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PubMed2002

Detection of quantitative trait loci influencing dairy traits using a model for longitudinal data.

A longitudinal-linkage analysis approach was developed and applied to an outbred population. Nonlinear mixed-effects models were used to describe the lactation patterns and were extended to include marker information following single-marker and interval mapping models. Quantitative trait loci (QTL) affecting the shape and scale of lactation curves for production and health traits in dairy cattle were mapped in three U.S. Holstein families (Dairy Bull DNA Repository families one, four, and five) using the granddaughter design. Information on 81 informative markers on six Bos taurus autosomes (BTA) was combined with milk yield, fat, and protein percentage and somatic cell score (SCS) test-day records. Six percent of the single-marker tests surpassed the experiment-wise significance threshold. Marker BL41 on BTA3 was associated with decrease in milk yield during mid-lactation in family one. The scale and shape of the protein percentage lactation curve in family four varied with BMC4203 (BTA6) allele that the son received from the grandsire. Some map locations were associated with variation in the lactation pattern of multiple traits. In family four, the marker HUJI177 (BTA3) was associated with changes in the milk yield and protein percentage curves suggesting a QTL with pleiotropic effects or multiple QTL in the region. The interval mapping model uncovered a QTL on BTA7 associated with variation in milk-yield pattern in family four and a QTL on BTA21 affecting SCS in family five. The developed approach can be extended to random regressions, covariance functions, spline, gametic and variance component models. The results from the longitudinal-QTL approach will help to understand the genetic factors acting at different stages of lactation and will assist in positional candidate gene research. Identified positions can be incorporated into marker-assisted selection decisions to alter the persistency and peak production or the fluctuation of SCS during a lactation.

Animals↗
PubMed1992

[Medical decision sciences in the context of clinical pathology].

Medical decision sciences are the scientific approaches to rational decision making under uncertainty. They are arbitrarily subdivided into prescriptive quantitative approach and descriptive psychological approach. The former approach, i.e., decision analysis, is a method of problem solving according to the following procedures: (1) structure the problem (creating a decision tree), (2) apply probabilities, (3) apply values, (4) calculate expected values, (5) perform sensitivity analysis. This methodology makes it clear that once the sensitivity and specificity of a test are determined, estimation of prior probability becomes critically important in interpreting the test results. Usually, prior probability in a given clinical situation is predicted based on patients' demographics, symptoms and previous medical history, physical examination and prior test results. There are, however, many psychological pitfalls leading to wrong estimation of prior probability as follows: (1) premature closure of information processing in the mind, (2) negligence of prior probability from the beginning, (3) regression toward the mean, (4) effect of the number of specimen on the probabilistic fluctuation, (5) gambler's fallacy, (6) effect of vivid memory, (7) selection bias, (8) negligence of negative data, (9) effect of group norm. In order to estimate prior probability as accurately as possible, several strategies are advocated: (1) cognitive psychological approaches, including always thinking about the results of other possible choices, paying attention to the negative data, and trying not to depend on memory as possible, (2) objective estimation using, e.g., the following formula: prior probability = [proportion of patient with abnormal test result-(1-specificity)]/[sensitivity-(1-specificity)].(ABSTRACT TRUNCATED AT 250 WORDS)

Cognition↗
PubMed1988

[The action of gramicidin S on the ionic permeability of bilayer lipid membranes].

The effect of cyclic decapeptide of gramicidin S on electrical conductivity of bilayer lipid membranes has been studied. The integral conductivity of bilayer has been shown to increase with the growth of antibiotic concentration. The integral conductivity increase occurs as series of conductivity discrete leaps, differing in amplitude from fluctuations of conductivity caused by linear gramicidins. In the series of selectivity of bilayer membranes for cations of alkaline metals the rubidium ion is before the cesium ion. This is the only difference between this series and the series of relative ionic mobility series of cations of alkaline metals in water solutions.

Cell Membrane Permeability↗
PubMedDate not supplied

[Schizophrenia: one or two psychoses? Positive and negative symptoms].

