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PubMed1990

Increase in the catalytic rate of beta-galactosidase by selection in chemostats at changing dilution rates.

The experiments presented in this paper explore whether mutants with catalytically more active beta-galactosidase (E.C. 3.2.1.23) can be selected in lactose-limited chemostats. This experimental system has been chosen because lactose metabolism in Escherichia coli is well understood both from a biochemical and genetic point of view. In a lactose-limited chemostat with constant dilution rates, both beta-galactosidase and the lactose permease increased in quantity. The catalytic rate (kcat) of beta-galactosidase in populations showed no change. On the other hand, in chemostats with periodically changing dilution rates, the catalytic rate of beta-galactosidase increased dramatically. Therefore, the selection for beta-galactosidase with improved catalytic rate occurs in chemostats with fluctuating dilution rates but not in ones with constant dilution. These observations may be of value in the selection of other enzymes with enhanced catalytic rates.

Bacteriological Techniques↗

PubMed1994

Fluctuating and/or progressive sensorineural hearing loss in children.

Sensorineural hearing loss (SNHL) which is sudden in onset, fluctuating, and/or progressive complicates medical management, hearing aid selection, and individualized educational planning for a hearing-impaired child. In spite of multidisciplinary evaluation and intervention, a gradual decrease in auditory acuity may continue unabated in a significant number of cases. Intercurrent middle ear disease and inconsistent audiologic technique can account for threshold variation in some cases. The study population consisted of 229 children (132 boys; 97 girls) aged 1 to 19.9 years at first audiogram which revealed at least a mild degree of sensorineural hearing loss in one or both ears (35 unilateral), and who demonstrated threshold variation of 10 dB or more in at least one ear at one or more of the standard audiometric test frequencies (250, 500, 1000, 2000, 4000, and 8000 Hz) and were without concurrent middle ear disease (mean length of follow-up, 4.9 years; mean number of audiograms, 10.3). Of 365 ears demonstrating threshold variation of 10 dB or more, 22 (6%) had purely progressive losses without intercurrent upward fluctuation, 208 (57%) had fluctuating thresholds with gradually progressive losses, and 135 (37%) had intermittent threshold fluctuation without permanent deterioration. The probability of contralateral threshold fluctuation if one ear fluctuated was 0.91, while the probability of contralateral progressive SNHL if one ear progressed was 0.67. Demographic data, presumptive etiology, degree of initial SNHL, audiometric configuration, and symmetry of threshold variation were considered as potential predictors of the likelihood of threshold fluctuation and/or progression.

Adolescent↗

PubMed1998

System-dependent Selection, Ecological Feedback and the Emergence of Functional Structure in Ecosystems.

Most models of natural selection assume either that the material environment remains constant or that it fluctuates in ways unrelated to changes in gene frequencies (and therefore changes in the distribution of phenotypes) of the organism undergoing selection. In this paper, we consider what happens when this assumption does not hold, that is, when ecological feedback between organism and environment is included in the evolutionary process. Specifically, we examine the unusual evolutionary dynamics that occur when changes in the distribution of phenotypes (resulting from selection) alter an environmental parameter in ways that, in turn, modify selection pressures. This process, which we term "system-dependent selection", can produce stable phenotypic diversity which functions to regulate the relevant environmental parameter within a much narrower range would occur in the absence of ecological feedback. This environmental regulation raises the mean fitness of the population and reduces variance in fitness among different phenotypes. Thus, system-dependent selection produces functional organization at the level of the system, as a whole, rather than at the level of the individual organism. We use James Lovelock's model of the imaginary planet Daisyworld to describe the unusual dynamics of this selective process and then use a similar model to examine the structure of an ancient system of wet-rice farming on the Indonesian island of Bali. This model accurately predicts the actual structure of functional organization along two Balinese rivers. We investigate the stability of such systems by exploring the conditions under which mutant phenotypes can invade Daisyworld. The results suggest that the phenotypic diversity and functional organization produced by system-dependent selection may be maintained when there exists variation, over evolutionary time, in the environmental parameters underlying system-dependent dynamics.Copyright 1998 Academic Press Limited

Journal Article↗

PubMed2004

Non-subtype-selective opioid receptor antagonism in treatment of levodopa-induced motor complications in Parkinson's disease.

