EE rats were also characterized by a larger proportion of sites with single RFs (88% compared with 79%). In addition, glabrous RFs from EE rats were smaller and more clustered on the digit tips and palmar pads than were RFs in SE rat maps. RF size on hairy skin surfaces remained unchanged. Because the RFs were smaller, the cutaneous maps of EE rats contained distinct representations of digit phalangeal glabrous skin. RFs tended to exhibit more orderliness in their progression across the digit glabrous skin of EE rats than they did in SE rats. The phalanges of EE rats were represented in distinct patches. Neurons in EE rats were more sensitive to light tactile stimulation than were neurons in SE rats. These alterations were presumably mediated by the selective potentiation of cutaneous over deep-receptor activation. More generally, the present study corroborates the view that cortical cutaneous maps are maintained in a permanent state of use-dependent fluctuation.

Animals↗

PubMed1996

Permeability increase induced by Escherichia coli hemolysin A in human macrophages is due to the formation of ionic pores: a patch clamp characterization.

Escherichia coli hemolysin is known to cause hemolysis of red blood cells by forming hydrophilic pores in their cell membrane. Hemolysin-induced pores have been directly visualized in model systems such as planar lipid membranes and unilamellar vesicles. However this hemolysin, like all the members of a related family of toxins called Repeat Toxins, is a potent leukotoxin. To investigate whether the formation of channels is involved also in its leukotoxic activity, we used patch-clamped human macrophages as targets. Indeed, when exposed to the hemolysin, these cells developed additional pores into their membrane. Such exogenous pores had properties very different from the endogenous channels already present in the cell membrane (primarily K+ channels), but very similar to the pores formed by the toxin in purely lipidic model membranes. Observed properties were: large single channel conductance, cation over anion selectivity but weak discrimination among different cations, quasilinear current-voltage characteristic and the existence of a flickering pre-open state of small conductance. The selectivity properties of the toxin channels appearing in phospholipid vesicles were also investigated, using a specially adapted polarization/depolarization assay, and were found to be completely consistent with that of the current fluctuations observed in excised macrophage patches.

Bacterial Proteins↗

PubMed1981

Fluctuation analyses of spontaneous mutations to 6-thioguanine resistance in Chinese hamster ovary cells in culture.

Fluctuation analyses of the spontaneous appearance of 6-thioguanine (TG)-resistant mutants in cultured Chinese hamster ovary (CHO) cells were performed to investigate (1) whether the resistance is induced by the selective agent or is the result of a mutation which occurs prior to the TG selection and (2) to estimate the spontaneous mutation rate at the hypoxanthine--guanine phosphoribosyl transferase (hgprt) locus. The potential problem of phenotypic delay was minimized by allowing an adequate expression time through maintenance of the cultures in a division-arrested, viable state. The results demonstrate that the TG-resistant (TGr) cells arise randomly in the cultures, independently of the selective agent, which is consistent with spontaneous mutations. The average values for mutation rate +/- standard deviation, based on 4 independent determinations and 2 methods of calculation, are 3.4 +/- 1.2 X 10(-7) (median method) and 5.1 +/- 1.8 X 10(-7) (mean method) mutants/cell/generation.

Animals↗

PubMed1994

Socio-economic causes and cultural explanations of childhood malnutrition among the Chagga of Tanzania.

This study provides an in-depth analysis of the complexity of factors involved in selective child survival among the Chagga people of Mt Kilimanjaro, Tanzania. Carried out during the first of a series of post-independence economic crises, the study analyzes the impact of fluctuations in world economy, ecological stresses, demographic pressures, and class formation in creating conditions of poverty and lessening the ability of many Chagga to provide adequate care for their children. Qualitative and quantitative information are given from a follow-up study of families whose children were placed in a nutrition rehabilitation program during the drought of 1972-73. Four cases from that study further demonstrate the impact of macroeconomic forces on individuals and provide material for analyzing a complex pattern of cultural beliefs which made up part of the Chagga people's explanations for child malnutrition.

Child↗

PubMed2005

Gender-related differences in general practice preferences: longitudinal evidence from the Netherlands 1982-2001.

The proportion of female doctors is increasing. Yet, there is little evidence that demonstrates changing career preferences over a long period, nor do we know the long-term impact of changing male-female ratios in medicine. We explored this within the GP profession. By means of a longitudinal cohort study (postal questionnaires) among all graduated GPs in the Netherlands between 1982 and 2001 we explored trends in career preferences and investigated whether practice preferences of men and women differ over the years. Preference of becoming a GP has significantly decreased among men. GPs prefer group practice more than solo practice. Female doctors were more likely to prefer a small practice and to associate. Men prefer to take over an established practice. Main reasons to abstain from practicing as a GP for men were having found another job or not having found a practice according to their preferences. Main reasons for women were having decided for another job and family life. We conclude that male and female GPs select differently on practice setting. Preferences change through the years but tend to converge. Gender differences are likely due to the circumstance that career choices for men are more influenced by fluctuating labour markets, while female choices are more based on family circumstances. We expect that as more women will become a GP the demand for small group practices will increase. Also, as many female GPs abstain from practicing after having finished a vocational GP training program it will be essential to create work facilities to keep them available for the GP labour market.

Adult↗

PubMed2005

Negative emotions and anosognosia.