In this paper are presented conceptions of the twofold idea of schizophrenia as disease of two types dependent on positive or negative symptoms. Actual examination of fundamental research about the fluctuating of brain turnover of neurotransmitters confirm Crow's theory of selected two types of schizophrenic patients. In conclusion the results suggest that, depending on the course of schizophrenia, individual and multiplex forms of treatment including pharmacotherapy, psychotherapy and psychosocial effects are required.

Antidepressive Agents↗
PubMed2004

Determination of mitotic recombination rates by fluctuation analysis in Saccharomyces cerevisiae.

The study of recombination in Saccharomyces cerevisiae benefits from the availability of assay systems that select for recombinants, allowing the study of spontaneous events that represent natural assaults on the genome. However, the rarity of such spontaneous recombination requires selection of events that occur over many generations in a cell culture, and the number of recombinants increases exponentially following a recombination event. To avoid inflation of the average number of recombinants by jackpots arising from an event early in a culture, the distribution of the number of recombinants in independent cultures (fluctuation analysis) must be used to estimate the mean number of recombination events. Here we describe two statistical analyses (method of the median and the method of p0) to estimate the true mean of the number of events to be used to calculate the recombination rate. The use of confidence intervals to depict the error in such experiments is also discussed. The application of these methods is illustrated using the intron-based inverted repeat recombination reporter system developed in our lab to study the regulation of homeologous recombination.

Colony Count, Microbial↗
PubMed1993

Osmotic stress variants in Chinese hamster cells.

Stable variants resistant to hypertonic stress have been obtained from V79 cells by one-step selection in media supplemented with graded concentrations of NaCl. Such variants retain a potential for resistance when isolated and propagated in isotonic media. On replating in graded NaCl, a family of dose-response curves is obtained, rising in level of resistance according to the degree of hypertonicity used to isolate the variants initially. In hybrids between variants and sensitive cells, phenotypic expression of resistance to hypertonic NaCl is recessive. Stable variants can also be isolated by one-step selection in media made hypertonic with D-mannitol. Clonal sublines selected with mannitol, as well as those obtained with NaCl, are resistant to both types of hypertonic media. Fluctuation tests in media supplemented with NaCl show that resistance arises spontaneously and at random, with measured rates of variation that depend on the concentration of NaCl used for selection. Treatment of sensitive cells with 5-azacytidine increases the frequency of resistant variants in assays with high levels of added NaCl but is less effective when selection is performed at lower concentrations. Exposure to ethyl methane sulfonate has little or no effect on variant frequency.

Animals↗
PubMed2005

Intra-oral temperatures during function.

There has been limited published research assessing the range of oral temperature that the dental hard and soft tissues are exposed to. The temperatures that tooth structure and dental restorations encounter affect the performance of dental materials within the oral environment. This study therefore assessed the range of temperatures that a selected group could tolerate when drinking and also assessed the range of temperatures encountered in various intra-oral sites. These temperature fluctuations are for very brief periods of time but have a wide and varied range. Miniature dataloggers allowed for accurate measurements and recording of temperature from selected sites. The range of temperature recorded amongst the individuals tested shows the protection afforded to the dental hard tissues by the soft tissues of the oral cavity. The maximum and minimum mouth temperatures recorded show that hot fluids can raise the intra-oral temperature of the front teeth to around 70 degrees C and the consumption of iced drinks lowers the same teeth to around 0 degrees C. The range of temperature of hot fluids that can be tolerated by a selected group vary, but this does not seem to be the case for cold fluids. The thermistor beads mounted on the buccal surface of the lower front teeth and the palatal of the upper front teeth are exposed to the greatest temperature fluctuations during drinking fluids from a cup. The importance of these temperatures recorded in terms of dental materials testing and the role of material conductivity warrants further investigation.

Adolescent↗
PubMed2003

Growth and developmental instability.

