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PubMed1995

Fluctuations in rotation rate of the flagellar motor of Escherichia coli.

The purpose of this work was to study the changes in rotation rate of the bacterial motor and to try to discriminate between various sources of these changes with the aim of understanding the mechanism of force generation better. To this end Escherichia coli cells were tethered and videotaped with brief stroboscopic light flashes. The records were scanned by means of a computerized motion analysis system, yielding cell size, radius of rotation, and accumulated angle of rotation as functions of time for each cell selected. In conformity with previous studies, fluctuations in the rotation rate of the flagellar motor were invariably found. Employing an exclusively counterclockwise rotating mutant ("gutted" RP1091 strain) and using power spectral density, autocorrelation and residual mean square angle analysis, we found that a simple superposition of rotational diffusion on a steady rotary motion is insufficient to describe the observed rotation. We observed two additional rotational components, one fluctuating (0.04-0.6 s) and one oscillating (0.8-7 s). However, the effective rotational diffusion coefficient obtained after taking these two components into account generally exceeded that calculated from external friction by two orders of magnitude. This is consistent with a model incorporating association and dissociation of force-generating units.

Antibodies↗
PubMed2001

Dynamic predictions: oscillations and synchrony in top-down processing.

Classical theories of sensory processing view the brain as a passive, stimulus-driven device. By contrast, more recent approaches emphasize the constructive nature of perception, viewing it as an active and highly selective process. Indeed, there is ample evidence that the processing of stimuli is controlled by top-down influences that strongly shape the intrinsic dynamics of thalamocortical networks and constantly create predictions about forthcoming sensory events. We discuss recent experiments indicating that such predictions might be embodied in the temporal structure of both stimulus-evoked and ongoing activity, and that synchronous oscillations are particularly important in this process. Coherence among subthreshold membrane potential fluctuations could be exploited to express selective functional relationships during states of expectancy or attention, and these dynamic patterns could allow the grouping and selection of distributed neuronal responses for further processing.

Animals↗
PubMed2001

Diabetes: energetics, development and human evolution.

The recent emergence of the thrifty phenotype as an explanation for metabolic efficiency has brought evolutionary perspectives on diabetes, as represented by the thrifty genotype, under scrutiny. However, the logic of natural selection along with evidence from non-human primates supports the role for energetic constraints in the evolution of metabolic efficiency, particularly in skeletal muscle physiology. Environmental fluctuation during human evolution would have provided selective pressures for the development of efficient skeletal muscle starting prenatally and continuing throughout the lifespan. Such mechanisms including, glucose transporters, mitochondrial gene expression, leptin receptors and uncoupling proteins, should be present in all humans, though some living populations may exhibit particular 'thriftier' alleles. A focus on physical activity and the factors underlying efficient muscle physiology has implications for prevention of diabetes in both developing and developed societies.

Biological Evolution↗
PubMed2003

The effect of temporal structure on rustling-sound detection in the gleaning bat, Megaderma lyra.

For a gleaning bat hunting prey from the ground, rustling sounds generated by prey movements are essential to invoke a hunting behaviour. The detection of prey-generated rustling sounds may depend heavily on the time structure of the prey-generated and the masking sounds due to their spectral similarity. Here, we systematically investigate the effect of the temporal structure on psychophysical rustling-sound detection in the gleaning bat, Megaderma lyra. A recorded rustling sound serves as the signal; the maskers are either Gaussian noise or broadband noise with various degrees of envelope fluctuations. Exploratory experiments indicate that the selective manipulation of the temporal structure of the rustling sound does not influence its detection in a Gaussian-noise masker. The results of the main experiment show, however, that the temporal structure of the masker has a strong and systematic effect on rustling-sound detection: When the width of irregularly spaced gaps in the masker exceeded about 0.3 ms, rustling-sound detection improved monotonically with increasing gap duration. Computer simulations of this experiment reveal that a combined detection strategy of spectral and temporal analysis underlies rustling-sound detection with fluctuating masking sounds.