Opioid peptide transmission is enhanced in the striatum of animal models and Parkinson's disease (PD) patients with levodopa-induced motor complications. Opioid receptor antagonists reduce levodopa-induced dyskinesia in primate models of PD; however, clinical trials to date have been inconclusive. A double-blind, placebo controlled, crossover design study in 14 patients with PD experiencing motor fluctuations was carried out, using the non-subtype-selective opioid receptor antagonist naloxone. Naloxone did not reduce levodopa-induced dyskinesia. The duration of action of levodopa was increased significantly by 17.5%. Non-subtype-selective opioid receptor antagonism may prove useful in the treatment of levodopa-related wearing-off in PD but not in dyskinesia.

Antiparkinson Agents↗

PubMed2003

[Fluctuation in the ratio between drug-resistant and -susceptible M. tuberculosis bacilli which were isolated from patients with prolonged anti-tuberculosis treatment].

PURPOSE: In this study, we examined the fluctuation in the ratio between strains of tuberculosis bacilli resistant and susceptible to the anti-tuberculosis drugs. MATERIAL & METHOD: We selected the cases in which the bacilli acquired drug resistance during the therapy and the cases in which drug resistance was fluctuating during prolonged anti-tuberculosis treatment. We selected the isolates throughout the medication period, and the selected isolates were separated into respective single colonies. Then we measured the minimal inhibitory concentration (MIC) for each colony by microdilution test for M. tuberculosis complex, BrothMIC MTB-1 (Kyokuto Pharmaceutical Inc., Tokyo). RESULTS: Five patients were eligible for analysis because their medical histories were clearly recorded and drug resistance changed during the course. The MIC of 19 isolates, 202 colonies were measured. Isolates with coexisting drug-resistant and -susceptible colonies were detected in 2 patients. From these results, we considered that the fluctuation in the ratio between drug-resistant and -susceptible bacilli changes with the progression of anti-tuberculosis medication. CONCLUSION: We showed in this article that the drug-resistant bacilli increased rapidly when the strains acquired the drug resistance during medication, and when the administration of particular anti-tuberculosis drug was stopped, the susceptible bacilli seemed to increase gradually. However, the strain immediately became fully drug-resistant when the particular antibacterial drug was readministered.

Antitubercular Agents↗

PubMed2005

Increased gastric motility during 5-HT4 agonist therapy reduces response fluctuations in Parkinson's disease.

We investigated the clinical efficacy and tolerability of 45 mg/day mosapride, a selective 5-hydroxytryptamine type 4 (5-HT4) agonist, in an open-label study involving five patients with Parkinson's disease (PD) who had response fluctuations (RFs). 'On' time and motor function scores were determined, and gastric motility was measured by a radionuclide gastric emptying (GE) test, the most reliable quantitative method available. We found that mosapride therapy significantly shortened GE half-time, reduced RFs, and improved motor functions in all patients. There were no adverse reactions. We conclude that selective 5-HT4 agonist therapy is beneficial for patients with PD who have RFs.

Aged↗

PubMed1991

Effects of artificial stabilizing selection on Drosophila populations subjected to directional selection for another trait.

Stabilizing selection for a set of morphometric wing traits was combined with directional selection for the increased expression of radius incompletus (ri) mutation of Drosophila melanogaster. Three experimental regimes were used: directional and stabilizing selection (stabilized lines); directional selection (unstabilized lines); no selection (controls). Response to selection for ri expression was similar in all selected lines but variation of this character was higher in the unstabilized lines compared to the stabilized ones. The competitive indices measured after termination of selection did not significantly differ under different treatments while fluctuating asymmetry was significantly lower in stabilized than in unstabilized lines. The possible causes of these differences are discussed.

Animals↗

PubMed2007

Rapid evolution of flowering time by an annual plant in response to a climate fluctuation.