Developmental stability reflects the ability of an individual to develop a regular phenotype under given environmental and genetic conditions. Measures of developmental instability include the degree of fluctuating asymmetry and the frequency of phenodeviants. Endocrine, neural and circulatory mechanisms that control similar development of morphological characters on the two sides of the body are also involved in controlling overall development. Cross-validation studies have shown that measures of developmental instability are positively correlated with other measures of welfare such as tonic immobility in poultry. Asymmetric animals grow less rapidly than symmetric individuals. Eleven studies have investigated the relationship between growth rate and developmental instability, and the observed effect size (Pearson correlation coefficient adjusted for sample size) is -0.15. Studies of chickens have shown that asymmetry increases as a response to selection for increased growth rate. As conditions for rearing deteriorate by higher density, fluctuating asymmetry increases and growth rate decreases, both within and among farms. Fluctuating asymmetry can be considered a measure of animal welfare since larger values reflect worse environmental conditions as experienced by the individual animal itself. Since growth rate and fluctuating asymmetry are negatively correlated, we can infer that improvement of rearing conditions leading to reduced asymmetry will both benefit the producer (in terms of increased growth), but also the animals in terms of better conditions for rearing.

Animal Welfare↗
PubMed1996

An add-on study of selegiline to Madopar in the treatment of parkinsonian patients with dose-related fluctuations: comparison between Jumexal and Parkryl.

BACKGROUND: To improve dose-related fluctuations in patients with Parkinson's disease, the efficacy of selegiline, a selective inhibitor of monoamine oxidase B, was determined. METHODS: Twenty parkinsonian patients were selected for a short-term, single-blind, cross-over trial. Each patient received one of the two brands of selegiline, Parkryl (Mei-Shih), 10 mg per day as an adjunct to Madopar. After a 6-week treatment period and a 4-week wash-out period, the treatment was switched to the other brand of selegiline, Jumexal (Labatec), for another 6 weeks. RESULTS: Five patients dropped out of the study because of the development of intolerable dyskinesia, hallucination or agitation. The 15 patients that completed the study made a mild improvement in the total motor scores of the on-period during both treatments of Parkryl (p < 0.01) and of Jumexal (p < 0.05). The recorded daily off-time decreased from 37.8% to 20.7% in the Parkryl group (p < 0.01), and to 21.0% in the Jumexal group (p < 0.01). CONCLUSION: Selegiline, as an adjunct therapy to Madopar, has a moderate effect in prolonging the duration of on-time in parkinsonian patients with dose-related fluctuations. Jumexal seemed to produce no greater effect than Parkryl.

Aged↗
PubMed2006

Molecular dynamics simulations of arachidonic acid complexes with COX-1 and COX-2: insights into equilibrium behavior.

The cyclooxygenase (COX) enzymes are responsible for the committed step in prostaglandin biosynthesis, the generation of prostaglandin H(2). As a result, these enzymes are pharmacologically important targets for nonsteroidal antiinflammatory drugs, such as aspirin and newer COX-2 selective inhibitors. The cyclooxygenases are functional homodimers, and each subunit contains both a cyclooxygenase and a peroxidase active site. These enzymes are quite interesting mechanistically, as the conversion of arachidonic acid to prostaglandin H(2) requires two oxygenation and two cyclization reactions, resulting in the formation of five new chiral centers with nearly absolute regio- and stereochemical fidelity. We have used molecular dynamics (MD) simulations to investigate the equilibrium behavior of both COX-1 and COX-2 enzyme isoforms with bound arachidonate. These simulations were compared with reference simulations of arachidonate in solution to explore the effect of enzyme on substrate conformation and positioning in the active site. The simulations suggest that the substrate has greater conformational freedom in the COX-2 active site, consistent with the larger COX-2 active site volume observed in X-ray crystal structures. The simulations reveal different conformational behavior for arachidonate in each subunit over the course of extended equilibrium MD simulations. The simulations also provide detailed information for several protein channels that might be important for oxygen and water transport to or from active sites or for intermediate trafficking between the cyclooxygenase and peroxidase active sites. The detailed comparisons for COX-1 versus COX-2 active site structural fluctuations may also provide useful information for design of new isozyme-selective inhibitors.

