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101.
Grella B Teitler M Smith C Herrick-Davis K Glennon RA 《Bioorganic & medicinal chemistry letters》2003,13(24):4421-4425
A series of ring-substituted (i.e., methoxy and bromo) 3,4-dihydro- and 1,2,3,4-tetrahydro-β-carbolines was examined at 5-HT2A and 5-HT2C serotonin receptors. Whereas most of the methoxy-substituted derivatives typically displayed affinities similar to their unsubstituted parents, certain (particularly 8-substituted) bromo derivatives displayed enhanced affinity. A binding profile was obtained for selected β-carbolines. 相似文献
102.
Rahman AA Daoud MK Dukat M Herrick-Davis K Purohit A Teitler M do Amaral AT Malvezzi A Glennon RA 《Bioorganic & medicinal chemistry letters》2003,13(6):1119-1123
The present investigation examined two features of arylbiguanide and arylguanidine 5-HT(3) ligands: conformation and partition coefficients. Several conformationally-constrained analogues of mCPBG (2) and mCPG (11; K(i)=32 nM) were prepared and of these only 2-amino-5-chloro-3,4-dihydroquinazoline (14; K(i)=34 nM) retained high affinity. The partition coefficient of compound 11 (LogP(app)=-0.64) was less than that of its corresponding arylbiguanide 2 (LogP(app)=-0.38). The quinazoline structure may represent a pharmacologically-active conformation of these agents, and the arylbiguanides were found more lipid soluble than their arylguanidine counterparts at physiological pH. 相似文献
103.
Human scFv antibody fragments specific for the epithelial tumour marker MUC-1, selected by phage display on living cells 总被引:4,自引:0,他引:4
Wong C Waibel R Sheets M Mach JP Finnern R 《Cancer immunology, immunotherapy : CII》2001,50(2):93-101
New anti-cancer agents are being developed that specifically recognise tumour cells. Recognition is dependent upon the enhanced
expression of antigenic determinants on the surface of tumour cells. The tumour exposure and the extracellular accessibility
of the mucin MUC-1 make this marker a suitable target for tumour diagnosis and therapy. We isolated and characterised six
human scFv antibody fragments that bound to the MUC-1 core protein, by selecting a large naive human phage display library
directly on a MUC-1-expressing breast carcinoma cell line. Their binding characteristics have been studied by ELISA, FACS
and indirect immunofluorescence. The human scFv antibody fragments were specific for the tandem repeat region of MUC-1 and
their binding is inhibited by soluble antigen. Four human scFv antibody fragments (M2, M3, M8, M12) recognised the hydrophilic
PDTRP region of the MUC-1 core protein, which is thought to be an immunodominant region. The human scFv antibody fragments
were stable in human serum at 37 °C and retained their binding specificity.
For imaging or targeting to tumours over-expressing MUC-1, it might be feasible to use these human scFv, or multivalent derivatives,
as vehicles to deliver anti-cancer agents.
Received: 2 November 2000 / Accepted: 11 January 2001 相似文献
104.
The Rheb GTPase is most similar in primary sequence to the Ras, Rap, R-Ras, and Ral GTPases, which regulate cell growth and differentiation in many cell types. A likely fission yeast homologue of mammalian Rheb, which we designated Rhb1, was identified by genome sequencing. Our investigation of rhb1 showed that rhb1(-) cells arrested cell growth and division with a terminal phenotype similar to that of nitrogen-starved cells. In particular, cells depleted of Rhb1 arrested as small, round cells with 1N DNA content, arrested more quickly in low-nitrogen medium, and induced expression of fnx1 and mei2 mRNA, two mRNAs that were normally induced by nitrogen starvation. Since mammalian Rheb binds and may regulate Raf-1, a Ras effector, we tested for functional overlap between Ras1 and Rhb1 in fission yeast. This analysis showed that Ras1 overexpression did not suppress rhb1(-) mutant phenotypes, Rhb1 overexpression did not suppress ras1(-) mutant phenotypes, and ras1(-) rhb1(-) double mutants had phenotypes equal to the sum of the corresponding single-mutant phenotypes. Hence, there is no evidence for overlapping functions between Ras1 and Rhb1. On the basis of this study, we hypothesize that Rhb1 negatively regulates entry into stationary phase when extracellular nitrogen levels are adequate for growth. If this hypothesis is correct, then Rhb1 and Ras1 regulate alternative responses to limiting nutrients. 相似文献
105.
