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1.
An analytic model is developed to explore the relationship between gene flow, selection, and genetic drift. We assume that a single copy of a mutant allele appears in a finite, partially isolated population and allow for the effects of immigration, genic selection, and mutation on the frequency of the mutant. Our concern is with the distribution of the mutant's frequency before it either is lost from the population or emigrates. Before either of these events, the allele will be a “private allele” and would be found in only one of several populations in a larger collection. Slatkin [(1985) Evolution 39, 53–65] found several simple properties of private alleles in his simulations. We use the method developed by Karlin and Tavaré [(1980) Genet. Res. 37, 33–46; (1981a), Theor. Pop. Biol. 19, 187–214; (1981b) Theor. Pop. Biol. 19, 215–229] for a model similar to ours to obtain a diffusion equation with a “killing term” and obtain the mean and variance of the mutant's frequency and its expected frequency in samples of a specified size. There is only fair agreement between the analytic results from this model and those from Slatkin's (loc. cit.) simulations. The rescaling method used to obtain the results indicates that if emigration is relatively frequent, the distribution of rare alleles is governed largely by the balance between genetic drift and emigration, with selection, mutation, and immigration playing a lesser role.  相似文献   

2.
Le Bras (Theor. Popul. Biol.2, 100–121, 1971) and Rogers (Demography11, 473–481, 1974), in two neglected papers, have generalized to the multisite case the Euler–Lotka renewal equation and demographic characteristics such as age structure and reproductive value. The purpose of this paper is twofold: first, to restate the multisite renewal equation in the matrix context; second, to derive results on age structure, net reproduction rate, generation time, and sensitivities, as generalizations of the one site case. The potential of this approach for population biology is illustrated using a model of a black-headed gullLarus ridibunduspopulation.  相似文献   

3.
4-(Substituted-benzylidine)-2-substituted-5,6-dihydrobenzo[h]quinazoline (5ap) and 4-(substituted-benzylidine)-2-substituted-3, 4, 5, 6-tetrahydrobenzo[h]quinazoline (6ap) have been synthesized from 2-(substituted-benzylidine)tetralone-1(3ad) and several substituted guanidine sulfates(4ad).These compounds were tested for their in vitro antileishmanial activity. The compounds 6i, 6f, 6g show promising antileishmanial activity against Leishmania donovani.  相似文献   

4.
Di-nor-benzofuran neolignan aldehydes, Δ7-3,4-methylenedioxy-3′-methoxy-8′,9′-dinor-4′,7-epoxy-8,3′-neolignan-7′-aldehyde (ocophyllal A) 1, Δ7-3,4,5,3′-tetramethoxy-8′,9′-dinor-4′,7-epoxy-8,3′-neolignan-7′-aldehyde (ocophyllal B) 2, and macrophyllin-type bicyclo[3.2.1]octanoid neolignans (7R, 8R, 3′S, 4′S, 5′R)-Δ8′-4′-hydroxy-5′-methoxy-3,4-methylenedioxy-2′,3′,4′,5′-tetrahydro-2′-oxo-7.3′,8.5′-neolignan (ocophyllol A) 3, (7R, 8R, 3′S, 4′S, 5′R)-Δ8′-4′-hydroxy-3,4,5′-trimethoxy-2′,3′,4′,5′-tetrahydro-2′-oxo-7.3′,8.5′-neolignan (ocophyllol B) 4, (7R, 8R, 3′S, 4′S, 5′R)-Δ8′-4′-hydroxy-3,4,5,5′-tetramethoxy-2′,3′,4′,5′-tetrahydro-2′-oxo-7.3′,8.5′-neolignan (ocophyllol C) 5, as well as 2′-epi-guianin 6 and (+)-licarin B 7, were isolated and characterized from leaves of Ocotea macrophylla (Lauraceae). The structures and configuration of these compounds were determined by extensive spectroscopic analyses. Inhibition of platelet activating factor (PAF)-induced aggregation of rabbit platelets were tested with neolignans 1–7. Although compound 6 was the most potent PAF-antagonist, compounds 3–5 showed some activity.  相似文献   