Arachidonic Acid↗
PubMed2000

Comparison of the antidepressants reboxetine, fluvoxamine and amitriptyline upon spontaneous pupillary fluctuations in healthy human volunteers.

RATIONALE: Spontaneous fluctuations in the size of the pupil in darkness are a recognised index of "sleepiness". OBJECTIVE: To evaluate the effects of single oral doses of three antidepressants: reboxetine (4 mg), a selective noradrenaline reuptake inhibitor, fluvoxamine (100 mg), a selective serotonin reuptake inhibitor, and amitriptyline (100 mg), a tricyclic antidepressant of known sedative property, upon spontaneous pupillary fluctuations in healthy male volunteers (n=16). METHODS: Using the recently developed pupillographic sleepiness test (PST), resting pupil diameter was recorded and two measures of pupillary fluctuations were obtained: total power obtained from a fast Fourier transform and spectral analysis, and the pupillary unrest index (PUI), a cumulative measure of changes in pupil size. Subjects also rated themselves on a battery of visual analogue scales for "alertness", "anxiety" and "contentedness". RESULTS: Resting pupil diameter was enhanced by reboxetine, but remained unaffected by the other two antidepressants. Amitriptyline, consistent with its sedative property, increased the total power of pupillary fluctuations and showed a tendency to increase PUI. These pupillary effects of amitriptyline were paralleled by reduced scores on the "alertness", "contentedness" and "anxiety" self ratings. Neither fluvoxamine nor reboxetine affected pupillary fatigue waves or subjective ratings of "alertness". Reboxetine caused a small reduction in subjectively rated "anxiety". CONCLUSIONS: The mydriatic effect of reboxetine may be due to noradrenaline reuptake blockade in the iris and/or in the central nervous system. The enhancement of pupillary fatigue waves by the sedative antidepressant amitriptyline, but not by the non-sedative antidepressants fluvoxamine and reboxetine, indicates that the PST is a suitable quantitative objective test for the detection of drug-induced changes in the level of arousal.

Adult↗
PubMed2003

Evolution in Darwin's finches: a review of a study on Isla Daphne Major in the Galápagos archipelago.

This paper reviews research pertaining to the problem of speciation of the finches on the Galápagos archipelago carried out by assistants, several colleagues, Peter Grant and myself. I give a brief history of the radiation, examine the process of divergence by natural selection over time, and then consider the nature of the reproductive barrier to gene flow between closely related species. Fluctuating climatic conditions have produced a continuously changing ecological landscape and altered feeding conditions for the finches over the last 30 years. Finch populations tracked these changes by natural selection and evolutionary responses to the main events. At each event significant morphological change occurred from one generation to the next generation. As a consequence of these accumulated changes, the mean bill shape and body size of the Geospiza fortis and G. scandens populations differed markedly from 1973 to 2002. Song, a learned culturally transmitted trait, acted as a barrier to reproduction between these species. Rare incidences of misimprinting on song led to hybridization and introgression. Low levels of gene flow from one species to another increased genetic variation on which selection acted. Although the major driving force of diversification was ecological change, the process of diversification involved a subtle interplay between ecology, genetic evolution and learned culturally transmitted traits. An important message for conservation is that neither the environment nor species are fixed entities, therefore a wise strategy for conserving endangered species should keep them capable of further change.

Journal Article↗
PubMed1987

Aphidicolin-resistant mutator strains of mouse teratocarcinoma.

