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1.
Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity agonist (HiAg) and a low affinity agonist (LowAg) state. The formation of the HiAg state is promoted by agonists, and the formation of this state of the receptor appears to be a critical factor in the generation of the effector-activating complex G alpha.GTP.Mg2+ and in the production of a stimulus. The magnitude of the difference in the affinity a compound has for the HiAg versus the LowAg state of the receptor has been related to the intrinsic activity of the compound. In this paper the HiAg and LowAg affinities (Ki) of full and partial dopamine agonists of varying levels of intrinsic activity were determined using membranes from Chinese hamster ovary cells stably transfected with the D2i receptor. The HiAg state was defined using the recently described dopamine agonist ligand [3H]U-86170, and the LowAg state was defined using [3H] raclopride plus 600 microM GTP. The LowAg/HiAg ratios for apomorphine (43), HW-165 (12.5), (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(-)-3-PPP] (4.5), terguride (1.6), SDZ-208-911 (1.2), and SDZ-208-912 (0.3) were found to correlate well with their electrophysiologically derived intrinsic activities (r = 0.92). Using this relationship, the intrinsic activity for compounds such as (+)-3-PPP (112%), quinpirole (104%), U-68553B (102%), and U-86170 (95%) was predicted to be high (greater than 90%); (-)-apomorphine (73%) was of high/moderate intrinsic activity, HW-165 (52%), (+)-apomorphine (51%), and (-)-3-PPP (34%) were in the intermediate range, and terguride (16.5%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were at the lower end of the intrinsic activity spectrum. The receptor state binding-determined intrinsic activity values for quinpirole (100%), U-86170F (94.8%), HW-165 (52.1%), (-)-3-PPP (34.3%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were found to correlate well (r = 0.908) with their maximum response (intrinsic activity), as determined using ATP-mediated increases in arachidonic acid release from CHO-D2i cells. In addition, the maximal effect of several of these compounds on rat striatal homovanillic acid (HVA) levels was determined. The drug-induced changes in tissue HVA levels were found to be consistent with the affinity-derived intrinsic activities of the drugs.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
2.
Analysis of the floral transcriptome uncovers new regulators of organ determination and gene families related to flower organ differentiation in Gerbera hybrida (Asteraceae)
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Laitinen RA Immanen J Auvinen P Rudd S Alatalo E Paulin L Ainasoja M Kotilainen M Koskela S Teeri TH Elomaa P 《Genome research》2005,15(4):475-486
Development of composite inflorescences in the plant family Asteraceae has features that cannot be studied in the traditional model plants for flower development. In Gerbera hybrida, inflorescences are composed of morphologically different types of flowers tightly packed into a flower head (capitulum). Individual floral organs such as pappus bristles (sepals) are developmentally specialized, stamens are aborted in marginal flowers, petals and anthers are fused structures, and ovaries are located inferior to other floral organs. These specific features have made gerbera a rewarding target of comparative studies. Here we report the analysis of a gerbera EST database containing 16,994 cDNA sequences. Comparison of the sequences with all plant peptide sequences revealed 1656 unique sequences for gerbera not identified elsewhere within the plant kingdom. Based on the EST database, we constructed a cDNA microarray containing 9000 probes and have utilized it in identification of flower-specific genes and abundantly expressed marker genes for flower scape, pappus, stamen, and petal development. Our analysis revealed several regulatory genes with putative functions in flower-organ development. We were also able to associate a number of abundantly and specifically expressed genes with flower-organ differentiation. Gerbera is an outcrossing species, for which genetic approaches to gene discovery are not readily amenable. However, reverse genetics with the help of gene transfer has been very informative. We demonstrate here the usability of the gerbera microarray as a reliable new tool for identifying novel genes related to specific biological questions and for large-scale gene expression analysis. 相似文献
3.
