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Background
Long-lasting insecticidal nets (LLINs) reduce malaria transmission by protecting individuals from infectious bites, and by reducing mosquito survival. In recent years, millions of LLINs have been distributed across sub-Saharan Africa (SSA). Over time, LLINs decay physically and chemically and are destroyed, making repeated interventions necessary to prevent a resurgence of malaria. Because its effects on transmission are important (more so than the effects of individual protection), estimates of the lifetime of mass distribution rounds should be based on the effective length of epidemiological protection.Methods
Simulation models, parameterised using available field data, were used to analyse how the distribution's effective lifetime depends on the transmission setting and on LLIN characteristics. Factors considered were the pre-intervention transmission level, initial coverage, net attrition, and both physical and chemical decay. An ensemble of 14 stochastic individual-based model variants for malaria in humans was used, combined with a deterministic model for malaria in mosquitoes.Results
The effective lifetime was most sensitive to the pre-intervention transmission level, with a lifetime of almost 10 years at an entomological inoculation rate of two infectious bites per adult per annum (ibpapa), but of little more than 2 years at 256 ibpapa. The LLIN attrition rate and the insecticide decay rate were the next most important parameters. The lifetime was surprisingly insensitive to physical decay parameters, but this could change as physical integrity gains importance with the emergence and spread of pyrethroid resistance.Conclusions
The strong dependency of the effective lifetime on the pre-intervention transmission level indicated that the required distribution frequency may vary more with the local entomological situation than with LLIN quality or the characteristics of the distribution system. This highlights the need for malaria monitoring both before and during intervention programmes, particularly since there are likely to be strong variations between years and over short distances. The majority of SSA's population falls into exposure categories where the lifetime is relatively long, but because exposure estimates are highly uncertain, it is necessary to consider subsequent interventions before the end of the expected effective lifetime based on an imprecise transmission measure. 相似文献23.
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Regulation of the specific DNA binding function of p53. 总被引:95,自引:0,他引:95
The DNA binding activity of p53 is required for its tumor suppressor function; we show here that this activity is cryptic but can be activated by cellular factors acting on a C-terminal regulatory domain of p53. A gel mobility shift assay demonstrated that recombinant wild-type human p53 binds DNA sequence specifically only weakly, but a monoclonal antibody binding near the C terminus activated the cryptic DNA binding activity stoichiometrically. p53 DNA binding could be activated by a C-terminal deletion of p53, mild proteolysis of full-length p53, E. coli dnaK (which disrupts protein-protein complexes), or casein kinase II (and coincident phosphorylation of a C-terminal site on p53). Activation of p53 DNA binding may be critical in regulation of its ability to arrest cell growth and thus its tumor suppressor function. 相似文献
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A cultured rat ovarian cell line (31 A-F(2)) was used to study the effect of growth factors (epidermal growth factor [EGF] and fibroblast growth factor [FGF]), a survival factor (ovarian growth factor [OGF]), a hormone (insulin), and an iron-binding protein (transferring) on cell proliferation and steroid production under defined culture conditions. EGF and insulin were shown to be mitogenic (half-maximal response at 0.12 nM and 0.11 muM, respectively) for 31A-F(2) cells incubated in serum-free medium. EGF induced up to three doublings in the cell population, whereas insulin induced an average of one cell population doubling. FGF, OGF, and transferrin were found not to have any prominent effect on cell division when incubated individually with 31A-F(2) cells in serum-free medium. However, a combination of EGF, OGF, insulin, and transferrin stimulated cell division to the same approximate extent as cells incubated in the presence of 5 percent fetal calf serum. EGF or insulin did not significantly affect total cell cholesterol levels (relative to cells incubated in serum-free medium) when incubated individually with 31A-F(2) cells. However, cell cholesterol levels were increased by the addition of OGF (250 percent), FGF (370 percent), or a combination of insulin and EGF (320 percent). Progesterone secretion from 31A-F(2) cells was enhanced by EGF (25 percent), FGF (80 percent), and insulin (115 percent). However, the addition of a mitogenic mixture of EGF, OGF, insulin, and transferrin suppressed progesterone secretion 150 percent) below that of control cultures. These studies have permitted us to determine that EGF and insulin are mitogenic factors that are required for the growth of 31A-F(2) cells and that OGF and transferrin are positive cofactors that enhance growth. Also, additional data suggest that cholesterol and progesterone production in 31A-F(2) cells can be regulated by peptide growth factors and the hormone insulin. 相似文献
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Human tissue kallikreins (KLKs) are members of a multigene family of serine proteases aberrantly expressed in many cancer types. In ovarian cancer, 12 KLKs are upregulated, and of those KLK5, 6 and 10 have been the focus of investigations into new diagnostic and prognostic biomarkers. However, little is known about the contributions of KLK5, 6 and 10 to ovarian cancer pathophysiology.In this study, a panel of 13 human ovarian cancer cell lines was screened by ELISA for secretion of KLK5, 6, 8, 10, 13, and 14. The ES-2 cell line, devoid of these kallikreins, was transfected with expression vectors of KLK5, 6 and 10 individually or in pairs. Co-expression of KLK5, 6 and 10 was correlated with lessened aggressivity of ovarian cancer cell lines as defined by reduced colony formation in soft agar and tumorigenicity in nude mice. ES-2 clones overexpressing KLK5, 10/5, 10/6, 5/6 made significantly fewer colonies in soft agar. When compared to control mice, survival of mice injected with ES-2 clones overexpressing KLK10, 10/5, 10/6, 5/6 was significantly longer, while KLK6 was shorter. All groups displaying a survival advantage also differed quantitatively and qualitatively in their presentation of ascites, with both a reduced incidence of ascites and an absence of cellular aggregates within those ascites. The survival advantage conferred by KLK10 overexpression could be recapitulated with the exogenous administration of a recombinant KLK10. In conclusion, these findings indicate that KLK5, 6 and 10 may modulate the progression of ovarian cancer, and interact together to alter tumour pathophysiology. Furthermore, results support the putative role of KLK10 as a tumour suppressor and suggest it may hold therapeutic potential in ovarian cancer. 相似文献
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