From among a series of stable, aphidicolin-resistant mutant strains of mouse teratocarcinoma, derived from a multipotent parental line (PSA-1-80), three were selected for further study on the basis of their comparatively high degrees of resistance and elevated frequencies of spontaneous forward mutation to 6-thioguanine and ouabain resistance. Fluctuation tests confirmed that they were mutator strains. Since each of the three mutants was isolated after multiple rounds of selection, and since a variety of biochemical abnormalities were observed, it is likely that a number of mechanisms, probably consisting of overlapping subsets, determine the phenotypes. Abnormalities in the metabolism of the nucleotide substrates for polymerization are likely to be of major importance in mutants designated Aph-2 and Aph-3, as there were marked alterations in the dCTP and dATP pool sizes. The specific activity of DNA polymerase alpha was also increased. For the case of Aph-3, which exhibited the greatest (400-fold) increase in resistance to aphidicolin, a mutation in the structural gene for DNA polymerase alpha may be an additional important component, since in vitro assays revealed that the isolated enzyme was resistant to aphidicolin. For the case of Aph-1 however, only minor alterations in dNTP pools were observed, and there was no increase in the specific activity of DNA polymerase alpha or in the aphidicolin resistance of the isolated DNA polymerase alpha, suggesting yet another mechanism(s) underlying the aphidicolin resistance/mutator phenotype. All three mutants formed subcutaneous tumors in syngeneic mice; both Aph-1 and Aph-2 were multipotent; whereas Aph-3 was nullipotent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A neural network model of kinetic depth.

We propose a network model that accounts for the kinetic depth in structure from motion phenomena. Using plausible neural mechanisms, the model accounts for (1) fluctuations in perception when viewing a simple kinetic depth stimulus, (2) disambiguation of this stimulus with stereoscopic information, and (3) subsequent bias of the percept of this stimulus following stereoscopic adaptation. The model comprises two levels: a layer of monocular directionally selective motion detectors that provide input to a second layer of disparity-selective and direction-selective binocular mechanisms. The network of facilitatory and inhibitory connections between binocular mechanisms gives rise to fluctuations in network activity that mimic the fluctuations in perception of kinetic depth in the absence of disparity information. The results of a psychophysical experiment are consistent with the nature of the proposed interactions.

Adaptation, Ocular↗
PubMed2006

Adaptive response of a gene network to environmental changes by fitness-induced attractor selection.

Cells switch between various stable genetic programs (attractors) to accommodate environmental conditions. Signal transduction machineries efficiently convey environmental changes to the gene regulation apparatus in order to express the appropriate genetic program. However, since the number of environmental conditions is much larger than that of available genetic programs so that the cell may utilize the same genetic program for a large set of conditions, it may not have evolved a signaling pathway for every environmental condition, notably those that are rarely encountered. Here we show that in the absence of signal transduction, switching to the appropriate attractor state expressing the genes that afford adaptation to the external condition can occur. In a synthetic bistable gene switch in Escherichia coli in which mutually inhibitory operons govern the expression of two genes required in two alternative nutritional environments, cells reliably selected the "adaptive attractor" driven by gene expression noise. A mathematical model suggests that the "non-adaptive attractor" is avoided because in unfavorable conditions, cellular activity is lower, which suppresses mRNA metabolism, leading to larger fluctuations in gene expression. This, in turn, renders the non-adaptive state less stable. Although attractor selection is not as efficient as signal transduction via a dedicated cascade, it is simple and robust, and may represent a primordial mechanism for adaptive responses that preceded the evolution of signaling cascades for the frequently encountered environmental changes.

Adaptation, Biological↗
PubMed2004

Direct influence of C-terminally substituted amino acids in the Dmt-Tic pharmacophore on delta-opioid receptor selectivity and antagonism.

