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381.
Schoonen WG Deckers G de Gooijer ME de Ries R Mathijssen-Mommers G Hamersma H Kloosterboer HJ 《The Journal of steroid biochemistry and molecular biology》2000,74(3):109-123
Norethisterone (NET) is a 19-nortestosterone derivative with progestagenic and some androgenic activity, which was used in the first generation of contraceptives. NET was succeeded by levonorgestrel (LNG) and later on by desogestrel (DSG) and gestodene (GSD). Although these latter two progestins had increased potency, there was still androgenicity with gestodene and to a lesser extent with desogestrel. New progestins were synthesized in order to further enhance progestagenic and to reduce androgenic activity. Four different chemical moieties were introduced in position 17 of 19-nortestosterone, viz. 17alpha-ethynyl, five- and six-membered spiromethylene ethers, and a six-membered-spiromethylene lactone. In combination with these structures seven different substituents were added at position 11, i.e. methylene, methyl, ethyl, ethenyl, ethynyl, 2-propenyl and 1-propynyl. All substituents except for methylene occupied the 11beta-position. All these 32 compounds were synthesized and analysed in vitro and in vivo against etonogestrel (ETG, 3-keto-desogestrel), the biologically active metabolite of desogestrel. Their relative binding potency to progesterone (PR), androgen (AR) and estrogen (ER) receptors were determined in cell lysates of human breast tumor MCF-7 cells and to glucocorticoid (GR) receptors in that of human leukemic IM-9 cells. Moreover, their relative agonistic activities were assessed in Chinese hamster ovary cell-based transactivation assays. All in vivo activities were determined in McPhail (progestagenic), ovulation inhibition (progestagenic and estrogenic), Hershberger (androgenic), hormone screening (glucocorticoid and estrogen) and Allen-Doisy (estrogenic) tests after oral and for the McPhail test also after subcutaneous administration. The progestagenic binding and transactivation potencies of all compounds in the three 17-spiro series were higher than those of the corresponding analogues in the 17alpha-ethynyl series. None of the compounds showed estrogenic or clear androgenic binding and transactivation potential except for a six-membered-spiromethylene lactone with a propynyl group. This compound showed strong androgenic binding. The glucocorticoid binding and transactivation were very low for the compounds with the 17alpha-ethynyl and the five-membered-spiromethylene ether groups, whereas both six-membered-spiro series showed, clearly with methyl and ethynyl substituents, and less pronounced with methylene and ethenyl, higher binding and transactivation values. For the 17alpha-ethynyl series, the McPhail test showed high potencies with methylene, methyl and ethenyl substituents after oral treatment or with propenyl after subcutaneous administration. The introduction of the spiro substituents in position 17 led to high potencies for other 11-substituents as well. Besides methyl, also ethyl, ethynyl and propynyl were potent substituents. With ovulation inhibition tests, the ethyl, ethenyl and ethynyl substituents were the more potent compounds in all four series. However, compounds with methyl or ethynyl additions appeared to be glucocorticoidal in the hormone screening test irrespective of the 17-substituent, while with the three spiro series even methylene and ethenyl groups became active. Androgenicity was only observed at dose levels at or above 5 mg/kg, which is 2.5-fold weaker than ETG. Moreover, estrogenicity appeared negligible with the three spiro series, while with the 17alpha-ethynyl series methyl, ethyl, ethenyl and ethynyl substituents, a very high estrogenic potential was assessed. Based on the high efficacy and low side-effects, the following compounds show a high selectivity: 17alpha-ethynyl with ethyl, ethenyl and 2-propenyl substituents, six-membered spiromethylene ether with ethyl and six-membered-spiromethylene lactone with ethyl, 2-propenyl or 1-propynyl substituents. (ABSTRACT TRUNCATED) 相似文献
382.
383.
384.
