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171.
Ruble JC Wakefield BD Kamilar GM Marotti KR Melchior E Sweeney MT Zurenko GE Romero DL 《Bioorganic & medicinal chemistry letters》2007,17(14):4040-4043
The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents which suffered from extensive protein binding has been previously reported. The structure-activity relationships around the carboxylic acid substituent are described herein. This acid was replaced by several alternative functional groups in attempts to retain bioactivity while reducing protein binding. Only groups with an acidic proton retained activity, and analogs containing those groups maintained the protein binding inherent to this class of antibacterial agents. 相似文献
172.
Background
Experimentally determined protein structures may contain errors and require validation. Conformational criteria based on the Ramachandran plot are mainly used to distinguish bet ween distorted and adequately refined models. While the readily available criteria are sufficient to detect totally wrong structures, establishing the more subtle differences between plausible structures remains more challenging. 相似文献173.
M A Findeis G M Musso C C Arico-Muendel H W Benjamin A M Hundal J J Lee J Chin M Kelley J Wakefield N J Hayward S M Molineaux 《Biochemistry》1999,38(21):6791-6800
Cellular toxicity resulting from nucleation-dependent polymerization of amyloid beta-peptide (Abeta) is considered to be a major and possibly the primary component of Alzheimer's disease (AD). Inhibition of Abeta polymerization has thus been identified as a target for the development of therapeutic agents for the treatment of AD. The intrinsic affinity of Abeta for itself suggested that Abeta-specific interactions could be adapted to the development of compounds that would bind to Abeta and prevent it from polymerizing. Abeta-derived peptides of fifteen residues were found to be inhibitory of Abeta polymerization. The activity of these peptides was subsequently enhanced through modification of their amino termini with specific organic reagents. Additional series of compounds prepared to probe structural requirements for activity allowed reduction of the size of the inhibitors and optimization of the Abeta-derived peptide portion to afford a lead compound, cholyl-Leu-Val-Phe-Phe-Ala-OH (PPI-368), with potent polymerization inhibitory activity but limited biochemical stability. The corresponding all-D-amino acyl analogue peptide acid (PPI-433) and amide (PPI-457) retained inhibitory activity and were both stable in monkey cerebrospinal fluid for 24 h. 相似文献
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175.
TGF-beta signaling: positive and negative effects on tumorigenesis. 总被引:34,自引:0,他引:34
TGF-beta binding to the cell surface triggers activation of multiple signal transduction pathways that are connected in intricate ways with each other, and with other response networks involved in sensing cellular information input. Recent data indicate that changes in signal intensity and connectivity of these pathways may underlie the complex transition of the TGF-beta pathway from tumor suppressor to oncogene during tumorigenesis. 相似文献
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177.
Torin Schaafsma Jon Wakefield Rachel Hanisch Freddie Bray Joachim Schüz Edward J. M. Joy Michael J. Watts Valerie McCormack 《PloS one》2015,10(10)
BackgroundThe aetiology of Africa’s easterly-lying corridor of squamous cell oesophageal cancer is poorly understood. Micronutrient deficiencies have been implicated in this cancer in other areas of the world, but their role in Africa is unclear. Without prospective cohorts, timely insights can instead be gained through ecological studies.MethodsAcross Africa we assessed associations between a country’s oesophageal cancer incidence rate and food balance sheet-derived estimates of mean national dietary supplies of 7 nutrients: calcium (Ca), copper (Cu), iron (Fe), iodine (I), magnesium (Mg), selenium (Se) and zinc (Zn). We included 32 countries which had estimates of dietary nutrient supplies and of better-quality GLOBCAN 2012 cancer incidence rates. Bayesian hierarchical Poisson lognormal models were used to estimate incidence rate ratios for oesophageal cancer associated with each nutrient, adjusted for age, gender, energy intake, phytate, smoking and alcohol consumption, as well as their 95% posterior credible intervals (CI). Adult dietary deficiencies were quantified using an estimated average requirements (EAR) cut-point approach.ResultsAdjusted incidence rate ratios for oesophageal cancer associated with a doubling of mean nutrient supply were: for Fe 0.49 (95% CI: 0.29–0.82); Mg 0.58 (0.31–1.08); Se 0.40 (0.18–0.90); and Zn 0.29 (0.11–0.74). There were no associations with Ca, Cu and I. Mean national nutrient supplies exceeded adult EARs for Mg and Fe in most countries. For Se, mean supplies were less than EARs (both sexes) in 7 of the 10 highest oesophageal cancer ranking countries, compared to 23% of remaining countries. For Zn, mean supplies were less than the male EARs in 8 of these 10 highest ranking countries compared to in 36% of other countries.ConclusionsEcological associations are consistent with the potential role of Se and/or Zn deficiencies in squamous cell oesophageal cancer in Africa. Individual-level analytical studies are needed to elucidate their causal role in this setting. 相似文献
178.
Maureen E. Wakefield Howard A. Bell Angharad M. R. Gatehouse 《Agricultural and Forest Entomology》2010,12(1):19-27
- 1 Adult female Eulophus pennicornis require a source of nutrition, provided by sources such as pollen, nectar and honeydew or by host feeding, to promote longevity and facilitate egg production. There is potential for parasitoids to be exposed directly to contaminants, including gene products in transgenic crops, through feeding on plant materials, honeydew or hosts. Among such potential contaminants are lectins such as Galanthus nivalis agglutinin (GNA) and concanavalin agglutinin (Con A).
- 2 The effect of direct exposure to honey diets containing GNA and Con A on the longevity and fecundity of E. pennicornis was examined. These lectins have been expressed in a number of plant species for the control for various insect pests. Both GNA and Con A significantly reduced longevity and fecundity at the highest concentration used (0.5% w/v). The effect on fecundity was shown to be related to a reduction in longevity.
- 3 Examination of the gustatory response of adult female E. pennicornis to honey diet containing 1% w/v GNA or Con A revealed no significant differences in consumption rate on first exposure. A significant reduction in the time spent feeding on diet containing 1% Con A was found on the second exposure to the diet. This could have been the result of either a conditioned aversion response or the intoxication of the insect. The effect of Con A on longevity and fecundity could have been, in part, a result of reduced food intake.
- 4 Studies on nutrition and egg resorption demonstrated that the availability of honey solution prolongs the longevity of E. pennicornis and the lack of a source of nutrition promotes oosorption.
- 5 A greater understanding of feeding behaviour and ovigeny is required to understand fully the potential ecological consequence of transgenic crops on parasitoid species through routes of direct exposure to transgene products.
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180.
Recently, there has been an increased interest in modeling the association between aggregate disease counts and environmental exposures measured, for example via air pollution monitors, at point locations. This paper has two aims: first, we develop a model for such data in order to avoid ecological bias; second, we illustrate that modeling the exposure surface and estimating exposures may lead to bias in estimation of health effects. Design issues are also briefly considered, in particular the loss of information in moving from individual to ecological data, and the at-risk populations to consider in relation to the pollution monitor locations. The approach is investigated initially through simulations, and is then applied to a study of the association between mortality in those over 65 in the year 2000 and the previous year's SO2, in London. We conclude that the use of the proposed model can provide valid inference, but the use of estimated exposures should be carried out with great caution. 相似文献