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243.
Robert W. Brueggemeier Jill M. O'Reilly Carl J. Lovely Patrick J. Ward Anne L. Quinn David Baker Michael V. Darby Xin-Ju Gu Nancy E. Gilbert 《The Journal of steroid biochemistry and molecular biology》1997,61(3-6)
The inhibition of aromatase, the enzyme responsible for converting androgens to estrogens, is therapeutically useful for the endocrine treatment of hormone-dependent breast cancer. Research by our laboratory has focused on developing competitive and irreversible steroidal aromatase inhibitors, with an emphasis on synthesis and biochemistry of 7α-substituted androstenediones. Numerous 7α-thiosubstituted androst-4-ene-3,17-diones are potent competitive inhibitors, and several 1,4-diene analogs, such as 7α-(4′-aminophenylthio)-androsta-1,4-diene-3,17-dione (7α-APTADD), have demonstrated effective enzyme-activated irreversible inhibition of aromatase in microsomal enzyme assays. One focus of current research is to examine the effectiveness and biochemical pharmacology of 7α-APTADD in vivo. In the hormone-dependent 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinoma model system, 7α-APTADD at a 50 mg/kg/day dose caused an initial decrease in mean tumor volume during the first week, and tumor volume remained unchanged throughout the remaining 5-week treatment period. This agent lowers serum estradiol levels and inhibits ovarian aromatase activity. A second research area has focused on the synthesis of more metabolically stable inhibitors by replacing the thioether linkage at the 7α position with a carbon-carbon linkage. Several 7α-arylaliphatic androst-4-ene-3,17-diones were synthesized by 1,6-conjugate additions of appropriate organocuprates to a protected androst-4,6-diene or by 1,4-conjugate additions to a seco-A-ring steroid intermediate. These compounds were all potent inhibitors of aromatase with apparent Kis ranging between 13 and 19 nM. Extension of the research on these 7α-arylaliphatic androgens includes the introduction of a C1---C2 double bond in the A-ring to provide enzyme-activated irreversible inhibitors. The desired 7α-arylaliphatic androsta-1,4-diene-3,17-diones were obtained from their corresponding 7α-arylaliphatic androst-4-ene-3,17-diones by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). These inhibitors demonstrated enzyme-mediated inactivation of aromatase with apparent kinacts ranging from 4.4 × 10−4 to 1.90 x 10−3 s−1. The best inactivator of the series was 7α-phenpropylandrosta-1,4-diene-3,17-dione, which exhibited a T1/2 of 6.08 min. Aromatase inhibition was also observed in MCF-7 human mammary carcinoma cell cultures and in JAr human choriocarcinoma cell cultures, exhibiting IC50 values of 64-328 nM. The 7α-arylaliphatic androgens thus demonstrate potent inhibition of aromatase in both microsomal incubations and in choriocarcinoma cell lines expressing aromatase enzymatic activity. Additionally, the results from these studies provide further evidence for the presence of a hydrophobic binding pocket existing near the 7α-position of the steroid in the active site of aromatase. The size of the 7α-substituent influences optimal binding of steroidal inhibitors to the active site and affects the extent of enzyme-mediated inactivation observed with androsta-1,4-diene-3,17-dione analogs. 相似文献
244.
Chang-Jie Jiang Alan G. Weeds Patrick J. Hussey 《The Plant journal : for cell and molecular biology》1997,12(5):1035-1043
The maize actin depolymerizing factor, ZmADF3, binds G-and F-actin, and increases in vitro actin dynamics. Polyclonal antibodies have been raised against ZmADF3 and these detect a single band of approximately 17 kDa in all maize tissues examined, with the exception of pollen. In the development of root hairs, the distribution of ZmADF3 is related to actin reorganization. In the early stages of hair development, ZmADF3 is distributed throughout the cytoplasm. As the hair emerges and the microfilament bundles redirect to the outgrowth there is a simultaneous redistribution of ZmADF3 which now concentrates at the tip of the emerging hair and remains in this position as elongation proceeds. These observations show that ZmADF3 localizes to a region where actin is being remodelled during tip growth. After cytochalasin D treatment which disrupts actin filaments, short rods of ZmADF3 and actin appear in the nucleus suggesting that ZmADF3 may function by guiding actin to sites of actin polymerization. 相似文献
245.
Ave Patrick Colucci-Guyon Emma Babinet Charles Huerre Michel-Rene 《Transgenic research》1997,6(1):37-40
The Escherichia coli -galactosidase gene is frequently used as a reporter gene in transgenic studies because its activity can be easily detected at the cellular level. Here we report a procedure for monitoring -galactosidase activity directly in tissue sections, which involves the use of a mixture of ethanol and poly-ethylene-glycol as a fixative (Kryofix) and a special paraffin characterized by a lower fusion point of 42 °C. After embedding and cutting, the sections are stained by the chromogenic substrate 5-bromo-4-chloro-3-indoyl--d galactopyranoside (X-Gal). This procedure allows both the retention of a high level of -galactosidase activity and the preservation of good tissue morphology. Furthermore, it can be combined with immunohistochemical methods to detect other cellular components without compromising reporter gene detection 相似文献
246.