5.
Synthesis and anti-inflammatory effects of certain furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives 1218 were studied. These compounds were synthesized from naphtho[1,2-b]furan-4,5-dione (10) which in turn was prepared from the known 2-hydoxy-1,4-naphthoquinone (7) in a one pot reaction. Furo[3′,2′:3,4]naphtho[1,2-d]imidazole (12) was inactive (IC50 value of >30 μM) while its 5-phenyl derivative 13, with an IC50 value of 16.3 and 11.4 μM against lysozyme and β-glucuronidase release, respectively, was comparable to the positive trifluoperazine. The same potency was observed for 5-furan derivative 16 with an IC50 value of 19.5 and 11.3 μM against lysozyme and β-glucuronidase release, respectively. An electron-withdrawing NO2 substituted on 5-phenyl or 5-furanyl group led to the devoid of activity as in the cases of 14 and 17. Among them, compound 15 exhibited significant inhibitory effects, with an IC50 value of 7.4 and 5.0 μM against lysozyme and β-glucuronidase release, respectively.For the LPS-induced NO production, the phenyl derivatives 12–15 were inactive while the nitrofuran counterparts 17 and 18 suppress LPS-induced NO production significantly, with an IC50 value of 1.5 and 1.3 μM, respectively, which are more active than that of the positive 1400 W. Compounds 16–18 were capable of inhibiting LPS-induced iNOS protein expression at a dose-dependent manner in which compound 18, with an IC50 of 0.52 μM in the inhibition of iNOS expression, is approximately fivefold more potent than that of the positive 1400 W. In the CLP rat animal model, compound 18 was found to be more active than the positive hydrocortisone in the inhibition of the iNOS mRNA expression in rat lung tissue. The sepsis-induced PGE2 production in rat serum decreased 150% by the pretreatment of 18 in a dose of 10 mg/kg.  相似文献   

6.
O-(2′-[18F]fluoroethyl)-l-tyrosine ([18F]FET) has gained much attention as a promising amino acid radiotracer for tumor imaging with positron emission tomography (PET) due to favorable imaging characteristics and relatively long half-life of 18F (110 min) allowing remote-site application. Here we present a novel type of chiral enantiomerically pure labeling precursor for [18F]FET, based on NiII complex of a Schiff’s base of (S)-[N-2-(N′-benzylprolyl)amino]benzophenone (BPB) with alkylated (S)-tyrosine, Ni-(S)-BPB-(S)-Tyr-OCH2CH2X (X = OTs (3a), OMs (3b) and OTf (3c)). A series of compounds 3ac was synthesized in three steps from commercially available reagents. Non-radioactive FET as a reference was prepared from 3a in a form of (S)-isomer and (R,S) racemic mixture. Radiosynthesis comprised two steps: (1) n.c.a. nucleophilic fluorination of 3ac (4.5–5.0 mg) in the presence of either Kryptofix 2.2.2.or tetrabutylammonium carbonate (TBAC) in MeCN at 80 °C for 5 min, followed by (2) removal of protective groups by treating with 0.5 M HCl (120 °C, 5 min). The major advantages of this procedure are retention of enantiomeric purity during the 18F-introduction step and easy simultaneous deprotection of amino and carboxy moieties in 3ac. Radiochemically pure [18F]FET was isolated by semi-preparative HPLC (C18 μ-Bondapak, Waters) eluent aq 0.01 M CH3COONH4, pH 4/C2H5OH 90/10 (v/v). Overall synthesis time operated by Anatech RB 86 laboratory robot was 55 min. In a series of compounds 3ac, tosyl derivative 3a provided highest radiochemical yield (40–45%, corrected for radioactive decay). Enantiomeric purity was 94–95% and 96–97%, correspondingly, for Kryptofix and TBAC assisted fluorinations. The suggested procedure involved minimal number of synthesis steps and suits perfectly for automation in the modern synthesis modules for PET radiopharmaceuticals. Preliminary biodistribution study in experimental model of turpentine-induced aseptic abscess and Glioma35 rat’s tumor (homografts) in Wistar rats has demonstrated the enhanced uptake of radiotracer in the tumor area with minimal accumulation in the inflamed tissues.  相似文献   

