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PubMed1988

Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease.

Deprenyl, a selective inhibitor of monoamine oxidase, type B, which is free of the "tyramine effect," may ameliorate symptom fluctuations in advanced Parkinson's disease (PD). We randomized 96 patients with marked symptom fluctuations at three centers to receive either deprenyl 5 mg b.i.d. or placebo in parallel fashion in addition to a previously optimized levodopa/carbidopa (Sinemet) regimen. Disability was recorded hourly at home by patients 3 days weekly during the 2-week baseline and the 6-week treatment period. Disability during the "on" state was assessed each week by examination. Mean hourly self-assessment of gait improved in 28 of 50 patients (56%) receiving deprenyl (mean degree of improvement 0.25 points on a 0-2 scale) and in 14 of 46 (30.4%) taking placebo (mean 0.15). Mean hourly overall symptom control improved in 29 (58%) taking deprenyl (mean 0.34) and in 12 (26.1%) taking placebo (mean 0.15) (p less than 0.01 for each parameter). No significant improvement occurred in the objective quality of the "on" state with deprenyl. Mean daily Sinemet dosage decreases were 17% in the deprenyl group and 7% in the placebo group. Adverse effects included nausea, light-headedness, dyskinesias, and hallucinations, all of which abated after the Sinemet dose was reduced. We conclude that deprenyl is of moderate benefit in a majority of patients with symptom fluctuations complicating PD and is generally well tolerated.

Adult↗
PubMed2000

MDR 1 activation is the predominant resistance mechanism selected by vinblastine in MES-SA cells.

Single-step selection with vinblastine was performed in populations of the human sarcoma cell line MES-SA, to assess cellular mechanisms of resistance to the drug and mutation rates via fluctuation analysis. At a stringent selection with 20 nM vinblastine, resulting in 5-6 logs of cell killing, the mutation rate was 7 x 10(-7)per cell generation. Analysis of variance supported the hypothesis of spontaneous mutations conferring vinblastine resistance, rather than induction of adaptive response elements. Surviving clones displayed a stable multidrug resistance phenotype over a 3-month period. All propagated clones demonstrated high levels of resistance to vinblastine and paclitaxel, and lower cross-resistance to doxorubicin and etoposide. Activation of MDR 1 gene expression and P-glycoprotein function was demonstrable in all clones. No elevation was found in the expression of the mrp gene, the LRP-56 major vault protein and beta-tubulin isotypes (M40, beta4, 5beta, and beta9) in these mutants. We conclude that initial-step resistant mechanism in these vinblastine-selected mutants commonly arises from a stochastic mutation event with activation of the MDR 1 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

A reduction in selective immune pressure during the course of chronic hepatitis C correlates with diminished biochemical evidence of hepatic inflammation.

It is considered that selection pressure exerted by the host immune response during early HCV infection might influence the outcome of that infection particularly as it relates to persistence or clearance of the agent. However, it is unclear whether positive selection pressure plays a role in determining the severity of hepatitis C during the course of persistent HCV infection. To address the evolutionary mechanism by which HCV escapes from the host immune response and to assess the relationship between viral evolution and hepatic inflammation, we determined 57 sequences (3-5 serial samples per patient) from 5 individuals with persistent HCV infection of genotype 1a who were under long-term follow-up ranging from 15.6 to 21.6 years. We applied a novel method to estimate serial alternations of selective pressure against the HCV enveloped region and compared this to fluctuation in transaminase level over time. Positive selection pressure was reduced over time postinfection, as evidenced by a reduction in nonsynonymous substitutions in the later phase of infection. Furthermore, serum transaminase, as a measure of inflammatory necrosis of hepatocytes, was reduced in parallel with decreased positive selection pressure. These results suggest that during persistent HCV infection, the virus faces diminished immune pressure over time, either from mutation to an immune resistant sequence or from immunologic exhaustion, and that this diminished immune attack is reflected in diminished inflammatory activity. This observation may be applicable to other viruses characterized by a slow rate of disease progression.

Aged↗
PubMed1998

Genomic fluidity is a necessary event preceding the acquisition of tumorigenicity during spontaneous neoplastic transformation of WB-F344 rat liver epithelial cells.

