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PubMed1993

Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates.

Substrate recognition by the hairpin ribozyme has been proposed to involve two short intermolecular helices, termed helix 1 and helix 2. We have used a combination of three methods (cleavage of mismatched substrates, in vitro selection, and site-specific mutational analysis) to systematically determine the substrate recognition rules for this RNA enzyme. Assays measuring substrate cleavage in trans under multiple turnover conditions were conducted using the wild-type ribozyme and substrates containing mismatches in all sites potentially recognized by the ribozyme. Molecules containing single- and multiple-base mismatches in helix 2 at sites distant from the cleavage site (g-4c, u-5a, g-4c: u-5a) were cleaved with reduced efficiency, whereas those with mismatches proximal to the cleavage site (c-2a, a-3c, c-2a: a-3c) were not cut. Analogous results were obtained for helix 1, where mismatches distal from the cleavage site (u+7a, u+8a, u+9a, u+7a: u+8a: u+9a) were used much more efficiently than those proximal to the cleavage site (c+4a, u-5a, g+6c, c+4a: u+5a: g+6c). In vitro selection experiments were carried out to identify active variants from populations of molecules in which either helix 1 or helix 2 was randomized. Results constitute an artificial phylogenetic data base that proves base-pairing of nucleotides at five positions within helix 1 and three positions within helix 2 and reveals a significant sequence bias at 3 bp (c+4.G6, c-2.G11, and a-3.U12). This sequence bias was confirmed at two sites by measuring relative cleavage rates of all 16 possible dinucleotide combinations at base pairs c+4.G6 and c-2.G11.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1996

A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache.

OBJECTIVES: Although the tricyclic antidepressant amitriptyline is extensively used in the prophylactic treatment of chronic tension-type headache, only few studies have investigated the efficacy of this treatment and the results are contradictory. In addition, the new selective serotonin reuptake inhibiting antidepressants, which are widely used in depression and of potential value in pain management, have never been investigated in a placebo controlled study of tension-type headache. The aim was to evaluate the efficacy of amitriptyline and of the selective serotonin reuptake inhibitor citalopram in chronic tension-type headache. METHODS: Forty non-depressed patients with chronic tension type headache were included in a 32 week, double blind, placebo controlled, three-way crossover study. RESULTS: Thirty four patients completed the trial. Amitriptyline reduced area under the headache curve by 30% compared with placebo (P = 0.002), whereas citalopram had no significant effect (P = 0.68). Explanatory analyses showed that amitriptyline significantly reduced the duration of headache (P = 0.01), headache frequency (P = 0.01), and intake of analgesics (P = 0.02) but not headache intensity (P = 0.12). CONCLUSION: Although amitriptyline did not eliminate the headache, it provided a clinically important reduction of headache in the majority of otherwise treatment resistant patients. The differential effect of amitriptyline and citalopram indicates that mechanisms other than inhibition of serotonin reuptake are involved in the analgesic effect of the tricyclic antidepressants. Amitriptyline, but not citalopram, is valuable in the prophylactic treatment of chronic tension type headache.

Adolescent↗
PubMed1988

Birth weight and natural selection: an example of selection relaxation in man.

Differential mortality as a function of birth weight was studied in Japan in the years 1969, 1974 and 1984. During the 15-year interval of observation a progressive equalization of mortality in the birth weight classes near the mean was found both for perinatal mortality as a whole and for its two components, stillbirth and mortality within the 1st week of life. The relaxation of selection on this metric trait is confirmed by the analysis of the variation over time of intensity of selection. A comparison of the Japanese population with other populations so far studied is also presented.

Birth Weight↗
PubMed1991

Sexual selection, natural selection and copulatory patterns in male primates.

Complex copulatory patterns, involving multiple brief intromissions or prolonged single intromissions (PI) occur most frequently among primate species in which females mate with a number of partners (multimale and dispersed mating systems). However, the PI pattern is also confined almost exclusively to arboreal primates - to either smaller-bodied, cryptic, nocturnal species or much larger diurnal forms. Predation pressures may have limited the evolution of the PI pattern, particularly where small-bodied diurnal primates or terrestrial forms are concerned. The available evidence indicates that both sexual selection and natural selection may have influenced the evolution of copulatory patterns.

Animals↗
PubMed2000

Runaway sexual selection when female preferences are directly selected.