Peter W. Schiller Ralf Schmidt Grazyna Weltrowska Irena Berezowska Thi M.-D. Nguyen Sébastien Dupuis Nga N. Chung Carole Lemieux Brian C. Wilkes Katharine A. Carpenter 《Letters in Peptide Science》1998,5(2-3):209-214
Novel conformationally constrained opioid peptide analogs with antagonist, mixed agonist/ antagonist or agonist properties were developed. TIP(P)-related antagonists showed unprecedented antagonist potency and receptor selectivity, and may have potential for use in analgesia in combination with agonists. A definitive model of their receptor-bound conformation was developed. Three prototype mixed agonist/ antagonists were discovered. They represent the only known compounds with this pharmacological profile and, as expected, one of them was shown to be a potent analgesic and to produce no dependence and less tolerance than morphine. Novel dipeptide derivatives turned out to be potent and selective agonists. Because of their low molecular weight and lipophilic character, these compounds may cross the blood-brain barrier and, thus, may have potential as centrally acting analgesics. 相似文献
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108.
Previous studies have suggested that negative feedback is more effective in driving learning than positive feedback. We investigated the effect on learning of providing varying amounts of negative and positive feedback while listeners attempted to discriminate between three identical tones; an impossible task that nevertheless produces robust learning. Four feedback conditions were compared during training: 90% positive feedback or 10% negative feedback informed the participants that they were doing equally well, while 10% positive or 90% negative feedback informed them they were doing equally badly. In all conditions the feedback was random in relation to the listeners’ responses (because the task was to discriminate three identical tones), yet both the valence (negative vs. positive) and the probability of feedback (10% vs. 90%) affected learning. Feedback that informed listeners they were doing badly resulted in better post-training performance than feedback that informed them they were doing well, independent of valence. In addition, positive feedback during training resulted in better post-training performance than negative feedback, but only positive feedback indicating listeners were doing badly on the task resulted in learning. As we have previously speculated, feedback that better reflected the difficulty of the task was more effective in driving learning than feedback that suggested performance was better than it should have been given perceived task difficulty. But contrary to expectations, positive feedback was more effective than negative feedback in driving learning. Feedback thus had two separable effects on learning: feedback valence affected motivation on a subjectively difficult task, and learning occurred only when feedback probability reflected the subjective difficulty. To optimize learning, training programs need to take into consideration both feedback valence and probability. 相似文献
109.
Hamed Mehdipoor Raul Zurita-Milla Alyssa Rosemartin Katharine L. Gerst Jake F. Weltzin 《PloS one》2015,10(10)
Recent improvements in online information communication and mobile location-aware technologies have led to the production of large volumes of volunteered geographic information. Widespread, large-scale efforts by volunteers to collect data can inform and drive scientific advances in diverse fields, including ecology and climatology. Traditional workflows to check the quality of such volunteered information can be costly and time consuming as they heavily rely on human interventions. However, identifying factors that can influence data quality, such as inconsistency, is crucial when these data are used in modeling and decision-making frameworks. Recently developed workflows use simple statistical approaches that assume that the majority of the information is consistent. However, this assumption is not generalizable, and ignores underlying geographic and environmental contextual variability that may explain apparent inconsistencies. Here we describe an automated workflow to check inconsistency based on the availability of contextual environmental information for sampling locations. The workflow consists of three steps: (1) dimensionality reduction to facilitate further analysis and interpretation of results, (2) model-based clustering to group observations according to their contextual conditions, and (3) identification of inconsistent observations within each cluster. The workflow was applied to volunteered observations of flowering in common and cloned lilac plants (Syringa vulgaris and Syringa x chinensis) in the United States for the period 1980 to 2013. About 97% of the observations for both common and cloned lilacs were flagged as consistent, indicating that volunteers provided reliable information for this case study. Relative to the original dataset, the exclusion of inconsistent observations changed the apparent rate of change in lilac bloom dates by two days per decade, indicating the importance of inconsistency checking as a key step in data quality assessment for volunteered geographic information. Initiatives that leverage volunteered geographic information can adapt this workflow to improve the quality of their datasets and the robustness of their scientific analyses. 相似文献
110.