Acoustic Stimulation↗
PubMed1995

Endogenous reproductive hormones and nocturnal rhythms in partner preference and sexual behavior of ATD-treated male rats.

Male rats received subcutaneously silastic capsules, containing the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD), shortly after birth. Control males were given silastic capsules containing cholesterol. The capsules were removed at the age of 21 days. In adulthood, blood serum was collected early and late in the dark phase of the light/dark cycle (experiment I). Testosterone and luteinizing hormone and follicle stimulating hormone (FSH) fluctuated nocturnally, both in ATD and control males, with highest levels late in the dark phase. FSH levels were significantly higher in ATD males. Nocturnal levels of inhibin, a selective suppressor of pituitary FSH secretion, also fluctuated in both ATD and control males, with lowest levels late in the dark phase. In experiment II, ATD and control males were tested for partner preference behavior in a three-compartment box (choice: sexually active male vs. estrous female) early and late in the dark phase. When gonadally intact, ATD males, but not controls, showed a clear nocturnal rhythmicity in partner preference behavior and sexual behavior. Early in the dark phase, such ATD males preferred the vicinity of and interaction with a sexually active male. Late in the dark phase, this preference for the active male shifted to a preference for the estrous female. Control males preferred the estrous female. After castration and subsequent treatment with testosterone via silastic capsules, which ensured constant blood serum levels, ATD males continued to show their nocturnal rhythms in partner preference behavior and in sexual behavior. Thus, the underlying mechanism of the nocturnal rhythmicity phenomenon is an organizational effect of neonatal ATD treatment rather than an activational effect of fluctuating serum hormone levels.

Animals↗
PubMed2003

Thermal adaptation in Drosophila serrata under conditions linked to its southern border: unexpected patterns from laboratory selection suggest limited evolutionary potential.

To investigate the ability of Drosophila serrata to adapt to thermal conditions over winter at the species southern border, replicate lines from three source locations were held as discrete generations over three years at either 19 degrees C (40 generations) or temperatures fluctuating between 7 degrees C and 18 degrees C (20 generations). Populations in the fluctuating environment were maintained either with an adult 0 degrees C cold shock or without a shock. These conditions were expected to result in temperature-specific directional selection for increased viability and productivity under both temperature regimes, and reduced development time under the fluctuating-temperature regime. Selection responses of all lines were tested under both temperature regimes after controlling for carry-over effects by rearing lines in these environments for two generations. When tested in the 19 degrees C environment, lines evolving at 19 degrees C showed a faster development time and a lower productivity relative to the other lines, while cold shock reduced development time and productivity of all lines. When tested in the fluctuating environment, productivity of the 7-18 degrees C lines selected with a cold shock was relatively lower than that of lines selected without a shock, but this pattern was not observed in the other populations. Viability and body size as measured by wing length were not altered by selection or cold shock, although there were consistent effects of source population on wing length. These results provide little evidence for temperature-specific adaptation in D. serrata-although the lines had diverged for some traits, these changes were not consistent with a priori predictions. In particular, there was no evidence for life-history changes reflecting adaptation to winter conditions at the southern border. The potential for D. serrata to adapt to winter conditions may therefore be limited.

Adaptation, Physiological↗
PubMed1977

Fluctuations in buoyant density during the cell cycle of Escherichia coli K12: significance for the preparation of synchronous cultures by age selection.

The buoyant densities of Escherichia coli K12 were investigated by isopycnic centrifugation in gradients of colloidal silica (Ludox) and polyvinylpyrrolidone. Bacteria from an exponential culture in a defined medium supplemented with hydrolysed casein banded at densities between 1-060 and 1-115 g ml-1; the mean density was 1-081 g ml-1. At the higher densities, two populations of cells were present: smaller cells were approximately twice as numerous as, and half the modal volume of, the population of larger cells. A homogeneous population of cells of intermediate volume equilibrated in the least dense region of the density band. Synchronous cultures were established by inoculating cells selected from the most or least dense regions of the band into spent growth medium. The results are consistent with a fluctuation between maximal density at cell birth and division, and minimal density near the middle of the cell cycle. In synchronous cultures prepared by continuous-flow age selection, the first division occurred after a period that was significantly shorter than the length of subsequent cell cycles. Cells selected by this procedure were of similar mean density to those in the exponential culture but were more homogeneous with respect to size. The possibility that the smallest (and densest) cells in an exponential culture are retained in the rotor, and are thus excluded from the synchronous culture, is discussed.