The utility of scintigraphic views obtained after administration of sodium bicarbonate-citric acid-simethicone crystals (E-Z-GAS) for the determination of gastric extrahepatic perfusion was evaluated in 20 technetium-99m macroaggregated albumin hepatic arterial perfusion studies performed in 19 patients. These crystals produce carbon dioxide gas, distend the stomach, and allow better delineation of gastric activity (extrahepatic perfusion to the stomach). Conversely, a lack of change in activity in the left upper quadrant after the effervescent crystals have been ingested suggests no gastric activity (and no extrahepatic perfusion to the stomach). These "air-contrast" views added useful information in 16 of 20 studies. In three cases prior hepatic arterial perfusion studies without air contrast were misinterpreted as lacking extrahepatic perfusion, which was only recognized on subsequent studies through the use of the air-contrast views. In another case extrahepatic perfusion was erroneously diagnosed on a hepatic arterial perfusion study without air contrast, with a follow-up air-contrast hepatic arterial perfusion study showing this to have been a false-positive diagnosis. Air-contrast views of the stomach can be extremely helpful in verifying or excluding the diagnosis of gastric extrahepatic perfusion on technetium-99m macroaggregated albumin hepatic arterial perfusion studies. 相似文献
4.
Lipids in the pulmonary circulation were determined biochemically and histologically in seven patients (group A) who died following multiple blunt trauma and in five patients (group B) who died of some other traumatic or nontraumatic cause. Autopsy was performed on average 4.5 hours after death. Blood samples were collected from the right ventricle (RV) and the left atrium (LA). The vasculature of the left lung was perfused in a retrograde direction. The inferior lobe of the right non-perfused lung was examined histologically. Intravascular pulmonary fat was observed in 4/6 cases in group A and in 1/5 cases in group B. No intravascular fat was observed in the tissue samples of brain, liver or kidney. The concentration of free fatty acids (FFA) in blood from RV was higher than in blood from LA both in group A (P is less than 0.01) and in group B (P is less than 0.05). The considerable difference in concentrations of FFA between RV and LA and the low concentration of FFA in the lung perfusate may be due to some kind of "fixation" of FFA in the lung tissue, possibly connected with the aetiological factors of the fat embolism syndrome (FES). 相似文献
5.
R. A. Lahti D. L. Evans L. M. Figur R. M. Huff M. W. Moon 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(5):509-513
Summary The biochemical, endocrine, receptor binding, and behavioral effects of the putative dopamine autoreceptor agonist, U-86170F, were evaluated in various in vivo and in vitro models. U-86170F and apomorphine were shown to cause a significant reversal of the effects of -butyrolactone (GBL) on dopamine accumulation in mouse striata. In contrast to apomorphine, U-86170F had a ceiling effect on the extent of the reversal of GBL effects (55%), whereas apomorphine had an 82% reversal. The effect on striatal homovanillic acid (HVA) levels was also monitored, and both compounds exerted a similar and significant reduction in striatal HVA. A comparison was made between the effects of intraperitoneal (i.p.) and oral administration of U-86170F in the -methyl-p-tyrosine (-MPT)/prolactin model in rats. When administered by the i.p. route, U-86170F suppressed the effects of -MPT on prolactin level increase, having an ED50 of about 0.03 mg/kg, and when administered by the oral route, its ED50 was approximately 0.1 mg/kg. U-86170F has been shown to be a potent dopamine autoreceptor agonist in the GBL, prolactin, and HVA models, with an effective i.p. dose of approximately 0.03 mg/kg. When evaluated for postsynaptic dopaminergic activity in the reserpinized mouse model, and compared to apomorphine, U-86170F was found to increase locomotor activity, but its maximum effect was only 65% of that attained with apomorphine. Higher doses were needed for postsynaptic effects.In receptor binding studies using cloned D2 receptor preparations, U-86170F was found to exhibit agonist binding properties similar to dopamine as demonstrated by their inhibition of 3H-raclopride binding. Both compounds exhibited biphasic inhibition curves, with U-86170F having Ki values of 7.5 nM and 250 nM, and for dopamine the Ki values were 34.7 nM and 1031 nM. Binding studies conducted in the presence of GTP yielded only one site with Kis of 289 nM and 670 nM, for both U-86170F and dopamine, respectively.The results presented in this report demonstrated that U-86170F is a potent dopamine autoreceptor agonist, with limited activity at the postsynaptic receptor.
Send offprint requests to R.A. Lahti at the above address 相似文献
6.
