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71.
Gravenor MB Lloyd AL Kremsner PG Missinou MA English M Marsh K Kwiatkowski D 《Journal of theoretical biology》2002,217(2):137-148
We describe an age-structured mathematical model of the malaria parasite life cycle that uses clinical observations of peripheral parasitaemia to estimate population dynamics of sequestered parasites, which are hidden from the clinical investigator. First, the model was tested on parasite populations cultured in vitro, and was found to account for approximately 72% of the variation in that sub-population of parasites that would have been sequestered in vivo. Next, the model was applied to patients undergoing antimalarial therapy. Using individual data sets we found that although the model fitted the peripheral parasite curves very well, unique solutions for the fit could not be obtained; therefore, robust estimates of sequestered parasite dynamics remained unavailable. We conclude that even given detailed data on individual parasitaemia, estimates of sequestered numbers may be difficult to obtain. However, if data on individuals undergoing similar therapy are collected at equal time intervals, some of these problems may be overcome by estimating specific parameters over groups of patients. In this manner we estimated sequestered parasite density in a group of patients sampled at identical time points following antimalarial treatment. Using this approach we found significant relationships between changes in parasite density, age structure and temperature that were not apparent from the analysis of peripheral parasitaemia only. 相似文献
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A coherent view of the structure and function of DNA polymerase processivity factors (sliding clamps and clamp loaders) is emerging from recent structural studies. Crystal structures of sliding clamps from the T4 and RB69 bacteriophages, and from an archaebacterium expand the gallery of ring-shaped processivity factors and clarify how the clamp interacts with the DNA polymerase. Crystallographic and electron microscopic views of clamp loaders from bacteria, archaebacteria and eukaryotes emphasize their common architecture and have produced models of how ATPbinding might be coupled to clamp opening/loading. 相似文献
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Identification of a histamine H4 receptor on human eosinophils--role in eosinophil chemotaxis 总被引:5,自引:0,他引:5
O'Reilly M Alpert R Jenkinson S Gladue RP Foo S Trim S Peter B Trevethick M Fidock M 《Journal of receptor and signal transduction research》2002,22(1-4):431-448
Eosinophils are recruited to sites of inflammation via the action of a number of chemical mediators, including PAF, leukotrienes, eotaxins, ECF-A and histamine. Although many of the cell-surface receptors for these mediators have been identified, histamine-driven chemotaxis has not been conclusively attributed to any of the three known histamine receptor subtypes, suggesting the possibility of a 4th histamine-responsive receptor on eosinophils. We have identified and cloned a novel G protein-coupled receptor (GPCR), termed Pfi-013, from an IL-5 stimulated eosinophil cDNA library which is homologous to the human histamine H3 receptor, both at the sequence and gene structure level. Expression data indicates that Pfi-013 is predominantly expressed in peripheral blood leukocytes, with lower expression levels in spleen, testis and colon. Ligand-binding studies using Pfi-013 expressed in HEK-293Galpha15 cells, demonstrates specific binding to histamine with a Kd of 3.28 +/- 0.76 nM and possesses a unique rank order of potency against known histaminergic compounds in a competitive ligand-binding assay (histamine > clobenpropit > iodophenpropit > thioperamide > R-alpha-methylhistamine > cimetidine > pyrilamine). We have therefore termed this receptor human histamine H4. Chemotaxis studies on isolated human eosinophils have confirmed that histamine is chemotactic and that agonists of the known histamine receptors (H1, H2, and H3) do not induce such a response. Furthermore, studies employing histamine-receptor antagonists have shown an inhibition of chemotaxis only by the H3 antagonists clobenpropit and thioperamide. Since these compounds are also antagonists of hH4 we postulate that the receptor mediating histaminergic chemotaxis is this novel histamine H4 receptor. 相似文献
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Plants have been propagating themselves by cloning for millennia. It is, however, widely recognised that mixing genes with other individuals of the same species makes better evolutionary sense, as it provides the variation that is the raw material for natural selection. How, then, do some plants prevent self-fertilisation? 相似文献
79.
Risk assessment of GM plants: avoiding gridlock? 总被引:2,自引:0,他引:2
Cultivation of genetically modified crops is presently based largely on four crops containing few transgenes and grown in four countries. This will soon change and pose new challenges for risk assessment. A more structured approach that is as generic as possible is advocated to study consequences of gene flow. Hazards should be precisely defined and prioritized, with emphasis on quantifying elements of exposure. This requires coordinated effort between large, multidisciplinary research teams. 相似文献
80.
Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase 总被引:21,自引:0,他引:21
Cell cycle progression depends on precise elimination of cyclins and cyclin-dependent kinase (CDK) inhibitors by the ubiquitin system. Elimination of the CDK inhibitor Sic1 by the SCFCdc4 ubiquitin ligase at the onset of S phase requires phosphorylation of Sic1 on at least six of its nine Cdc4-phosphodegron (CPD) sites. A 2.7 A X-ray crystal structure of a Skp1-Cdc4 complex bound to a high-affinity CPD phosphopeptide from human cyclin E reveals a core CPD motif, Leu-Leu-pThr-Pro, bound to an eight-bladed WD40 propeller domain in Cdc4. The low affinity of each CPD motif in Sic1 reflects structural discordance with one or more elements of the Cdc4 binding site. Reengineering of Cdc4 to reduce selection against Sic1 sequences allows ubiquitination of lower phosphorylated forms of Sic1. These features account for the observed phosphorylation threshold in Sic1 recognition and suggest an equilibrium binding mode between a single receptor site in Cdc4 and multiple low-affinity CPD sites in Sic1. 相似文献