Ries J Schwille P 《BioEssays : news and reviews in molecular, cellular and developmental biology》2012,34(5):361-368
Fluorescence correlation spectroscopy (FCS) is a powerful technique to measure concentrations, mobilities, and interactions of fluorescent biomolecules. It can be applied to various biological systems such as simple homogeneous solutions, cells, artificial, or cellular membranes and whole organisms. Here, we introduce the basic principle of FCS, discuss its application to biological questions as well as its limitations and challenges, present an overview of novel technical developments to overcome those challenges, and conclude with speculations about the future applications of fluorescence fluctuation spectroscopy. 相似文献
385.
Shahar Rotem Ofer Cohen Erez Bar-Haim Liat Bar-On Sharon Ehrlich Avigdor Shafferman 《PloS one》2014,9(1)
Recently we described an unbiased bacterial whole-genome immunoinformatic analysis aimed at selection of potential CTL epitopes located in “hotspots” of predicted MHC-I binders. Applying this approach to the proteome of the facultative intra-cellular pathogen Francisella tularensis resulted in identification of 170 novel CTL epitopes, several of which were shown to elicit highly robust T cell responses. Here we demonstrate that by DNA immunization using a short DNA fragment expressing six of the most prominent identified CTL epitopes a potent and specific CD8+ T cell responses is being induced, to all encoded epitopes, a response not observed in control mice immunized with the DNA vector alone Moreover, this CTL-specific mediated immune response prevented disease development, allowed for a rapid clearance of the bacterial infection and provided complete protection against lethal challenge (10LD50) with F. tularensis holarctica Live Vaccine Strain (LVS) (a total to 30 of 30 immunized mice survived the challenge while all control DNA vector immunized mice succumbed). Furthermore, and in accordance with these results, CD8 deficient mice could not be protected from lethal challenge after immunization with the CTL-polyepitope. Vaccination with the DNA poly-epitope construct could even protect mice (8/10) against the more demanding pulmonary lethal challenge of LVS. Our approach provides a proof-of-principle for selecting and generating a multi-epitpoe CD8 T cell-stimulating vaccine against a model intracellular bacterium. 相似文献
386.
387.
Yung-Tsi Bolon Adrian O. Stec Jean-Michel Michno Jeffrey Roessler Pudota B. Bhaskar Landon Ries Austin A. Dobbels Benjamin W. Campbell Nathan P. Young Justin E. Anderson David M. Grant James H. Orf Seth L. Naeve Gary J. Muehlbauer Carroll P. Vance Robert M. Stupar 《Genetics》2014,198(3):967-981
Fast neutron radiation has been used as a mutagen to develop extensive mutant collections. However, the genome-wide structural consequences of fast neutron radiation are not well understood. Here, we examine the genome-wide structural variants observed among 264 soybean [Glycine max (L.) Merrill] plants sampled from a large fast neutron-mutagenized population. While deletion rates were similar to previous reports, surprisingly high rates of segmental duplication were also found throughout the genome. Duplication coverage extended across entire chromosomes and often prevailed at chromosome ends. High-throughput resequencing analysis of selected mutants resolved specific chromosomal events, including the rearrangement junctions for a large deletion, a tandem duplication, and a translocation. Genetic mapping associated a large deletion on chromosome 10 with a quantitative change in seed composition for one mutant. A tandem duplication event, located on chromosome 17 in a second mutant, was found to cosegregate with a short petiole mutant phenotype, and thus may serve as an example of a morphological change attributable to a DNA copy number gain. Overall, this study provides insight into the resilience of the soybean genome, the patterns of structural variation resulting from fast neutron mutagenesis, and the utility of fast neutron-irradiated mutants as a source of novel genetic losses and gains. 相似文献
388.
Osteoblasts and osteoclasts are known to adhere tenaciously to bone surfaces even when the fibrous periosteal covering is removed. Brush-smear isolates and in situ, whole bone mounts of the osteogenic periosteum on the inner and outer calvarial tables of young adult rats were examined at the light microscopic level after exposing the cells by removing the fibrous periosteum. Based on staining, enzymatic activity, and overall morphology, most of the cells could be classified as osteogenic in nature. However, detailed analysis revealed that some cells exhibited certain unique morphologic appearances that suggested the existence of subpopulations or variant forms of the conventional or prototypic osteoblast. Three variant forms were the large nucleate, small nucleate, and multinucleate osteoblast-like cells, the latter with nuclear numbers ranging from 2-10. The finding of all such forms in smears, short-term cell cultures, and in situ specimens greatly lessened the probability that the unusual forms were artifactual. Phase contrast microscopic studies and sectioning of cellular isolates for study at both the light and electron microscopic levels provided additional support for the existence of the multinucleate osteoblast-like cell. The small size of these osteoblast-like subpopulations and the orientation of the cells to the commonly used plane of section of most histologic bone specimens, particularly with the multinucleate type, could explain why they had escaped earlier detection. 相似文献
389.