We introduce models for the runaway coevolution of female mating preferences and male display traits. The models generalize earlier results by allowing for direct natural selection on the preference, arbitrary forms of mate choice, and fairly general assumptions about the underlying genetics. Results show that a runaway is less likely when there is direct selection on the preference, but that it is still possible if there is a sufficiently large phenotypic correlation between the female's preference and the male's trait among mated pairs. Comparison of three preference functions introduced by Lande (1981) shows that open-ended preferences are particularly prone to a runaway, and that absolute preferences require very large differences between females in their preferences. We analyze the causes of the runaway seen in a model developed by Iwasa and Pomiankowski (1995).

Animals↗
PubMed1999

Systematic review and guide to selection of selective serotonin reuptake inhibitors.

A meta-analysis of 20 short term comparative studies of 5 selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) has shown no difference in efficacy between individual compounds but a slower onset of action of fluoxetine. There were suggestions that fluoxetine caused more agitation, weight loss and dermatological reactions than the other SSRIs. More patients discontinued fluvoxamine and fewer patients stopped sertraline because of adverse effects than their comparator SSRIs. The most common adverse reactions to the SSRIs were gastrointestinal (especially nausea) and neuropsychiatric (particularly headache and tremor). Data from the Committee on Safety of Medicines showed more reports of suspected reactions (including discontinuation reactions) to paroxetine, and of gastrointestinal reactions to fluvoxamine and paroxetine, than the other SSRIs during their first 2 years of marketing. Prescription-event monitoring revealed a higher incidence of adverse events related to fluvoxamine than its comparators. There were higher incidences of gastrointestinal symptoms, malaise, sedation and tremor during treatment with fluvoxamine and of sedation, tremor, sweating, sexual dysfunction and discontinuation reactions with paroxetine. Fluoxetine was not associated with a higher incidence of suicidal, aggressive and related events than the other SSRIs. Patients have survived large overdoses of each of the compounds, but concern has been expressed over 6 fatalities following overdoses of citalopram. Drug interactions mediated by cytochrome P450 enzymes are theoretically less likely to occur during treatment with citalopram and sertraline, but there is a sparsity of clinical data to support this. Methodological difficulties and price changes do not allow choice for recommendations on the choice of SSRI based on pharmacoeconomic data. Taking into account the strengths and weaknesses of the methods used to compare drugs, guidelines to the selection of individual SSRIs in clinical practice are proposed. Citalopram should be avoided in patients likely to take overdoses. Fluoxetine may not be the drug of first choice for patients in whom a rapid antidepressant effect is important or for those who are agitated, but it may have advantages over other SSRIs in patients who are poorly compliant with treatment and those who have previously had troublesome discontinuation symptoms. Fluvoxamine, and possibly paroxetine, should not be used as first choice in patients especially prone to SSRI-related adverse reactions, while paroxetine should be avoided if previous discontinuation of treatment was troublesome. When in doubt about the risks of drug interactions, citalopram or sertraline should be considered given the lower theoretical risk of interactions.

Humans↗
PubMed1983

Selection in guinea pigs: III. Correlated responses to selection for litter size and body weight.

Correlated responses in number born, number born alive, number weaned, birth weight, weaning weight, 13-wk weight and index were evaluated in a guinea pig population after four generations of single trait and index selection for number born alive and 13-wk weight. Regressions of correlated response on generation number in the 13-wk weight line were all positive, but were significant only for birth weight (5.65 +/- .66 g) and index (25.58 +/- 9.90). In the litter size line, significant responses were found for 13-wk weight (21.17 +/- 5.34 g) and birth weight (.80 +/- .21 g). All other responses in this line, except number weaned (-.05 +/- .08), were positive but nonsignificant. There were no significant trends in the index line. Regression coefficients from weighted multiple regression analyses suggested significant improvement in number born (.07 +/- .002), number born alive (.006 +/- .002) and number weaned (.01 +/- .001) in the 13-wk weight line. Regression values in the litter size line were .03 +/- .001 and -.04 +/- .001 for number born and number weaned, respectively. The other regressions were positive but nonsignificant except for weaning weight, which was nonsignificantly negative. None of the correlated responses to index selection was significant. Realized genetic correlations between 13-wk weight and number born alive and index were .37 +/- 1.54 and .31 +/- .98, respectively. The correlation between index and number born alive was .19 +/- 5.18.

Animals↗
PubMed1994

Selection for high and low threshold body weight at first egg in broiler strain females. 4. Photoperiodic drive in the selection lines and in commercial layers and broiler breeders.