Incipient Speciation by Sexual Isolation in Drosophila Melanogaster: Extensive Genetic Divergence without Reinforcement
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The collection of Drosophila melanogaster from Zimbabwe and nearby regions (the Z-type) yield females who would not mate with the cosmopolitan D. melanogaster males (the M-type). To dissect the genetic basis of this sexual isolation, we constructed 16 whole-chromosome substitution lines between two standard Z-and M-lines. The results were as follows: (1) All substitution lines appear normal in viability and fertility in both sexes, indicating no strong postmating isolation. (2) The genes for the behaviors are mapped to all three major chromosomes with the same ranking and comparable magnitude of effects for both sexes: III > II >> X >/= 0 (III, II and X designate the effects of the three chromosomes). The results suggest less evolution on the X than on autosomes at loci of sexual behavior. (3) The genes for ``Z-maleness' are many and somewhat redundant. Whole-chromosome effects for Z-maleness appear nearly additive and show little dominance. (4) In contrast, ``Z-femaleness' has less redundancy as partial genotypes never exhibit full phenotypic effects. Epistatic interactions and incomplete dominance can sometimes be detected. (5) The extensive genetic divergence underlying sexual isolation has evolved in the absence of detectable reduction in hybrid fitnesses. Sexual selection has apparently been a driving force of multiple facets of speciation at the nascent stage without reinforcement. 相似文献
247.
George V. Triantaphyllidis Godelieve R. J. Criel Theodore J. Abatzopoulos Patrick Sorgeloos 《Hydrobiologia》1997,357(1-3):155-163
Eleven morphometric and one meristic character in 15 parthenogeneticArtemia populations have been studied by using discriminant andcluster analysis as well as scanning electron microscopy.Discriminant analysis revealed five main groups of morphologicalpatterns: (i) the coastal Chinese populations together with apopulation from Kazakhstan, (ii) the inland Chinese salt lakepopulations, (iii) the Greek populations, (iv) one African populationfrom Namibia and (v) a Chinese population from Xuyu (Jiangsuprovince). Cluster analysis was not always in agreement withdiscriminant analysis and these results are discussed. 相似文献
248.
Pickering Gisele P.; Fellmann Nicole; Morio Beatrice; Ritz Patrick; Amonchot Aime; Vermorel Michel; Coudert Jean 《Journal of applied physiology》1997,83(4):1300-1306
Pickering, Gisèle P., Nicole Fellmann, BéatriceMorio, Patrick Ritz, Aimé Amonchot, Michel Vermorel, and JeanCoudert. Effects of endurance training on the cardiovascularsystem and water compartments in elderly subjects. J. Appl. Physiol. 83(4): 1300-1306, 1997.Theeffects of endurance training on the water compartments and thecardiovascular system were determined in 10 elderly subjects [age62 ± 2 yr, pretraining maximal oxygen consumption(O2 max)/kg = 25 ± 2 ml · min1 · kg1body wt]. They trained on a cycloergometer 3 times/wk for 16 wk(50-80%O2 max,then 80-85%O2 max). They werechecked at 8 wk, 16 wk, and 4 mo after detraining. Training improvedO2 max (+16%) andinduced plasma volume expansion (+11%). No change in total body water,extracellular fluid, interstitial and intracellular fluid volumes,fat-free mass, and body weight was detected in this small sample withtraining. Body fat mass decreased (2.1 ± 2.2 kg).Echocardiography at rest showed increased fractional shortening andejection fraction and decreased left ventricular end-systolic dimension(P < 0.05). Blood volume expansioncorrelates with cardiac contractility and has an impact on cardiacfunction. These improvements are precarious, however, and arecompletely lost after 4 mo of detraining, when elderly subjects losethe constraints and the social stimulation of the imposed protocol. 相似文献
249.
Sublocalization of an Ataxia-Telangiectasia Gene Distal to D11S384 by Ancestral Haplotyping In Costa Rican Families 总被引:8,自引:4,他引:4
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Nancy Uhrhammer Ethan Lange Oscar Porras Arash Naeim Xiaoguang Chen Sepideh Sheikhavandi Sujata Chiplunkar Lan Yang Sugandha Dandekar Teresa Liang Nima Patel Sharon Teraoka Nitin Udar Nidia Calvo Patrick Concannon Kenneth Lange Richard A. Gatti 《American journal of human genetics》1995,57(1):103-111
In an effort to localize a gene for ataxia-telangiectasia (A-T), we have genotyped 27 affected Costa Rican families, with 13 markers, in the chromosome 11q22-23 region. Significant linkage disequilibrium was detected for 9/13 markers between D11S1816 and D11S1391. Recombination events observed in these pedigrees places A-T between D11S1819 and D11S1960. One ancestral haplotype is common to 24/54 affected chromosomes and roughly two-thirds of the families. Inferred (ancestral) recombination events involving this common haplotype in earlier generations suggest that A-T is distal to D11S384 and proximal to D11S1960. Several other common haplotypes were identified, consistent with multiple mutations in a single gene. When considered together with all other evidence, this study further sublocalizes the major A-T locus to ≈200 kb, between markers S384 and S535. 相似文献
250.
Mapping of a Gene for Long QT Syndrome to Chromosome 4q25-27 总被引:21,自引:0,他引:21
Jean-Jacques Schott Flavien Charpentier Sophie Peltier Patrick Foley Emmanuel Drouin Jean-Brieuc Bouhour Patricia Donnelly Gilles Vergnaud Lucien Bachner Jean-Paul Moisan Herv Le Marec Olivier Pascal 《American journal of human genetics》1995,57(5):1114-1122
Long QT syndrome (LQTS) is a heterogeneous inherited disorder causing syncope and sudden death from ventricular arrhythmias. A first locus for this disorder was mapped to chromosome 11p15.5. However, locus heterogeneity has been demonstrated in several families, and two other loci have recently been located on chromosomes 7q35-36 and 3p21-24. We used linkage analysis to map the locus in a 65-member family in which LQTS was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction. Linkage to chromosome 11p15.5, 7q35-36, or 3p21-24 was excluded. Positive linkage was obtained for markers located on chromosome 4q25-27. A maximal LOD score of 7.05 was found for marker D4S402. The identification of a fourth locus for LQTS confirms its genetic heterogeneity. Locus 4q25-27 is associated with a peculiar phenotype within the LQTS entity. 相似文献