The genomic evolution of a cohort of WB-F344 rat liver epithelial cell lineages undergoing spontaneous neoplastic transformation was followed to define the mechanistic relationship between genomic instability and progression to the neoplastic phenotype. Eighteen independent populations of WB-F344 cells (initiated from a single diploid-founding population) were subjected to 12 cycles of selective growth at confluent cell density, and cellular DNA contents were measured after each selection cycle. Flow cytometry demonstrated significant gains in the amount of G1 DNA after selection cycles 3, 6, and 7 in 44% (8 of 18), 89% (16 of 18), and 39% (7 of 18) of the cell populations, respectively. All populations subsequently lost DNA and returned to a diploid or pseudo-diploid DNA content within 1 to 2 selection cycles after the appearance of an increased DNA content. Additionally, appearance and subsequent disappearance of aneuploid or tetraploid subpopulations was observed in 11% (2 of 18) and 83% (15 of 18) of the experimental lineages, respectively. Although perturbations of G1 DNA content were apparent as early as selection cycle 3, at least 8 cycles of selective growth were required for the acquisition of tumorigenicity. While the independent lineages demonstrated significant fluctuations in G1 DNA content between selection cycles 3 and 8, the majority (11 of 13) of the populations contained a diploid or pseudo-diploid DNA content at the time tumorigenicity was expressed. Genomic instability preceded the acquisition of tumorigenic potential in rat liver epithelial cells subjected to selective growth conditions of maintenance at confluence, and may be required for its expression.

Aneuploidy↗
PubMed1990

[Efficiency of feedback selection for recombination in Drosophila].

A number of theoretical models have been developed in population genetics to explain the evolution of recombination system under natural selection for adaptive traits. Using Drosophila cage populations of large size the effect of selection for resistance to daily temperature fluctuations on the rec-system was studied in this work. It is established that selection for population adaptability to extreme conditions leads during several tens of generations to significant increase in crossing-over rate within various parts of the genome (especially in b-cn and ru-h of chromosomes 2 and 3), as well as to relaxation of exchange interference for adjacent and non-adjacent segments. The Fisher's theoretical prognosis about tightening of linkage in optimal constant conditions was experimentally confirmed for the first time.

Adaptation, Physiological↗
PubMed1990

Lack of response to family selection for directional asymmetry in Drosophila melanogaster: left and right are not distinguished in development.

Family selection for directional asymmetry in the expression of the Drosophila melanogaster mutant scute had no result. Fluctuating asymmetry did not show a selection differential correlated with directional asymmetry. The unfolding of bilateral symmetry in embryogenesis can be used to explain the lack of genetic variation for directional asymmetry. Directional asymmetry provides a well-understood example of a developmental constraint in evolution. It is proposed that as no evidence is available for an independent left-right gradient in the embryo, quantitative traits can only be expressed variably along an existing gradient of positional information or a morphogen.

Animals↗
PubMed2003

A female melanin ornament signals offspring fluctuating asymmetry in the barn owl.

Sexual selection theory predicts that males advertise quality by displaying extravagant ornaments. By contrast, whether phenotypic variation in females has a signalling function remains an open question. Here, to our knowledge, we provide the first evidence that a female plumage trait can signal fluctuating asymmetry in the offspring. We experimentally demonstrate in wild barn owls (Tyto alba) that the extent to which females display black spots on their plumage does not only signal offspring parasite resistance as shown in a previous study but also developmental homeostasis in the offspring. A greater number of spotted females produced offspring that had more symmetrical feathers during the period of growth. Males, that pair non-randomly with respect to female plumage spottiness therefore appear to gain substantial benefits by mating with heavily spotted females. Genetic variation in plumage spottiness is nevertheless maintained as the covariation between offspring body mass and mother plumage spottiness varies annually depending on environmental conditions.

Animals↗
PubMed1981

Stationary gene frequency distribution in the environment fluctuating between two distinct states.