Patients with anosognosia fail to acknowledge, or feel distressed by, their disability. Given the recent suggestion that right (frontal) systems are selectively involved in negative emotions, it might be claimed that anosognosia results from a disruption in negative emotions. This is not consistent with the finding that some anosognosic patients exhibit substantial fluctuations in emotion, including the experience of negative emotions such as sadness. The present study investigates a patient (IW) with a right convexity lesion and anosognosia. He reported being frequently overcome by powerful emotions, especially sadness. IW was assessed on a self-report emotion questionnaire, where his reports were typically of higher levels of emotion than the control group. He was also assessed on the more indirect measure of Affective Story Recall. Here his pattern of emotional experience was similar to that of two control groups, one of which consisted of non-anosognosic patients with hemiparesis. His performance on Story Recall was notable in that he directed his emotions to a different 'object' to that of controls (other vs. self, respectively). These findings are not consistent with any claim that anosognosia results from an absence of negative emotions.

Aged↗

PubMed1999

Evidence that most radiation-induced HPRT mutants are generated directly by the initial radiation exposure.

Radiation-induced HPRT mutants are generally assumed to arise directly from DNA damage that is misrepaired within a few hours after X-irradiation. However, there is the possibility that mutations result indirectly from radiation-induced genomic instability that may occur several days after the initial radiation exposure. The protocols that commonly employ a 5-7 day expression period to allow for expression of the mutant phenotype prior to replating for selection of mutants would not be able to discriminate between mutants that occurred initially and those that arose during or after the expression period. To address this question, we performed a fluctuation analysis in which synchronous or asynchronous populations of human bladder carcinoma cells were treated with single doses of X-irradiation. For comparison, radiation was delivered during the expression period, either from an initial dose of 1.0 Gy followed by two 1.0 Gy doses separated by 24 h or from disintegrations resulting from I125dU incorporated into DNA. The mutation frequency observed at the time of replating was used to calculate the average number of mutants in the initial irradiated culture by assuming that the mutants were induced directly at the time of irradiation. Then, this average number was used to calculate the fraction of the irradiated cultures that would be predicted by a Poisson distribution to have zero mutants. There was reasonably good agreement between the predicted poisson distribution and the observed distribution for the cultures that received single doses. Moreover, as expected, when cultures were irradiated during the expression period, the fraction of the cultures having zero mutants was significantly less than that predicted by a Poisson distribution. These results indicate that most radiation-induced HPRT mutations are induced directly by the initial DNA damage, and are not the result of radiation-induced instability during the 5-7 day expression period.

DNA↗

PubMed1985

A method for consistent precision radiation therapy.

Using a meticulous setup procedure in which repeated portal films were taken before each treatment until satisfactory portal verifications were obtained, a high degree of precision in patient positioning was achieved. A fluctuation from treatment to treatment, over 11 treatments, of less than +/- 0.10 cm (S.D.) for anatomical points inside the treatment field was obtained. This, however, only applies to specific anatomical points selected for this positioning procedure and does not apply to all points within the portal. We have generalized this procedure and have suggested a means by which any target volume can be consistently positioned which may approach this degree of precision.

Chondrosarcoma↗

PubMed2003

A universal denoising and peak picking algorithm for LC-MS based on matched filtration in the chromatographic time domain.

A new denoising and peak picking algorithm (MEND, matched filtration with experimental noise determination) for analysis of LC-MS data is described. The algorithm minimizes both random and chemical noise in order to determine MS peaks corresponding to sample components. Noise characteristics in the data set are experimentally determined and used for efficient denoising. MEND is shown to enable low-intensity peaks to be detected, thus providing additional useful information for sample analysis. The process of denoising, performed in the chromatographic time domain, does not distort peak shapes in the m/z domain, allowing accurate determination of MS peak centroids, including low-intensity peaks. MEND has been applied to denoising of LC-MALDI-TOF-MS and LC-ESI-TOF-MS data for tryptic digests of protein mixtures. MEND is shown to suppress chemical and random noise and baseline fluctuations, as well as filter out false peaks originating from the matrix (MALDI) or mobile phase (ESI). In addition, MEND is shown to be effective for protein expression analysis by allowing selection of a large number of differentially expressed ICAT pairs, due to increased signal-to-noise ratio and mass accuracy.

Algorithms↗

PubMed2004

An evaluation of parameters for the detection of subclinical rumen acidosis in dairy herds.

An observational study was conducted in six Danish dairy herds. A specially designed stomach tube was compared to the rumenocentesis technique as part of the monitoring of rumen pH. In contrast to a previous study, the use of the stomach tube appeared to reduce saliva contamination. However, correlation with the rumenocentesis technique was poor ( r = 0.33; p = 0.019) and a linear model could only partly explain variations between either results. The presence of subclinical rumen acidosis (SRA) was evidenced in one herd only, as judged by results obtained by the rumenocentesis technique. The present study revealed some limitations of the rumenocentesis technique in small or medium-sized herds due to difficulties in selecting sufficient numbers of cows in the respective groups at risk. The finding of two apparently clinical normal cows with rumen pH values below 5.0 leads to the consideration that such fluctuations may be temporary and at least does not give rise to clinical symptoms. However, the long-term effect of such fluctuations is not known. In general, primiparous cows seemed more prone to low ruminal pH values (< 6.0), higher ruminal concentrations of short-chain fatty acids, and possibly to metabolic acidosis, than were multiparous cows. Ruminal propionate was the most precise predictor of rumen pH, whereas milk fat percentage varied greatly between lactational groups. Blood lactate dehydrogenase (LDH), beta-hydroxybutyrate (BHB) and fructosamine as well as urine phosphorus excretion and renal net acid-base excretion (NABE) were related to ruminal acid load, but were not predictive of rumen pH. Monitoring of dairy herds for SRA should be performed routinely and employ several diagnostic tools (rumenocentesis, renal NABE determination) as well as specific knowledge of herd management and feeding routines.

3-Hydroxybutyric Acid↗