7.
Ginkgolic acids (GAs) are toxic phenolic compounds present in the fruits and leaves of Ginkgo biloba L. (Ginkgoacae). Their maximum level in phytopharmaceuticals containing ginkgo extracts has been recently restricted to 5 μg/g by the Commission E of the former Federal German Health Authority. In order to detect ginkgolic acids at these low levels, a sensitive and selective analytical method, based on liquid chromatography–electrospray mass spectrometry (LC–ES-MS) has been developed. The three main phenolic acids (13) of the chloroform fruit extract were isolated and used as standards for quantification. In the LC–ES-MS negative ion mode, calibration curves with good linearities (r=0.9973, n=6) were obtained in the range of 0.5–10 μg/g for compounds 1, 2 and between 0.1 and 7.5 μg/g (r=0.9949, n=6) for ginkgolic acid 3. The detection limits at a S/N ratio of 3 were 0.1 (3) and 0.25 μg/g (1, 2). Recoveries were around 101% at 5 μg/g for the substances detected in the leaf extracts. Good precision was achieved with relative standard deviations of less than 4% (n=6). The optimised method was applied to verify whether the amount of gingkolic acids was below 5 μg/g in a standardised leaf extract which is a constituent of a phytopreparation.  相似文献   

8.
A series of m-alkyl α,α,α-trifluoroacetophenones (1–5) was synthesized and evaluated as inhibitors of acetylcholinesterase from Torpedo california. All ketones (1–5) were found to be potent inhibitors of the enzyme; m-t-butyl α,α,α-trifluoroacetophenone (4) was the most potent inhibitor with a Ki value of 3.7 pM.  相似文献   

9.
Benzoylation of benzyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-α-d-glucopyranoside, benzyl 2-deoxy-2-(dl-3-hydroxytetradecanoylamino)-4,6-O-isopropylidene-α-d-glucopyranoside, and benzyl 2-deoxy-4,6-O-isopropylidene-2-octadecanoylamino-β-d-glucopyranoside, with subsequent hydrolysis of the 4,6-O-isopropylidene group, gave the corresponding 3-O-benzoyl derivatives (4, 5, and 7). Hydrogenation of benzyl 2-acetamido-4,6-di-O-acetyl-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-α-d-glucopyranoside, followed by chlorination, gave a product that was treated with mercuric actate to yield 2-acetamido-1,4,6-tri-O-acetyl-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-β-d-glucopyranose (11). Treatment of 11 with ferric chloride afforded the oxazoline derivative, which was condensed with 4, 5, and 7 to give the (1→6)-β-linked disaccharide derivatives 13, 15, and 17. Hydrolysis of the methyl ester group in the compounds derived from 13, 15, and 17 by 4-O-acetylation gave the corresponding free acids, which were coupled with l-alanyl-d-isoglutamine benzyl ester, to yield the dipeptide derivatives 19–21 in excellent yields. Hydrolysis of 19–21, followed by hydrogenation, gave the respective O-(N-acetyl-β-muramoyl-l-alanyl-d-isoglutamine)-(1→6)-2-acylamino-2-deoxy-d-glucoses in good yields. The immunoadjuvant activity of these compounds was examined in guinea-pigs.  相似文献   

10.
A series of 5-aryl-3-alkylidenedihydrofuran-2(3H)-ones 6ag″ and 11a,b as well as 5-aryl-3-methylidenepyrrolidin-2-ones 10ac and 12 were synthesized starting from 4-aryl-2-diethoxyphosphoryl-4-oxobutanoates 3ag. Reaction sequence includes reduction or reductive amination of the carbonyl group, lactonization or lactamization step and finally the Horner–Wadsworth–Emmons olefination of aldehydes using thus obtained 5-aryl-3-diethoxyphosphoryl-3,4-dihydrofuran-2(5H)-ones 5ag″ or 5-aryl-3-diethoxyphosphorylpyrrolidin-2-ones 9ac. Furanones 6 and 11, as well as pyrrolidinones 10 and 12, were evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines HL-60 and NALM-6. Several of the obtained furanones proved to be very potent against all three cell lines with IC50 values lower than 6 μM. Structure–activity relationships of these compounds, as well as 5-alkyl or 5-arylmethyl-3-methylidenedihydrofuran-2(3H)-ones 13ae, previously obtained in our laboratory, are discussed.  相似文献   