Cell Division↗
PubMed1997

The meaning of near-neutrality at coding and non-coding regions.

The nature of weak selection differs between coding and non-coding regions. Coding regions contain genetic information, whereas most non-coding regions do not have any information. Genetic information may be regarded as interaction systems, and the NK model of Kauffman was analysed. This model assumes that each amino acid makes a fitness contribution that depends on the amino acid and on K other amino acids among the N that make the protein. Through simulations, it was found that there are numerous nearly-neutral mutations under this model. Therefore, evolution is rapid in small populations, and slow in large populations. The variance of the evolutionary rate is not quite as large as data indicate under the model, and additional factors, such as environmental change or population-size fluctuation, need to be considered. Weak selection at non-coding regions may come from chromosome organization, and may be regional in character, which differs from that at coding regions. The problem of genetic load is thought to disappear in these circumstances.

Gene Frequency↗
PubMed2005

Molecular evolution in the Drosophila melanogaster species subgroup: frequent parameter fluctuations on the timescale of molecular divergence.

Although mutation, genetic drift, and natural selection are well established as determinants of genome evolution, the importance (frequency and magnitude) of parameter fluctuations in molecular evolution is less understood. DNA sequence comparisons among closely related species allow specific substitutions to be assigned to lineages on a phylogenetic tree. In this study, we compare patterns of codon usage and protein evolution in 22 genes (>11,000 codons) among Drosophila melanogaster and five relatives within the D. melanogaster subgroup. We assign changes to eight lineages using a maximum-likelihood approach to infer ancestral states. Uncertainty in ancestral reconstructions is taken into account, at least to some extent, by weighting reconstructions by their posterior probabilities. Four of the eight lineages show potentially genomewide departures from equilibrium synonymous codon usage; three are decreasing and one is increasing in major codon usage. Several of these departures are consistent with lineage-specific changes in selection intensity (selection coefficients scaled to effective population size) at silent sites. Intron base composition and rates and patterns of protein evolution are also heterogeneous among these lineages. The magnitude of forces governing silent, intron, and protein evolution appears to have varied frequently, and in a lineage-specific manner, within the D. melanogaster subgroup.

Amino Acid Substitution↗
PubMed2001

Heme deficiency selectively interrupts assembly of mitochondrial complex IV in human fibroblasts: revelance to aging.

Heme deficiency was studied in young and old normal human fibroblasts (IMR90). Regardless of age, heme deficiency increased the steady-state level of oxidants and lipid peroxidation and sensitized the cells to fluctuations in intracellular Ca(2+). Heme deficiency selectively decreased the activity and protein content of mitochondrial complex IV (cytochrome c oxidase) by 95%, indicating a decrease in successful assembly. Complexes I-III and catalase remained intact under conditions of heme deficiency, whereas ferrochelatase was up-regulated. Complex IV is the only hemeprotein in the cell that contains heme a, which may account for its susceptibility. The rate of removal and assembly of complex IV declines with age. These findings are relevant to worldwide iron deficiency in women and children and to an age-related decline in complex IV in Alzheimer's disease patients.

Cells, Cultured↗
PubMed2004

The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal analysis.