A series of 17 analogues were developed on the basis of the general formula H-Dmt-Tic-NH-CH(R)-R' (denotes chirality; R = charged, neutral, or aromatic functional group; R' = -OH or -NH(2)). These compounds were designed to test the following hypothesis: the physicochemical properties of third-residue substitutions C-terminal to Tic in the Dmt-Tic pharmacophore modify delta-opioid receptor selectivity and delta-opioid receptor antagonism through enhanced interactions with the mu-opioid receptor. The data substantiate the following conclusions: (i) all compounds had high receptor affinity [K(i)(delta) = 0.034-1.1 nM], while that for the mu-opioid receptor fluctuated by orders of magnitude [K(i)(mu) = 15.1-3966 nM]; (ii) delta-opioid receptor selectivity [K(i)(mu)/K(i)(delta)] declined 1000-fold from 22,600 to 21; (iii) a C-terminal carboxyl group enhanced selectivity but only as a consequence of the specific residue; (iv) amidated, positive charged residues [Lys-NH(2) (6), Arg-NH(2) (7)], and a negatively charged aromatic residue [Trp-OH (11)] enhanced mu-opioid affinity [K(i)(mu) = 17.0, 15.1, and 15.7 nM, respectively], while Gly-NH(2) (8), Ser-NH(2) (10), and His-OH (12) were nearly one-tenth as active; and (v) D-isomers exhibited mixed effects on mu-opioid receptor affinity (2' << 3' < 4' < 1' < 5') and decreased delta-selectivity in D-Asp-NH(2) (1') and D-Lys(Ac)-OH (5'). The analogues exhibited delta-opioid receptor antagonism (pA(2) = 6.9-10.07) and weak mu-opioid receptor agonism (IC(50) > 1 microM) except H-Dmt-Tic-Glu-NH(2) (3), which was a partial delta-opioid receptor agonist (IC(50) = 2.5 nM). Thus, these C-terminally extended analogues indicated that an amino acid residue containing a single charge, amino or guanidino functionality, or aromatic group substantially altered the delta-opioid receptor activity profile (selectivity and antagonism) of the Dmt-Tic pharmacophore, which suggests that the C-terminal constituent plays a major role in determining opioid receptor activity as an "address domain".

Amino Acid Substitution↗
PubMed1988

A combined regimen of subcutaneous lisuride and oral Madopar HBS in Parkinson's disease.

At the first stage of a pilot study involving 14 parkinsonians with motor fluctuations, treatment with standard Madopar was substituted by a sustained-release form, Madopar HBS, which attenuated fluctuations in patients with end-of-dose impairment, but achieved only moderate improvement in patients with on-off phenomena. In a second phase of the trial, 4 parkinsonians exhibiting the most severe fluctuations of mobility and the poorest response to Madopar HBS (Hydrodynamically Balanced System) were selected for treatment with a combined regimen utilizing subcutaneous lisuride infusions as the additional component. The sequence of the trial was as follows: 1. standard Madopar, 2. Madopar HBS, 3. standard Madopar combined with lisuride infusions and 4. Madopar HBS combined with lisuride infusions. Steady improvement was observed along the lines of this schedule, but the best results were obtained when Madopar HBS was combined with lisuride infusions. Subsequently motor fluctuations were less marked or disappeared, early-morning Parkinson symptoms decreased and dystonia was not recorded any longer. Even better results could be accomplished in an extended trial attempting to establish the best dosage ratio of the combination, possibly admitting increased dosage. The tolerance of the combined regimen was excellent, except in one patient who transiently exhibited delusions and postural hypotension. The combination of sustained-release Madopar and continuous infusions of the dopaminergic agonist lisuride seems to prove a more physiological and effective regimen for the treatment of severe motor fluctuations.

Administration, Oral↗
PubMed1984

[Isolation and characteristics of Chinese hamster cells resistant to colchicine].

Several ClchR clones of CHO-K1 have been isolated by a single- and multistep selection. They are distinct from each other both in the level of colchicine resistance and in the phenotypic stability of this feature. Fluctuation tests showed that the generation of drug resistant variants in the wild type population was random and did not depend on the action of selective agent. The rate of spontaneous occurrence of these variants was approximatley 1.79 x 10(-6) per cell per generation. Treatment with MNNG enhanced the frequency of ClchR variants by 100 fold. Cytotoxic effect of Clch on resistant cells has been potentiated by non-ionic detergent Tween 80. All the stable resistant clones appeared to be cross resistant to unrelated drugs such as actinomycin D, ethydium bromide and aminopterine . These two observations allow to suggest the alteration of membrane permeability as a mechanism of resistance to Clch . Genetical mechanisms of Clch -resistance of cells are discussed.

Aminopterin↗