11.
To verify that maximization of endurance is important among the functional criteria determining trunk muscle activation patterns, symmetric and asymmetric exertions were simulated using a detailed model consisting of 114 muscle slips crossing the lumbosacral junction and employing a cost function which maximizes endurance. First, the question whether meaningful comparisons can be made between activity predictions for individual muscle slips and surface EMG data recorded from larger anatomical entities was addressed. This was answered affirmatively, since activation patterns predicted by a coarse and a middle version of the model, in which activation was constrained to be equal within 14 or 32 groups of muscle slips, were similar to those predicted with each muscle slip controlled independently. Median correlation coefficients between activity vectors predicted by the simplified models and the detailed model were 0.88 and 0.97, respectively. The coarse model underestimated the endurance capacity by a median of 21%, the middle model by only 0.7%. Second, predicted activities within anatomical entities defined at this level of detail were compared to reference data derived from the literature (Lavender et al. 1992, Human Factors 34, 239–247; 1992, Journal of Orthopaedic Research 10, 691–700; Vink et al., 1988, Electromyography and Clinical Neurophysiology 28, 517–525). The predicted activity patterns of the crector spinae, external oblique and rectus abdominis muscles closely resembled the EMG patterns (r2 = 0.48–0.99). Furthermore, the observed distribution of activity between parts of the crector spinae muscle was adequately predicted.  相似文献   

12.
Six novel isoflavone derivatives along with four known isoflavones were isolated from a culture of a highly nickel-resistant strain of Streptomyces mirabilis from a former uranium mining area. The structures of 7-hydroxy-3′,5′-dihydroxyisoflavone (5), 5,7-dihydroxy-3′,5′-dihydroxyisoflavone (6), 2′-hydroxy-3′-methoxygenistein (7), as well as hydroisoflavones A–C (810) were elucidated by MS and NMR analyses. Compounds 810 feature yet unprecedented types of non-aromatic, hydroxylated B rings, which result from plant isoflavone biotransformation. All new compounds display weak cytotoxic but potent antiproliferative activities. The anti-oestrogenic properties of 8 against MCF-7 human breast cancer cell line (GI50: 6 μM) is even higher than the reference compound genistein.  相似文献   

13.
Using the model of exploitative competition of R. H. MacArthur and R. Levins (1967, Amer. Natur. 101, 377–385), evolution at a gene locus which influences the niche position is considered. The locus has multiple alleles, and the contributions of the alleles to the genotypic value are additive. The resource spectrum and the utilization functions of the genotypes are assumed to be Gaussian. Evolution will make the mode of the niche converge to the resource optimum, as long as the allele contributions are small compared to the distance between the mode of the niche and the resource optimum. When this distance is of the same order of magnitude as the allele contributions, then the globally stable equilibrium will maintain at most two alleles in the population, unless the allele contributions are large. Classical overdominance is not needed to maintain polymorphism. This result predicts high linkage disequilibrium in similar multilocus models. It is concluded that intraspecific competition can be a powerful force in maintaining two-allele polymorphisms, and that it can maintain high linkage disequilibrium among closely linked loci.  相似文献   

14.
Baeyer–Villiger oxidation of 5-aryl-7,11,11-trimethyltricyclo[5.4.0.03,6]-undec-1-en-4-ones 4ah by H2O2 and formic acid in methanol yields mixtures of 3b,7,7-trimethyl-3-phenyl-3,3a,3b,4,5,6,7,8a-octahydro-1H-indeno-[1,2-c]furan-1-ones 8ah and 3b,7,7-trimethyl-3-phenyl-3,3a,3b,4,5,6,7,8a-octahydro-1H-indeno-[1,2-c]furan-2-ones 9ah in high yields. The obtained butyrolactones 8ah display cytotoxic activity against a number of human cancer cells.  相似文献   