Growth and the efficiency of root respiration of Pisum sativum as dependent on the source of nitrogen 总被引:1,自引:0,他引:1
Growth and efficiency of root respiration were investigated in Pisum sativum L. cv. Alaska and cv. Rondo. Plants were grown in culture solutions, either in symbiosis with Rhizobium leguminosanm , or with an abundant supply of nitrate or ammonium and completely lacking nodules. In comparison with plants utilizing nitrate or ammonium, Ni-fixing plants showed lower rates of dry matter and nitrogen accumulation, as well as lower rates of total and cytochrome-mediated root respiration. Rates of shoot dry matter accumulation and root respiration in plants utilizing ammonium were lower than in plants utilizing nitrate. The efficiency of root respiration was high in N2 -fixing plants, as indicated by a low activity of the SHAM-sensitive, alternative, non-phosphorylating pathway. In nitrate and ammonium grown plants of cv. Alaska, the efficiency of root respiration was about the same, and in both cases lower than in N2 -fixing plants. The efficiency of root respiration in non-symbiotically grown pea plants was generally higher than in many non-legumes. Comparison of the ATP costs of synthesis of root dry matter for different N-sources was complicated by large differences in relative growth rate of the root and in shoot to root ratio between N-treatments. A quantitative correction of the ATP production during synthesis of root dry matter for differences in shoot to root ratio and root maintenance respiration has been made. It is concluded that ATP costs of root dry matter production are highest in the case of N2 -fixing plants. In plants utilizing ammonium, ATP costs of synthesis of root dry matter were slightly lower than in plants utilizing nitrate. The physiological significance of the alternative pathway in root metabolism is discussed in relation to the assimilation of different sources of nitrogen. 相似文献
390.
Ayeleth Reshef Henrik Nissen Liat Triger Torben Stiig Hensen Osnat Eliav Danny Schurr Rifaat Safadi Meir Gare E. Leitersdorf 《Human genetics》1996,98(5):581-586
Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by a multitude of low density lipoprotein receptor
(LDL-R) mutations. The purpose of the current investigation was to define the spectrum of mutations causing FH in Israel and
determine their relative distribution among diverse origin groups. A total of 193 FH families were recruited in Israel, 54
of them through the MED PED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDL-R using single-strand
conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) or both has been completed in 95 index
cases. This analysis resulted in the identification of 15 LDL receptor mutations, including 7 novel mutations (del 197, C308G,
R385W, splice junction mutation of intron 14, del 328, del 502–505, stop 10, del 165), that were present in 49 index cases
(52%). The 15 mutations are mapped to three known functional domains of the receptor (7 in the LDL-binding region, 7 in the
epidermal growth factor precursor homology region and 1 in the membrane-spanning region). Screening for the identified mutations
in the remaining 98 index cases enabled the molecular diagnosis of 31 additional cases. It is therefore concluded that 80
out of 193 index cases (41%) harbor 1 of the 15 mutations described here. Three mutations – del197 (FH-Lithuania), D147H (FH-Sephardic), and stop660 (Lebanese allele) – were found in a total of 66 index cases (34%); these may be regarded as founder mutations in the three
respective origin groups. In conclusion, in Israel molecular heterogeneity at the LDL receptor gene locus reflects the ethnic
distribution of its origin groups. The results of the present investigation provide valuable diagnostic tools for a subset
of the Israeli patients with FH who are at high risk for atherosclerosis and its complications.
Received: 1 February 1996 / Revised: 22 May 1996 相似文献