A general method is given to obtain a stationary distribution in a "stochastic" one-dimensional dynamical system in which an environmental parameter specifying the dynamical system is a stationary Markov process with only two states. By applying this method, the exact stationary gene frequency distribution is obtained for a genic selection model in the environment fluctuating between two distinct states. Several limiting stationary distributions are obtained therefrom, and one of them is shown to coincide with a stationary solution of the diffusion equation heuristically derived by us for more general cases. Discussion is given on the relationship between the diffusion equations obtained by various authors starting from discrete, non-overlapping generation models.

Animals↗
PubMed1976

Evolutionary processes and evolutionary noise at the molecular level. II. A selectionist model for random fixations in proteins.

On account, notably, of a competition between different component functions for individual sites in polypeptide chains, each protein molecule represents a functional compromise, with some functions optimized, but the overall state of the molecule "suboptimal". The proposal is made that the selection coefficient relating to a protein molecule under given conditions can in principle be broken down into partial selection coefficients relevant to the different functions that the molecule carries out. At general-function sites, each fixation improves some function, while others deteriorate, at first nonsignificantly, and the overall adaptive state of the molecule fluctuates around its maximum. A selective mechanism is described whereby kaleidoscopic changes in primary structure at variable sites are indefinitely promoted, independently of any environmental changes and with the molecule remaining close to a state of maximal overall adaptation. The paradoxical aspect of this proposal is analyzed. The implication of specific functions in substitutions at general-function sites is noted. Further, it is shown that a certain category of changes in the internal environment of the organism can be integrated into the constant-environmental model for selection. Genetic sufficiency is considered a notion more adequate than genetic optimality for describing biological fitness and for providing a basis for the present model. On this basis selection occurs without genetic load. Multipolymorphism is one of the consequences. Several lines of evidence, in particular observations on polymorphism in deep sea organisms, seem to support the model. It is pointed out that it provides a theoretical foundation for a molecular evolutionary clock. The theoretical constancy of the clock depends on the constancy of functional density. The question of the evolution of functional density is examined. Comparisons of observed substitution frequencies with values expected on a random basis are rejected as a measure of the contribution to evolution of nondetermination. They are considered to reflect a hierarchy in the resistance of the molecules to different amino acid residues as substituents. A limited component of "true" randomness, again accompanied by selection, is on the other hand provided by the model. Most amino acid substitutions are considered evolutionary noise, even though noise compatible with selection. It is proposed that evolutionary significant substitutions may be identified by monitoring changes in functional density and weighted functional density.

Alleles↗
PubMed2001

Ferromagnetic and antiferromagnetic fluctuations of pi-d itinerant electrons disclosed by band-selective NMR.

We present a band-selective NMR method to probe the constituent electronic bands separately in the condensed molecular matter. This method is applied to an organic-inorganic pi-d hybrid metal, and its utility to give the static and dynamic spin susceptibilities for the constituent bands is demonstrated. The analysis of the results uncovers an exotic feature; the antiferromagnetic and ferromagnetic correlations are enhanced in separate bands in a single material. This finding provides a novel scope connecting the metal-insulator transitions in this system and the manganese oxides.

Journal Article↗
PubMed2004

Fluctuations in somatosensory responsiveness and baseline firing rates of neurons in the lateral striatum of freely moving rats: effects of intranigral apomorphine.

Somatosensory responsiveness and baseline firing rates of 102 striatal neurons were studied in freely moving rats. For individual neurons, mean levels of responsiveness and baseline firing fluctuated unpredictably in direction and magnitude and independently of each other throughout an experiment. Following microinjections of apomorphine into the substantia nigra, which were used as a means of reducing nigral output activity, the magnitude of fluctuations in striatal somatosensory responsiveness significantly increased, while the magnitude of fluctuations in baseline firing was unaltered. The receptive zones of 54 neurons studied in control experiments remained stable, whereas receptive zones changed in 12 of 25 neurons studied after apomorphine microinjection. Normal nigrostriatal dopamine transmission appears to selectively restrict the magnitude of fluctuations in responsiveness of striatal neurons to corticostriatal synaptic input and may exert additional control over afferent projections from cutaneous receptive zones to these neurons.

Animals↗
PubMed1994

Functional expression of Ca(2+)-mobilizing opioid receptors in Xenopus oocytes injected with rat brain mRNA.