OBJECTIVE: Radiologic progression in rheumatoid arthritis (RA) is considered the consequence of persistent inflammatory activity. To determine whether a change in disease activity is related to a change in radiologic progression in individual patients, we investigated the longitudinal relationship between inflammatory disease activity and subsequent radiologic progression. METHODS: The databases of the University Medical Center Nijmegen (UMCN) cohort and the Maastricht Combination Therapy in RA (COBRA) followup study cohort were analyzed. The UMCN cohort included 185 patients with early RA who were followed up for up to 9 years. Patients were assessed every 3 months for disease activity and every 3 years for radiologic damage. The COBRA cohort included 152 patients with early RA who were followed up for up to 6 years. Patients were assessed at least every year for disease activity and every 12 months for radiologic damage. Disease activity was assessed with the Disease Activity Score (DAS) (original DAS in the UMCN cohort, DAS28 in the COBRA cohort). Radiologic damage was measured by the Sharp/van der Heijde score in both cohorts. Data were analyzed with longitudinal regression analysis (generalized estimating equations [GEE]), using autoregression for longitudinal associations and radiologic damage as the dependent variable. Time, time(2) baseline predictors for radiologic progression and their interactions with time, as well as DAS/DAS28 (actual values or interval means and interval SDs of the means) were subsequently modeled as explanatory variables. RESULTS: Data analyzed by GEE showed a decrease in radiologic progression over time (regression coefficient for time(2) -1.0 [95% confidence interval -1.4, -0.6] in the UMCN cohort and -0.4 [95% confidence interval -0.8, 0.0] in the COBRA cohort). After adjustment for time effects and baseline predictors of radiologic progression and their interactions with time, a positive longitudinal relationship was indicated by autoregressive GEE between the mean interval DAS and radiologic progression in the UMCN cohort (regression coefficient 5.4 [95% confidence interval 2.1, 8.6]), and between the DAS28 and radiologic progression in the COBRA cohort (regression coefficient 1.4 [95% confidence interval 0.8, 2.0]). In the UMCN cohort, the SD of the mean interval DAS was independently longitudinally related to the radiologic progression over the same periods (regression coefficient 20.2 [95% confidence interval 7.2, 33.3]). In both cohorts, the longitudinal relationships between (fluctuations in) disease activity and radiologic progression were found selectively in rheumatoid factor (RF)-positive patients. CONCLUSION: Radiologic progression is not linear in individual patients. Fluctuations in disease activity are directly related to changes in radiologic progression, which supports the hypothesis that disease activity causes radiologic damage. This relationship might only exist in RF-positive patients.

Adult↗
PubMed2006

Selectivity principle of the ligand escape process from a two-gate tunnel in myoglobin: molecular dynamics simulation.

We proposed a selectivity principle for the ligand escape process from two fluctuating bottlenecks in a cavity with a multigate inside a myoglobin pocket. Our previous analytical theory proposed a fluctuating bottleneck model for a Brownian particle passing through two gates on a cavity surface of an enzyme protein and has determined the escape rate in terms of the time-dependent gate function and the competition effect. It illustrated that with two (or more than two) gates on a cavity surface the gate modulation, which is controlled by protein fluctuation, dominates the ligand escape pathway. We have performed a molecular dynamics simulation to investigate the selectivity principle of the ligand escape process from two-gate tunnel in myoglobin. The simulation results confirm our theoretical conjecture. It indicates that the escape process is actually entropy driven, and the ligand escape pathway is chosen via the gate modulation. This suggests an interesting intrinsic property, that is, the oxymyoglobin tertiary structure is favorable to the departure of the ligand from one direction rather than through a biased random walk.

Computer Simulation↗
PubMed1995

Apomorphine infusional therapy in Parkinson's disease: clinical utility and lack of tolerance.

We assessed the clinical utility of apomorphine infusional therapy in patients with parkinsonism and motor fluctuations and sought evidence for alterations in drug response resulting from chronic treatment. Six patients with Parkinson's disease were treated for 3 months with s.c. infusions of apomorphine administered during waking hours. At the beginning and the end of the study, test doses of apomorphine (12.5-100 micrograms/kg) were administered to establish a dose-response curve. Over the study, the patients reported a significant improvement in the number of "on" hours experienced per day and substantially reduced the dose and frequency of levodopa and other antiparkinsonian medications. No average change in apomorphine dose-response relationships or pharmacokinetics was observed during the study. However, two patients lowered the infusion rate during the 3-month observation and exhibited higher drug levels and longer responses following test doses of apomorphine given at the end of the study. Although pragmatic concerns with the use of infusion pumps solutions and adverse effects limited the overall benefit afforded by the treatment, this kind of drug treatment may be useful in selected patients with severe parkinsonism and fluctuations.