Holcomb HH Lahti AC Medoff DR Weiler M Dannals RF Tamminga CA 《The American journal of psychiatry》2000,157(10):1634-1645
OBJECTIVE: The biological characteristics of schizophrenia are often studied by using functional imaging techniques. However, since volunteers with schizophrenia routinely fail to perform as accurately or as quickly as healthy volunteers, it is difficult to ascertain whether a particular deficit in blood flow to a brain region is due to behavior or to the underlying illness. In this report, investigators used an auditory recognition task to assess brain blood flow patterns and behavioral correlates of schizophrenic patient volunteers trained on the task. METHOD: Twelve healthy volunteers and 18 volunteers with schizophrenia were trained to make tone frequency recognitions. Accuracy and stimuli were matched between groups. Participants were required to press a button to indicate whether a briefly presented tone was the high-frequency (1500 Hz) reference tone or one of a lower frequency level (level chosen to elicit an 80% accuracy score). Subjects underwent bolus [(15)O]H(2)O blood flow positron emission tomography during inactive rest, a sensory motor control condition, and the decision task. Blood flow patterns were assessed between conditions and between groups. RESULTS: As a group, the patients with schizophrenia (who performed as quickly and accurately as the comparison subjects) exhibited significantly less change in regional cerebral blood flow (rCBF) to the anterior cingulate and supplementary motor cortices when switching from the sensory motor control to the decision condition. There were also marked between-group differences in correlations between rCBF and response time. Whereas the comparison subjects exhibited progressively greater blood flow to the frontal cortex in association with longer response times, the schizophrenic patients exhibited progressively lower blood flow in conjunction with extended response times. CONCLUSIONS: The failure to appropriately enhance cingulate activity when engaged in a demanding task and the progressive, time-dependent decline in frontal blood flow suggest that patients with schizophrenia are unable to make optimal use of frontocingulate systems when maximally engaged in high-error tasks. 相似文献
7.
Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. 总被引:5,自引:0,他引:5
Satu M?nnist? Stephanie A Smith-Warner Donna Spiegelman Demetrius Albanes Kristin Anderson Piet A van den Brandt James R Cerhan Graham Colditz Diane Feskanich Jo L Freudenheim Edward Giovannucci R Alexandra Goldbohm Saxon Graham Anthony B Miller Thomas E Rohan Jarmo Virtamo Walter C Willett David J Hunter 《Cancer epidemiology, biomarkers & prevention》2004,13(1):40-48
Intervention trials with supplemental beta-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7-16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. beta-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87-1.11; highest versus lowest quintile). The RRs for alpha-carotene, lutein/zeaxanthin, and lycopene were also close to unity. beta-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67-0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in beta-cryptoxanthin, such as citrus fruit, may modestly lower the risk. 相似文献
8.
Karen M Emmons Rita M Butterfield Elaine Puleo Elyse R Park Ann Mertens Ellen R Gritz Maureen Lahti Fredrick P Li 《Journal of clinical oncology》2003,21(2):189-196
PURPOSE: This article describes baseline data collection and the intervention design of Partnership for Health, a smoking cessation intervention for smokers in the Childhood Cancer Survivors Study. The purpose of this article is to evaluate demographic, psychosocial, and cancer-related factors that are associated with smoking behavior and mediators of smoking cessation. PATIENTS AND METHODS: This study includes 796 smokers from the Childhood Cancer Survivors Study database who were diagnosed with cancer before the age of 21, had survived at least 5 years, and were at least 18 years of age at the time of the baseline survey. Correlates of smoking behaviors included smoking rate, number of recent quit attempts, and nicotine dependence; two key mediators of smoking cessation, readiness to quit smoking and self-efficacy, were also assessed. RESULTS: Participants smoked, on average, 14 cigarettes/day; 53.2% were nicotine dependent, and 58% had made at least one quit attempt in the past year. Smoking behaviors were primarily associated with demographic variables; mediators of cessation were primarily associated with age at cancer diagnosis and perceived vulnerability to smoking-related illnesses. Severity of psychologic symptoms was associated with increased smoking rate, high nicotine dependence, and low self-efficacy. Support for quitting was related to smoking rate, number of quit attempts, readiness to quit smoking, and self-efficacy. CONCLUSION: These findings indicate that many cancer survivors who smoke are receptive to smoking cessation interventions. Factors related to mediators of smoking cessation might be particularly good targets for intervention. 相似文献
9.
10.