Ongoing climate change has affected the ecological dynamics of many species and is expected to impose natural selection on ecologically important traits. Droughts and other anticipated changes in precipitation may be particularly potent selective factors, especially in arid regions. Here we demonstrate the evolutionary response of an annual plant, Brassica rapa, to a recent climate fluctuation resulting in a multiyear drought. Ancestral (predrought) genotypes were recovered from stored seed and raised under a set of common environments with descendant (postdrought) genotypes and with ancestorxdescendant hybrids. As predicted, the abbreviated growing seasons caused by drought led to the evolution of earlier onset of flowering. Descendants bloomed earlier than ancestors, advancing first flowering by 1.9 days in one study population and 8.6 days in another. The intermediate flowering time of ancestorxdescendant hybrids supports an additive genetic basis for divergence. Experiments confirmed that summer drought selected for early flowering, that flowering time was heritable, and that selection intensities in the field were more than sufficient to account for the observed evolutionary change. Natural selection for drought escape thus appears to have caused adaptive evolution in just a few generations. A systematic effort to collect and store propagules from suitable species would provide biologists with materials to detect and elucidate the genetic basis of further evolutionary shifts driven by climate change.

Biological Evolution↗

PubMed2001

Two inbred strains of mice with high and low mammary tumor potentials established from the same basal stock of Swiss albino (SHN and SLN): history of mammary tumorigenesis and reproduction after the 30th generation of full-sib mating.

We established SHN and SLN strains of mice with a high and a low mammary tumor potentials from the same basal stock of Swiss albino. The selection history of females (mothers) for subsequent generations, mammary tumorigenesis and reproduction up to recent generations are presented and compared with the results up to F30 published in 1979. The changes with generation of each parameter varied in both strains except the conditions of female (mother) selection for subsequent generations, which were generally constant. However, the fluctuations in parameters up to F30 became generally smaller with advancing generations. Based on the fluctuations from generation to generation of mammary tumorigenic and reproductive parameters, an interdependency between mammary tumor potential and reproductivity is suggested in SLN, but less so in SHN. The pup growth rate was increased and associated with selection for mammary tumorigenesis in SHN; this parameter is usually used as an indicator of mother lactational performance in mice. The significance of selection for mammary tumor potential in association with reproductivity was further discussed.

Aging↗

PubMed1993

Punctuated equilibria or gradual evolution: fluctuating asymmetry and variation in the rate of evolution.

The debate on long-term rates of evolution is polarized around two models: the punctuated equilibrium hypothesis (long periods of very little evolution interrupted by periods of relatively rapid evolutionary change) and the gradual view (the rate of evolution is gradual, albeit with variable rate). Here we suggest that the pace of evolutionary change can be independently determined by estimating the degree of trait asymmetry. Fluctuating asymmetry occurs as a result of random deviations in the development of bilaterally symmetric traits. The degree of fluctuating asymmetry closely reflects the ability of individuals to cope with stress. Traits subject to strong directional selection become less developmentally canalized and more susceptible to the influence of stress. Strong stabilizing selection has the opposite effect. Characters of individuals from periods of rapid evolutionary change should hence be characterized by high variability, high fluctuating asymmetry and fluctuating asymmetry should increase with trait size in the direction of selection. In contrast, characters of individuals from periods of little evolutionary change should demonstrate low variability, low asymmetry and a flat or U-shaped relationship between size and asymmetry.

Animals↗

PubMed1999

Evolution of genetic variability and the advantage of sex and recombination in changing environments.