Administration, Cutaneous↗
PubMed1978

Cellular autolytic activity in synchronized populations of Streptococcus faecium.

The autolytic capacity of Streptococcus faecium (S. faecalis ATCC 9790) varied during synchronous cell division. This phenomenon was initially observed in rapidly dividing populations (TD=30 to 33 min) synchronized by a combination of induction and size selection techniques. To minimize the problems inherent in studies of cells containing overlapping chromosome cycles and possible artifacts generated by induction techniques, the autolytic capacities of slowly dividing populations (TD=60 to 110 min) synchronized by selection only were examined. Although the overall level of cellular autolytic capacity was observed to decline with decreasing growth rate, sharp, periodic fluctuations in cellular autolytic capacity were seen during synchronous growth at all growth rates examined. On the basis of similar patterns of cyclic fluctuations in autolytic capacity of cultures synchronized by (i) selection, (ii) amino acid starvation followed by size selection, and (iii) amino acid starvation followed by inhibition of DNA synthesis, a link of such fluctuations with the cell division cycle has been postulated.

Amino Acids↗
PubMed2001

Urgent carotid endarterectomy for stroke in evolution.

BACKGROUND: Carotid endarterectomy (CEA) is well established as the elective treatment for moderate or severe carotid stenoses with a history of neurologic symptoms. In contrast, the merits of carotid revascularisation performed in emergency in patients with acute stroke or fluctuating neurological deficit remain controversial. PATIENTS AND METHODS: A total of 445 CEAs were performed on 424 patients for 212 (48%) asymptomatic and 233 (52%) symptomatic carotid stenoses within a 5 years period between January, 1995, and December, 1999. Of the latter, CEA was performed in emergency on 16 patients (3.8%) within 4 to 24 hours after the onset of symptoms. Patients selected for urgent surgery fulfilled the following criteria: acute onset of fluctuating hemispheric neurological symptoms, significant carotid pathology, absence of cerebral hemorrhage, uncompromised vigilance and stable cardiopulmonary conditions. Selected patients presented with a crescendo-TIA (n = 7) or fluctuating neurological deficits (n = 9) corresponding to a contralateral carotid stenosis. RESULTS: Following CEA, the neurological deficits improved instantaneously to complete recovery in 9 patients. The symptoms of 4 patients improved to non-disabling deficits, remained unchanged in one and worsened in 2 patients from hemihypaesthesia to hemiparesis. 14/16 patients were discharged within 8 days after admission. The neurologic status after discharge did not deteriorate in any of the patients during follow up of 19.3 +/- 13 months, but improved in 4 of the patients. CONCLUSION: Our retrospective study suggests that rescue CEA may be beneficial for selected patients with stroke in evolution and fluctuating neurological deficits. Careful adherence to selection criteria, intraoperative shunting, intensive care post surgery surveillance and an experienced team are recommended.

Aged↗
PubMed1997

Malignant vagotonia due to selective baroreflex failure.

Baroreflex failure is characterized by dramatic fluctuations of sympathetic activity and paroxysms of hypertension and tachycardia. In contrast, unopposed parasympathetic activity has not been described in patients with baroreflex failure because of concurrent parasympathetic denervation of the heart. We describe the unusual case of a patient with baroreflex failure in a setting of preserved parasympathetic control of HR manifesting episodes of severe bradycardia and asystole. Thus, parasympathetic control of the HR may be intact in occasional patients with baroreflex failure. Patients with this selective baroreflex failure require a unique therapeutic strategy for the control of disease manifestations.

Baroreflex↗
PubMed2001

Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease.