15.
Alkyl-substituted derivatives of 2-aminonaphthalene (2-AN) 1, 2-aminofluorene (2-AF) 6 and 4-aminobiphenyl (4-ABP) 11 were synthesized and the mutagenic activity of these compounds determined in Salmonella typhimurium strains TA98 and TA100 with and without S9 mix. In the case of the ortho-substituted 4-aminobiphenyls 1215 (3-alkyl=ethyl, iso-propyl, n-butyl, tert-butyl) the substituent with the strongest steric demand (3-tert-butyl) shows the strongest influence on the decrease of mutagenicity if compared with the parent compound. In the series of the bis-ortho-disubstituted compounds 1618 (3,5-dimethyl-, 3,5-diethyl- and 3,5-diisopropyl-4-aminobiphenyl) generation of non-mutagenic species occurs already with the introduction of two ethyl groups. For the 4-aminobiphenyl derivatives 1215 and 1618, as well as for the 1-alkylated 2-aminofluorenes 710 and the 1-alkylated 2-aminonaphthalenes 25 a smaller mutagenicity was observed if compared with predicted mutagenicities as calculated by the QSAR equations of Debnath et al. (Environ. Mol. Mutagen. 19 (1992) 37). The largest differences resulted in the cases of the tert-butyl substituted compounds. Only with smaller alkyl groups like ethyl the QSAR predictions and the experimentally determined mutagenicities come close to each other. Thus, these results show that appropriate alkyl substitution reduces (eliminates) mutagenicity, secondly, it is necessary to introduce steric parameters to predict the mutagenicity of such compounds correctly.  相似文献   

16.
Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme regulating the metabolism of folate and methionine. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair presents MTHFR as a candidate for being a cancer-predisposing gene. In the present study, we have examined a large study population to determine whether the C677T polymorphism at the MTHFR locus affects susceptibility for cervical cancer or its precursor, cervical intraepithelial neoplasia (CIN). In addition, we have investigated whether this polymorphism is causal, and not merely associated, by typing microsatellite markers in the region surrounding the MTHFR gene. A total of 311 CIN and 695 cervical cancer patients and 115 family-based and 586 unrelated controls was analysed. Association analysis showed a decreased cervical cancer risk for individuals heterozygous or homozygous for the T-allele, both for squamous cell carcinoma (heterozygous odds ration [OR] 0.66 [0.51–0.86]; homozygous OR 0.76 [0.49–1.16]) and adenocarcinoma (heterozygous OR 0.71 [0.49–1.03]; homozygous OR 0.34 [0.14–0.81]). No difference was found for high grade CIN (heterozygous OR 1.03 [0.76–1.40]; homozygous OR 0.91 [0.54–1.55]). A microsatellite haplotype containing the C allele was associated with an increased risk for cervical cancer and CIN (both among squamous cell carcinomas, adenocarcinomas and CIN II–III; OR=2.61 [1.59–4.27]). Our study thus lends further support to the hypothesis that the MTHFR C677T polymorphism is involved in susceptibility cervical cancer but also illustrates that, despite the large sample size analysed, still larger studies are needed to establish fully the nature of this association.  相似文献   

17.
Our recent studies with 2-(3′-hydroxypropylidene) analogs of 1α,25-dihydroxy-19-norvitamin D3 showed that this 2-substituent creates compounds with very potent biological activity. In the continuing search for vitamin D compounds with selective activity profiles, we prepared a series of 1α-hydroxy-19-norvitamin D analogs characterized by the presence of a 3′-hydroxypropylidene substituent at C-2 and a truncated side chain. These vitamin D compounds were efficiently prepared using convergent syntheses. The C,D-fragments, namely the Grundmann ketones 19, 20, 27, 36 and 37 were synthesized from the known 8β-benzoyloxy-22-aldehydes 12 and 29. These hydrindanones were subjected to Lythgoe type Wittig–Horner coupling with phosphine oxide 21, prepared by us previously, and after hydroxyl deprotection the set of 19-norvitamins 711 was successfully obtained. According to our expectations, all analogs (with an exception of the 20R-compound 7) have pronounced in vitro activity. When compared to the natural hormone 1α,25-(OH)2D3 (1), they show the same or only slightly reduced affinity for the vitamin D receptor while being similarly effective as 1 in differentiation of HL-60 cells into monocytes.  相似文献   