A two-way selection program, carried out for high and low threshold BW at onset of lay (ThrWtLay), decreased photoperiodic drive of the high line (HL) relative to the low line (LL). Photoperiodic drive in modern broiler breeder females was compared to layer females in experiments using the HL and LL lines, a commercial layer cross (LX), and a commercial broiler breeder female line cross (BX). Treatment groups were: NS, natural decreasing light to 20 wk, followed by natural light supplemented to 16 h daily with artificial light; NN, natural decreasing light to end of experiment; DD, dark room from hatch to end of experiment; ND, natural decreasing light to 20 wk, dark room thereafter. Under NS, mean age and BW at first egg was greater for the HL line than for the LL line. The difference increased by a further 8.9 d and 217.5 g under NN. Similarly, under NS, mean age and BW at first egg was greater for BX than for LX, and the difference increased by a further 22.6 d and 256.1 g under NN. These interactions indicate greater photoperiodic drive of LX and LL stocks relative to the HL and BX stocks. Prepeak and peak egg production (EP) was greatest for the LX, lower for the LL, and lower yet for HL and BX. Photoperiodic drive may be of major importance in determining prepeak and peak EP. Except for the DD treatment, age and BW of the LX cross at first egg were virtually identical across treatments, those of the LL line were similar, whereas those of the HL and BX stocks showed differences. Similarly, EP curves of the LX cross were virtually identical across treatments, those of the LL line were relatively uniform, but those of the HL and BX stocks again showed great differences. Standard deviation and coefficient of variation of peak EP were very low for the LX cross, still low, but significantly greater for the LL line, and significantly greater yet again for both HL and BX stocks. Thus, increased photoperiodic drive may also be associated with greater stability of reproductive performance. Selection for early onset of lay on release from feed restriction may provide a means of increasing photoperiodic drive and consequent reproductive performance of broiler breeders.

Age Factors↗
PubMed2001

[Behavioral and neurochemical study on the mechanism of the anxiolytic effect of a selective serotonin reuptake inhibitor, a selective serotonin1A agonist and lithium carbonate].

The authors investigated the effects of citalopram [selective serotonin (5-HT) reuptake inhibitor; SSRI] and MKC-242 (a selective 5-HT1A agonist) following treatment with subchronic lithium (p.o., 1 week) on the expression of conditioned freezing, an index of anxiety, and on extracellular 5-HT concentrations in the medial prefrontal cortex (mPFC). In conditioned fear stress experiments, acute administration of citalopram (s.c.) reduced freezing significantly at a high dose (30 mg/kg), while showing no effect at lower doses (3 and 10 mg/kg). Acute administration of MKC-242 (s.c.; 0.1-10 mg/kg) dose-dependently reduced freezing. Subchronic lithium treatment (1 week; 0.05 or 0.2% lithium carbonate in diet; p.o.) showed no effect on freezing behavior. Acute treatment with both citalopram (3 and 30 mg/kg) and MKC-242 (1 mg/kg) after subchronic treatment with high, but not low, concentrations of lithium (1 week) reduced freezing markedly and significantly, as compared with either drug alone. In brain microdialysis experiments, acute treatment with citalopram showed significant increases in the extracellular 5-HT concentrations in a dose-dependent manner. Subchronic lithium group showed significantly higher basal levels of extracellular 5-HT, compared with normal diet controls. Acute citalopram (3 and 30 mg/kg) treatment with subchronic lithium treatment showed significant increases in the extracellular 5-HT concentrations, compared with citalopram treatment alone. Subchronic lithium did not cause decreases in extracellular 5-HT after presynaptic stimulation of 5-HT1A receptors by MKC-242. These results suggest that subchronic lithium treatment enhanced the anxiolytic-like effects of these serotonergic drugs by facilitating central 5-HT neurotransmission at clinically therapeutic plasma lithium levels. It is hypothesized that subchronic lithium treatment gives an additive effect to the treatment with citalopram (3 and 30 mg/kg) by increasing the extracellular 5-HT concentrations in the mPFC, and that subchronic lithium treatment enhances the anxiolytic effect of MKC-242 by increasing sensitivity of postsynaptic 5-HT1A receptors.

Animals↗
PubMed2005

Selective estrogen receptor modulator and selective progesterone receptor modulator: therapeutic efficacy in the treatment of uterine leiomyoma.

Recent advances in endocrinology open a door for clinical application of selective estrogen receptor modulator (SERM) and selective progesterone receptor modulator (SPRM) in the treatment of uterine leiomyoma. With regard to SERM, treatment with raloxifene is shown to reduce leiomyoma size in postmenopausal women. Although raloxifene causes shrinkage of leiomyomas in combination with gonadotropin-releasing hormone agonist in premenopausal women, the effects of monotherapy with raloxifene on leiomyoma growth in premenopausal women remain controversial. By contrast, tamoxifen may not be suitable for long-term treatment of leiomyomas due to an agonistic action on the endometrium. Treatment with progesterone antagonist (RU486) or SPRM (J867) has been demonstrated to inhibit leiomyoma growth and improve clinical symptoms in premenopausal women. No serious adverse effects associated with SERM or SPRM have been reported. In light of therapeutic efficacy and few adverse effects, SERM and SPRM may hold promise as novel treatment modalities for leiomyoma. Further studies are warranted to determine the optimal strategy for the treatment of leiomyoma with SERM and SPRM.