BACKGROUND: When levodopa therapy is used in Parkinson's disease, degradation of the drug in the peripheral nervous system is associated with dyskinesias and motor fluctuations. Much of this degradation is produced by catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of catecholamines and catechol compounds. Inhibition of COMT activity prolongs the action of levodopa and reduces fluctuations in response. Entacapone is a selective inhibitor of COMT whose activity is primarily in the peripheral nervous system, with little effect in the central nervous system. OBJECTIVE: This paper reviews the pharmacologic properties and clinical usefulness of entacapone in the treatment of Parkinson's disease. METHODS: Recent studies, abstracts, and reviews published in the English-language literature were identified through searches of MEDLINE (1966-September 2000), International Pharmaceutical Abstracts (1970-September 2000), and PharmaProjects (September 2000 version), and from the Web sites of Parkinson's disease conferences held from 1996 to September 2000. Relevant human studies provided further information on the pharmacologic properties and clinical usefulness of entacapone. RESULTS: Entacapone is rapidly absorbed, with a time to maximum concentration of approximately 1 hour. Its plasma elimination half-life is 0.4 to 0.7 hour in the beta phase and 2.4 hours in the gamma phase, and it has 35% absolute bioavailability after oral administration, secondary to first-pass clearance. Entacapone is 98% protein bound; thus, it is not distributed widely in tissues and is almost completely metabolized before excretion (0.1%-0.2% of dose unchanged in urine). The drug inhibits erythrocyte-soluble COMT activity in a dose-dependent fashion (48% after a 400-mg dose, 82% after an 800-mg dose). The inhibitory effect is reversible, with recovery of soluble COMT activity within 4 to 8 hours. In levodopa-treated patients with Parkinson's disease who experience motor fluctuations, clinical trials have demonstrated entacapone's effectiveness in increasing "on" time (the period during which medications relieve the symptoms of Parkinson's disease) by up to 1.2 hours, decreasing "off" time (the period during which symptoms increase) by 0.9 to 1.3 hours, and producing overall total improvement in scores on the Unified Parkinson's Disease Rating Scale. The recommended dosage of entacapone is 200 mg administered orally with each dose of levodopa/carbidopa, up to 8 doses per day. The drug is generally well tolerated, with most adverse effects attributed to levodopa-related dopaminergic effects, including dyskinesias and nausea. CONCLUSIONS: In clinical trials, adjuvant treatment with entacapone appeared to be an effective and well-tolerated therapeutic strategy in patients with Parkinson's disease who experience fluctuations in the response to levodopa therapy. The increased elimination half-life of levodopa with concomitant entacapone results in greater and more sustained plasma levodopa levels, with more constant dopaminergic stimulation in the brain and greater amelioration of parkinsonian symptoms.

Antiparkinson Agents↗
PubMed1987

Optimal recombination rate in fluctuating environments.

The optimal recombination rate which maximizes the long-term geometric average of the population fitness is studied for a two-locus haploid model, assuming that the fitnesses of genotypes AB, Ab, aB and ab are 1 + s(t), 1 - s(t), 1 - s(t), and 1 + s(t), respectively, where s(t) follows various stationary stochastic processes with the average zero. With positive recombination, the polymorphism is stably maintained at both loci. After an initial transient phase, the dynamics are reduced to one dimension, and are analyzed for weak selection limit, strong selection limit, and selection with two state Markovian jump. Results are: (1) If the environmental fluctuation has a predominant periodic component, ropt is approximately inversely proportional to the period irrespective of selection intensity. (2) If the fluctuation is a superposition of many periodic components, the one with the longest period is the most effective in determining ropt because the genetic dynamics cannot track very quick fluctuations (low pass filter effect). (3) If the power spectrum density is decreasing with the frequency, as in pink, or 1/f noises, ropt is small when selection is weak, and increases with the selection intensity. Numerical calculation of the genetic dynamics of a recombination modifier supports all these predictions for the evolutionarily stable recombination rate.

Alleles↗