Functional expression of opioid receptors was detected in the Xenopus oocyte translation system by a voltage-clamp recording. After injection of poly(A)+ RNA isolated from 3-week-old rat striatum or whole brain, the oocytes often demonstrated intracellular Ca(2+)-mediated oscillatory responsiveness to [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAMGO), [D-Pen2, D-Pen5]enkephalin (DPDPE) and U50488H at a concentration of 1 microM. These responses were very transiently expressed after injection of the mRNA, however, water-injected oocytes never responded to any of these opioid agonists. After fractionation by a sucrose-density gradient, an RNA size of about 3-4 kb encoded these opioid receptors. In the oocytes injected with size-selected striatal mRNA, DPDPE evoked the fluctuating current with higher probability and larger amplitude than other agonists, whereas oocytes injected with size-selected whole brain mRNA produced DAMGO and U50488H responses predominantly. The DPDPE response of striatal mRNA-injected oocytes was antagonized by naloxone as well as the delta-specific antagonist ICI 174864. The DAMGO and U50488H responses have not been characterized yet because of a strong desensitizing property making repeated recordings impossible. These observations suggest that putative mu, delta and kappa subtypes of opioid receptors mobilizing intracellular Ca2+ are expressed in Xenopus oocytes by rat brain mRNA.

Animals↗
PubMed1998

The question of fluctuating asymmetry in the blacklegged tick Ixodes scapularis (Acari: Ixodidae).

An analysis of fluctuating asymmetry was conducted on populations of the blacklegged tick Ixodes scapularis. The eight groups used in this study consisted of larvae and nymphs and males and females from the states of Minnesota, Massachusetts, Maryland, Missouri, North Carolina and Georgia and the F1 progenies of reciprocal crosses between ticks from Massachusetts and Georgia. Measurements included 16 larval, 19 nymphal, ten female and 12 male bilateral characters. Only five differences between the right and left bilateral characters had normal distributions with means of zero and differences in variances between the groups. These five characters included three setal lengths of the larvae, the spiracular plate length of females and the coxa I internal spur widths of males. Bivariate plots of character size ((R + L)/2) and asymmetry (R-L) showed no correlation. In the spiracular plate lengths of females and one of the setal lengths, ticks from Massachusetts had significantly less within-group variance than all the other groups. The only character in which fluctuating asymmetry was observed was the coxa I internal spur width of males, in which ticks from Minnesota, Missouri and North Carolina had significantly greater variance than the remaining groups; fluctuating asymmetry in this character may be explained by sexual selection. The cross progeny did not demonstrate any fluctuating asymmetry, as would be expected if the northern and southern forms of I. scapularis were true species. The virtual lack of fluctuating asymmetry in the characters used in this study further supports the conclusions of other studies which concluded that I. scapularis is a species with clinical variation and a broad geographic distribution.

Animals↗
PubMed2000

Molecular dynamics of the KcsA K(+) channel in a bilayer membrane.

Molecular dynamics (MD) simulations of an atomic model of the KcsA K(+) channel embedded in an explicit dipalmitoylphosphatidylcholine (DPPC) phospholipid bilayer solvated by a 150 mM KCl aqueous salt solution are performed and analyzed. The model includes the KcsA K(+) channel, based on the recent crystallographic structure of, Science. 280:69-77), 112 DPPC, K(+) and Cl(-) ions, as well as over 6500 water molecules for a total of more than 40,000 atoms. Three K(+) ions are explicitly included in the pore. Two are positioned in the selectivity filter on the extracellular side and one in the large water-filled cavity. Different starting configurations of the ions and water molecules in the selectivity filter are considered, and MD trajectories are generated for more than 4 ns. The conformation of KcsA is very stable in all of the trajectories, with a global backbone root mean square (RMS) deviation of less than 1.9 A with respect to the crystallographic structure. The RMS atomic fluctuations of the residues surrounding the selectivity filter on the extracellular side of the channel are significantly lower than those on the intracellular side. The motion of the residues with aromatic side chains surrounding the selectivity filter (Trp(67), Trp(68), Tyr(78), and Tyr(82)) is anisotropic with the smallest RMS fluctuations in the direction parallel to the membrane plane. A concerted dynamic transition of the three K(+) ions in the pore is observed, during which the K(+) ion located initially in the cavity moves into the narrow part of the selectivity filter, while the other two K(+) ions move toward the extracellular side. A single water molecule is stabilized between each pair of ions during the transition, suggesting that each K(+) cation translocating through the narrow pore is accompanied by exactly one water molecule, in accord with streaming potential measurements (, Biophys. J. 55:367-371). The displacement of the ions is coupled with the structural fluctuations of Val(76) and Gly(77), in the selectivity filter, as well as the side chains of Glu(71), Asp(80), and Arg(89), near the extracellular side. Thus the mechanical response of the channel structure at distances as large as 10-20 A from the ions in the selectivity filter appears to play an important role in the concerted transition.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1991