The role of recombination and sexual reproduction in enhancing adaptation and population persistence in temporally varying environments is investigated on the basis of a quantitative-genetic multilocus model. Populations are finite, subject to density-dependent regulation with a finite growth rate, diploid, and either asexual or randomly mating and sexual with or without recombination. A quantitative trait is determined by a finite number of loci at which mutation generates genetic variability. The trait is under stabilizing selection with an optimum that either changes at a constant rate in one direction, exhibits periodic cycling, or fluctuates randomly. It is shown by Monte Carlo simulations that if the directional-selection component prevails, then freely recombining populations gain a substantial evolutionary advantage over nonrecombining and asexual populations that goes far beyond that recognized in previous studies. The reason is that in such populations, the genetic variance can increase substantially and thus enhance the rate of adaptation. In nonrecombining and asexual populations, no or much less increase of variance occurs. It is explored by simulation and mathematical analysis when, why, and by how much genetic variance increases in response to environmental change. In particular, it is elucidated how this change in genetic variance depends on the reproductive system, the population size, and the selective regime, and what the consequences for population persistence are.

Animals↗

PubMed2003

Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause.

Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.

Affect↗

PubMed1987

Immunoglobulin heavy chain switch region recombination within a retroviral vector in murine pre-B cells.

We have employed a retroviral vector, ZN(Smu/S gamma 2b)tk1, as a substrate for detecting the presence of immunoglobulin heavy chain constant region (CH) gene switch (S) recombination activity in murine pre-B cells. ZN(Smu/S gamma 2b)tk1 contains a neomycin (neo) resistance gene in addition to the herpes simplex virus thymidine kinase (Htk) gene which is positioned between murine Smu and S gamma 2b sequences. Stable acquisition of the ZN(Smu/S gamma 2b)tk1 vector was selected in G-418 and switch region recombination within these proviruses was selected by resistance to the drug bromodeoxyuridine (BUdR). Fluctuation analyses of ZN(Smu/S gamma 2b)tk1 infected 18-8tk- and 38B9tk- pre-B lines revealed Htk gene inactivations with apparent frequencies of 5 X 10(-5) and 1 X 10(-5) events/cell/generation, respectively, while G-418 resistant Ltk- fibroblasts lost the HTK phenotype at an apparent rate of 4 X 10(-8). Southern blot analysis demonstrated that switch recombination caused the deletion of the Htk gene in all pre-B clones examined while the loss of Htk in Ltk- clones was not mediated by S region recombination. In 21 out of 24 pre-B clones, the recombinations involved the tandemly repetitive portions of the Smu and S gamma 2b sequences. These results demonstrate that the CH gene S region segments inserted into ZN(Smu/S gamma 2b)tk1 are sufficient for B-cell-specific recombination/deletion within the S region tandem repeats.

Animals↗

PubMed1988

Apparent stresses in disturbed pulsatile flows.

Traditional attempts at decomposing measured velocities into repeatable and random components are examined for a set of velocity data measured under pulsatile flow conditions distal to a 90% axisymmetric constriction. The Reynolds numbers, which are typical of those found in the human carotid artery, are such that transitional phenomena occur during portions of the pulsatile cycle at several axial stations. The implications of the method selected for velocity decomposition upon the computation of fluctuating or 'apparent' stresses is a point of major focus. It is shown that the usual estimation of Reynolds stresses in a pulsatile flow by subtracting the ensemble-averaged velocity from the instantaneous velocity leads to an underestimation of the apparent stress when coherent or repeatable disturbances exist in the flow. An alternative decomposition using a frequency domain approach is presented which combines both random and coherent stresses into a single apparent stress, and it is proposed that this approach is preferable to the traditional ensemble averaging method when estimating fluctuating stresses in arterial flows.

Blood Flow Velocity↗

PubMed2004

Contemporary paradigms for cholinergic ligand design guided by biological structure.

The identification of the various nicotinic receptor subtypes, when coupled with the recent development of three-dimensional structures of surrogate extracellular receptor domains, offers new opportunities to design nicotinic ligands. Conformation and fluctuations in receptor structure are critical to ligand selectivity, and we present here how a flexible receptor template can be used in the development of selective ligands affecting cholinergic neurotransmission.

Binding Sites↗

PubMed2026

Metabolic niche differentiation and napA evolution stabilize partial denitrification in wastewater ecosystems.