18.
On the basis of systematic studies on the structure–activity relationships in arylpiperazine group of serotonin ligands, 12 new derivatives containing quinazolidin-4(3H)-one (14), 2-phenyl-2,3-dihydrophthalazine-1,4-dione (58) or 1-phenyl-1,2-dihydropyridazine-3,6-dione (912) fragments were synthesized. The majority of the tested compounds (2, 4, 7, 8 and 1012) showed a high affinity for 5-HT1A receptors (Ki=11–54 nM) and two (1, 2) were found active at 5-HT2A sites (16 and 68 nM, respectively). All the new 5-HT1A ligands tested in vivo revealed an antagonistic activity at postsynaptic 5-HT1A receptors, and three of them behaved as agonists at presynaptic ones. Additionally, both the meta-chlorophenylpiperazine derivatives containing quinazolidin-4-one fragment showed features of 5-HT2A receptor antagonists. The dual 5-HT1A/5-HT2A receptor ligand (2) was further tested for its potential psychotropic activity. It showed a distinct anxiolytic-like activity in a conflict drinking test in rats and the observed effect was more potent in terms of the active dose, than that produced by diazepam (used as a reference drug).  相似文献   

19.
Complexes [M(η12-C8H12OMe)((2,6-(R)2---C6H3)N=C(R′)---C(R′)=N((2,6-(R)2---C6H3))]PF6 (where M=Pd, R=H and R′2=Me2 (1), M=Pd, R=Me and R′2=Me2 (2), M=Pd, R=Et and R′2=Me2 (3), M=Pd, R=iPr and R′2=Me2 (4), M=Pd, R=iPr and R′2=An (5), M=Pt, R=iPr and R′2=An (6)) were synthesized by the reaction of [M(η12-C8H12OMe)Cl]2 with the appropriate α-diimine ligand in the presence of NH4PF6. Their ion pair structure in solution was investigated by detecting dipolar interactions between protons belonging to the cation and fluorine nuclei of the anion (interionic contacts) in the 19F, 1H-HOESY NMR spectra. In complexes 14, the anion in solution is located close to the peripheral protons of the α-diimine ligand and it interacts with the R′ protons and with the R protons that point toward the R′ groups. The steric protection of apical position exerted by the R substituents is clearly illustrated by the absence of interionic contacts between any protons of the cycloctenylmethoxy-moiety and the anion for R≥Me in 14. In complexes 5 and 6 the interactions between the anion and the peripheral N,N protons also predominate but other anion–cation orientations are significantly present and, consequently, the interionic structure is less specific.  相似文献   

20.
Synopsis The numbers of trout,Salmo trutta, in Granslev », Denmark, were estimated by the removal method on 18 dates from March 1974 to March 1976. Populations density varied from 0.39 to 0.74 trout m–2 in 1974–1975 and from 0.36 to 0.59 m–2 in 1975–1976 and at all times four or five year classes were present. The age structure of the population was unstable and the variable natural survival, immigration into and emigration from the study site could not be separated. An annual growth cycle with the most rapid growth for all year classes taking place from May to early August was found. Statistically significant differences between different years occurred in the growth of the 0,I and II age groups, but no evidence of density-dependent growth was found. The biomass ranged from 35.4 to 9.5 g m–2. The total mean annual biomass was 22.8 and 14.7 g m–2 in the two years and the II group made the greatest contribution, 44 and 48%, respectively. During 1975–1976 the mean annual biomass of each year class only was about two-thirds of that in 1974–1975. Annual production in the two years was 25.7 (range 24.7–28.5) and 12.6 g m–2 (range 11.7–15.0) and the II group accounted for about 46 and 38% of the production. In addition eel,Anguilla anguilla, produced about 0.5 g m–2 yr–2. The unstable age structure of the trout population was compared with trout populations from other streams. The importance of immigration as a recruitment process in middle and lower reaches of streams and of migrations as a mechanism to optimise utilization of the total stream habitat, as well as temperature as a factor controlling the growth rate are discussed.  相似文献   

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