Sublingual apomorphine in the treatment of Parkinson's disease complicated by motor fluctuations.

Subcutaneous apomorphine is a useful treatment for refractory motor fluctuations in Parkinson's disease. We have now clinically evaluated a formulation of sublingual apomorphine (57 mg) and performed preliminary pharmacokinetic studies. In acute studies, all 10 patients switched "on" after a mean latency of 25 min with a mean duration of motor benefit of 118 min. In three patients followed for a mean of 4.7 months, we have shown that chronic sublingual use can be effective, safe, and convenient in controlling motor fluctuations. The pattern of clinical response followed closely the plasma profile of apomorphine with a mean Cmax of 76 pmol/ml (50-106 pmol/ml) and a mean Tmax of 60 min (45-80 min), with moderate interpatient variability in bioavailability. Sublingual apomorphine is a practical alternative to subcutaneous use in selected patients with severe motor fluctuations.

Administration, Sublingual↗
PubMed1974

An analysis of the cost-of-selection concept.

It is shown for a continuous haploid model that the common standard assumptions used in calculating the cost of gene substitution, namely, large constant population size and small constant selective value, are unnecessary. Population size may fluctuate during the course of substitution without affecting the calculated total cost. The selective intensity does not need to be small and constant to give the standard result for substitution cost. Diploid models with multiple alleles are analyzed and contrasted with standard two-allele models in respect to calculation of substitution cost. The influence of population structure on the probability of occurrence of complete gene substitution is discussed on the basis of a numerical example. The robust nature of the cost-of-selection concept is examined in the light of a conservation principle.

Alleles↗
PubMed1989

[Increased recombination in a multi-locus system during environmental fluctuations].

The role of variability of environment as a factor of recombination evolution is studied. It was shown that selection in multilocus system under cyclic or random fluctuations of external conditions results in rapid increase in recombination frequency, even under free recombination between the rec-modificator and the selected system (SS). If so, pair-vise linkage disequilibrium coefficients have unchanged signs and are negative, and the advantage of rec+ alleles is provided by changes in signs of disequilibriums of higher order. The low frequency environmental fluctuations maintain recombination as it is, while high frequency ones induce the substitution of the low level by high. It was established that the recombination promoting mechanism of crossing-over maintenance, due to elimination of non-optimal allelic combinations of SS loci under temporal optimum variations, may be accomplished by smaller genetic load, than under elimination of deleterious mutations.

Environment↗
PubMed2001

Evolution of faster development does not lead to greater fluctuating asymmetry of sternopleural bristle number in Drosophila.

Both strong directional selection and faster development are thought to destabilize development, giving rise to greater fluctuating asymmetry (FA), although there is no strong empirical evidence supporting this assertion. We compared FA in sternopleural bristle number in four populations of Drosophila melanogaster successfully selected for faster development from egg to adult, and in four control populations. The fraction of perfectly symmetric individuals was higher in the selected populations, whereas the FA levels did not differ significantly between selected and control populations, clearly indicating that directional selection for faster development has not led to increased FA in sternopleural bristle number in these populations. This may be because: (i) development time and FA are uncorrelated, (ii) faster development does result in FA, but selection has favoured developmentally stable individuals that can develop fast and still be symmetrical, or (iii) the increased fraction of symmetric individuals in the selected populations is an artifact of reduced body size. Although we cannot discriminate among these explanations, our results suggest that the relationship between development time, FA and fitness may be far more subtle than often thought.

Animals↗