Although partial denitrification (PD) is increasingly applied as a nitrite-supplying strategy for anammox-based nitrogen removal, the ecological distribution, metabolic specialization, and genomic determinants of stable nitrite accumulation remain poorly understood at the ecosystem scale. Here, we reconstructed 516 high-quality metagenome-assembled genomes (MAGs) using high-depth metagenomic sequencing of 107 wastewater treatment plants and classified denitrifiers according to their nitrite production or consumption capacities. Of these genomes, 23% (120 MAGs) were classified as partial denitrifiers, 41% (211 MAGs) as complete denitrifiers, and 36% (185 MAGs) as nitrite-reducing denitrifiers, revealing pronounced functional partitioning rather than dominance by complete denitrification pathways. Comparative genomics showed that partial denitrifiers possess metabolic architectures favoring rapid carbon oxidation and NADH generation while exhibiting constrained NADPH production and biosynthetic investment, thereby promoting nitrate-to-nitrite conversion but limiting subsequent nitrite reduction. Nitrite accumulation does not result from incomplete denitrification pathways but from metabolic niche differentiation. These metabolic trade-offs were further associated with the evolutionary divergence of the periplasmic nitrate reductase gene, napA, which displayed distinct sequence characteristics and genomic contexts between partial and complete denitrifiers. Integration of carbohydrate-active enzyme repertoires further revealed metabolic complementarity between partial denitrifiers and anammox bacteria, supporting efficient carbon handoff without direct substrate competition. From an engineering perspective, operating conditions that impose moderate electron limitation, such as low or fluctuating C/N ratios and intermittent carbon feeding, may selectively enrich partial denitrifiers and enhance a stable nitrite supply for PD-anammox systems. Together, these findings identify PD as a predictable ecological state shaped by genome-encoded metabolic specialization and provide a mechanistic basis for designing robust, low-carbon nitrogen-removal processes.

Anammox↗

PubMed2000

Different stimulatory opioid effects on intracellular Ca(2+) in SH-SY5Y cells.

Present study revealed the stimulatory effects of delta opioid receptor on intracellular Ca(2+) concentration ([Ca(2+)](i)) in SH-SY5Y cells. Fura-2 based single cell fluorescence ratio (F345/F380) was used to monitor the fluctuation of [Ca(2+)](i). Application of the selective delta-opioid receptor agonist alone, [D-Pen(2,5)]-enkephalin (DPDPE), hardly had any effects on cells cultivated for 3-10 days. However, after the cells had been pre-stimulated with cholinoceptor agonist, carbachol, variable calcium elevation was found in 59% of the cultures. The response was naltridole-reversible and dose-dependent, and was abolished completely by thapsigargin (TG) treatment but not by administration of CdCl(2) or 0-Ca(2+) bath solutions. DPDPE-mediated [Ca(2+)](i) elevation was abolished by pertussis toxin (PTX) pretreatment but not cholera toxin (CTX), indicating coupling via G proteins of G(i)/G(o) subfamily. In 17.5% of the responding cells, biphase response was found which may be due to both the stimulatory and the inhibitory effects of opioid. On the other hand, in acutely dissociated cells, DPPDE alone induced [Ca(2+)](i) increase in 50% of the cultures. The probability and the amplitude of the elevation were decreased considerably by application of nifedipine or 0-Ca(2+) bath solution and was little affected by application of TG. DPDPE activated [Ca(2+)](i) increase via a PTX-insensitive and CTX-sensitive pathway suggesting coupling through G(s) subunit. All these indicated the opioid modulated the intracellular Ca(2+) regulation system through different pathways. SH-SY5Y cell line might be a suitable model for the investigation of the complex mechanism which underlies opioid function.

Analgesics, Opioid↗

PubMed1991

The diabetogenic and acidotropic effects of chelators.

Diabetogenic and acidotropic effects of dithizone, 8-(p-toluenesulfonylamino)-quinoline and 8-(benzenesulfonylamino)-quinoline were studied in experiments on cats, rabbits, golden hamsters and mice. Selective damage of insulin producing cells, phase glycemic fluctuations and permanent diabetes development were shown to be connected with chelator zinc binding in the lysosome-segregation apparatus of these cells.

Animals↗