Female↗
PubMed1989

[The effects of longterm selection on the genetic structure of populations--a simulation study. II. The effects of selection on genetic variances].

Monte Carlo simulation has been done to study the effects of longterm artificial selection on genetic variances under additive, dominant, and over-dominant models. The effects of population size, linkage, and heritability have been considered. Just as under the additive model, the additive variance under the dominant and over-dominant models has also been decomposed into three components which represent changes in gene frequencies (VT), departure from Hardy-Weinberg equilibrium (VHW) and from linkage equilibrium (VLD) respectively. These present a resonable approach to study the association among multiple genes. In small populations, genetic variance fluctuates wildly over generations and replicates due to the establishment of linkage disequilibrium. Rapid decrease of VT observed. Intense linkage retained a greater additive variance in the small populations while slowing down responses, which makes it difficult to predict responses during longterm selection.

Animals↗
PubMed1997

Noradrenaline-selective versus serotonin-selective antidepressant therapy: differential effects on social functioning.

The outcome of antidepressant therapy in terms of social functioning was evaluated in a randomized, placebo-controlled, double-blind study comparing the selective noradrenaline reuptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Of the 381 patients with major depression participating in the study, 302 patients were assessed using the new self-rating Social Adaptation Self-evaluation Scale (SASS). Mean SASS total score at last assessment was superior (p < 0.05) to placebo for both reboxetine and fluoxetine. Moreover, reboxetine was superior (p < 0.05) to fluoxetine. Evaluation of the sensitivity to change in individual items by point-biserial correlation analysis showed a significant correlation between improvement in item score and reboxetine treatment in all but one item for the reboxetine-placebo comparison. In the fluoxetine-placebo comparison, a significant correlation was evident for only 12 of the 21 items. Direct comparison of reboxetine with fluoxetine revealed a significant correlation between change in item score and treatment for nine items, in favour of reboxetine. The association was maximal for six items, mainly related to negative self-perception and to active social behaviour. In the subset of patients in remission at last assessment (n = 91), the mean SASS total score for reboxetine was superior to that of both fluoxetine and placebo (p < 0.05). Point-biserial correlation analysis revealed that most items sensitive to change under active treatment in the total population did so with reboxetine (17 items) or fluoxetine (nine items) in patients in remission. In the reboxetine-fluoxetine comparison, 14 items showed a significant association with reboxetine treatment. In conclusion, while social motivation and behaviour in depression are significantly affected by both noradrenergic and serotonergic antidepressant treatment, noradrenergic therapy seems particularly effective in improving negative self-perception and motivation towards action, resulting in a better quality of remission in terms of social functioning.

Adolescent↗
PubMedDate not supplied

Selective and sensitive determination of protein and non-protein amino acids by capillary gas chromatography with nitrogen-phosphorus selective detection.

A selective and sensitive method for the determination of protein and non-protein amino acids by capillary gas chromatography (GC) has been developed. The amino acids were converted into their N(O,S)-isobutoxycarbonyl methyl ester derivatives and measured by GC with nitrogen-phosphorus selective detection using a DB-17ht capillary column. Using this method, the derivatives of the 21 protein amino acids and the 33 non-protein amino acids provided excellent NPD responses, and were quantitatively and reproducibly resolved within 28 min. The detection limits of these amino acids were 6-150 pg per injection. The calibration curves were linear in the range 0.02-2 micrograms for each amino acid, the correlation coefficients being above 0.990. This method was successfully applied to small urine samples without prior clean-up, and analysed without any influence from coexisting substances. Overall recoveries of amino acids added to urine sample were 83-108%. The analytical results of free amino acid contents in urine samples of normal subjects are presented.

Amino Acids↗
PubMed2002

Selective and shape-selective Baeyer-Villiger oxidations of aromatic aldehydes and cyclic ketones with Sn-beta zeolites and H2O2.

Sn-Beta is used as a heterogeneous catalyst for the Baeyer-Villiger reaction with hydrogen peroxide. Cyclic ketones are transformed into the corresponding lactones, while unsaturated ketones are oxidized to the corresponding unsaturated lactones with very high chemoselectivity. The catalyst is also selective for the oxidation of aromatic aldehydes with H2O2, producing the formate ester or the corresponding hydrolyzed product, that is the alcohol. Shape-selective oxidations are observed for isomeric reactants with different molecular shapes. The catalytic Sn sites have been characterized by 119Sn MAS-NMR spectroscopy, and tetrahedral incorporation into the zeolite framework has been demonstrated. In situ IR spectroscopy and 18O labeling experiments have shown that the oxidation mechanism involves an intermediate of the Criegee type.

Journal Article↗
PubMed1987

Selection bias in occupational case-control studies that use death registries to select subjects: a discussion and demonstration.

Some epidemiologic studies have selected subjects from death registries. This method is, however, subject to substantial systematic bias that arises from the fact that different segments of society have different risks of death in any year. Different occupational groups will thus have unequal probabilities of entering the pool of potential controls, and biased estimates of the odds ratios that relate occupation to disease will result. Failure to recognize the bias may lead to invalid conclusions. This selection bias is discussed, with particular reference to studies of malignancies among farmers. The bias is demonstrated by using data from studies of Parkinson's disease and sinonasal cancer.

Aged↗
PubMed2004

Synthesis, enantiomeric resolution, and selective C-11 methylation of a highly selective radioligand for imaging the norepinephrine transporter with positron emission tomography.

Reboxetine, 2-[alpha-(2-ethoxyphenoxy)benzyl]morpholine, is a highly selective norepinephrine transporter (NET) blocker that has been used for the treatment of depression. Its methyl analogue, 2-[alpha-(2-methoxyphenoxy)benzyl]morpholine (MRB), has been radiolabeled with C-11 for studies of the NET system with positron emission tomography (PET). The normethyl precursor, 2-[alpha-(2-hydroxyphenoxy)benzyl]morpholine (desethylreboxetine), was synthesized in 6% overall yield via a multi-step regio- and stereo-specific synthesis, starting from a mono-O-protected catechol. The resulting racemic mixture of desethylreboxetine was resolved by chiral HPLC to provide the (2S,3S) and (2R,3R) enantiomers in >98% enantiomeric excess. These enantiomers were then used as precursors for radiosynthesis to prepare enantiomerically pure individual 11C-labeled MRB enantiomers for comparative PET studies in baboons. Selective C-11 methylation at the phenolic oxygen with [11C]CH3I was achieved in the presence of excess base. After HPLC purification, racemic ((2S,3S)/(2R,3R)) or enantiomerically pure ((2S,3S) or (2R,3R)) [11C]MRB was obtained in 61-74% decay-corrected radiochemical yields from [11C]CH3I in a synthesis time of 40 min with a radiochemical purity of >96% and a specific activity of 1.7-2.3 Ci/micromol (63-85 GBq/micromol) corrected from the end of bombardment (EOB).

Carbon Radioisotopes↗
PubMed1993

Rapid transformant selection by human complement using HRF20 (CD59) cDNA as a selection marker.

The 20 kDa homologous restriction factor (HRF20, CD59) prevents formation of membrane attack complexes of human complement. Transfection of the cDNA of HRF20 to heterologous cells, which are sensitive to human complement, thereby renders these cells resistant to human complement attack. This property can then be used as a selection marker of transfection. In addition, the procedure is short and can be performed within 8 h. Since only 1 h is required for incubation with complement, the damage to the transfected cells is limited compared with damage resulting from selection for drug resistance which requires 10 days or more of incubation in the presence of harmful agents.

Animals↗
PubMed2004

Selective missing pulse steady state free precession (MP-SSFP): inner volume and chemical shift selective imaging in a steady state sequence.

PURPOSE: To examine new sequences that restrict acquisition of spins to those excited by both of the RF pulses in missing pulse steady state free precession (MP-SSFP) MRI. MATERIALS AND METHODS: New MP-SSFP sequences were created by replacing one of the slice selective pulses (SSPs) with an orthogonal SSP for inner volume imaging, and with a chemical shift selective (CHESS) pulse for chemical shift imaging. The inner volume sequence was applied to a reduced field of view at the center of a resolution phantom; resulting images were evaluated for differences in the aliased signal. The CHESS sequence was applied to volunteers, as well as to and fat, water, and acetic acid phantoms. Results were evaluated with SNR measurements. RESULTS: The inner volume sequence eliminated the aliased signal, while nonselected fat and water levels were suppressed to that of noise by the CHESS sequence. CONCLUSION: Results suggest a novel steady state technique for rapid inner volume or chemical shift imaging.

Humans↗