The Neurofibromatosis 2 (NF2) gene product merlin is a tumour suppressor, which in addition to inhibiting cell proliferation regulates cell morphology. The morphogenic properties of merlin may play a role in tumour suppression, as patient-derived tumour cells demonstrate cytoskeletal abnormalities. However, it is still unclear how these functions are linked. The N-terminal FERM-domain of merlin is highly homologous to the oncogenic protein ezrin, while the C-termini are less conserved, suggesting that the opposite effect of the proteins on proliferation could be mediated by their distinct C-terminal regions. In this study we characterize the role of the most C-terminal residues of merlin in the regulation of proliferation, cytoskeletal organization, phosphorylation and intramolecular associations. In addition to the two full-length merlin isoforms and truncating mutations found in patients, we focused on the evolutionally conserved C-terminal residues 545-547, also harbouring disease-causing mutations. We demonstrate that merlin induces cell extensions, which result from impaired retraction of protrusions rather than from increased formation of filopodia. The residues 538-568 were found particularly important for this morphogenic activity. The results further show that both merlin isoforms are able to equally inhibit proliferation, whereas C-terminal mutants affecting residues 545-547 are less effective in growth suppression. This study demonstrates that the C-terminus contains distinct but overlapping functional domains important for regulation of the morphogenic activity, intramolecular associations and cell proliferation. 相似文献
In pregnant women, Plasmodium falciparum infections are an important cause of maternal morbidity as well as fetal and neonatal mortality. Erythrocytes infected by these malaria-causing parasites accumulate through adhesive interactions in placental intervillous spaces, thus evading detection in peripheral blood smears. Sequestered infected erythrocytes induce inflammation, offering the possibility of detecting inflammatory mediators in peripheral blood that could act as biomarkers of placental infection. In a longitudinal, prospective study in Tanzania, we quantified a range of different cytokines, chemokines and angiogenic factors in peripheral plasma samples, taken on multiple sequential occasions during pregnancy up to and including delivery, from P. falciparum-infected women and matched uninfected controls. The results show that during healthy, uninfected pregnancies the levels of most of the panel of molecules we measured were largely unchanged except at delivery. In women with P. falciparum, however, both comparative and longitudinal assessments consistently showed that the levels of IL-10 and IP-10 increased significantly whilst that of RANTES decreased significantly, regardless of gestational age at the time the infection was detected. ROC curve analysis indicated that a combination of increased IL-10 and IP-10 levels and decreased RANTES levels might be predictive of P. falciparum infections. In conclusion, our data suggest that host biomarkers in peripheral blood may represent useful diagnostic markers of P. falciparum infection during pregnancy, but placental histology results would need to be included to verify these findings. 相似文献
Currently there is a great interest in using scanning probe microscopy to study living cells. However, in most cases the contact the probe makes with the soft surface of the cell deforms or damages it. Here we report a scanning ion conductance microscope specially developed for imaging living cells. A key feature of the instrument is its scanning algorithm, which maintains the working distance between the probe and the sample such that they do not make direct physical contact with each other. Numerical simulation of the probe/sample interaction, which closely matches the experimental observations, provides the optimum working distance. The microscope scans highly convoluted surface structures without damaging them and reveals the true topography of cell surfaces. The images resemble those produced by scanning electron microscopy, with the significant difference that the cells remain viable and active. The instrument can monitor small-scale dynamics of cell surfaces as well as whole-cell movement. 相似文献
The scaffolding protein gephyrin is a core component of many inhibitory synapses.Bai and colleagues now show that phase separation of gephyrin with the subunits... 相似文献
Context: Genotoxicity assays are widely employed in human biomonitoring studies to assess genetic damage inflicted by genotoxic agents.
Objective: Evaluation of micronuclei (MN) as a screening marker of occupational ionizing radiation (IR) exposure.
Materials and methods: Using micronucleus test, peripheral blood lymphocytes (PBL) of 402 control and exposed subjects were screened for genetic damage.
Results: The mean frequencies of micronucleus test parameters were significantly higher in exposed persons. Increase of micronucleus yield with duration of exposure (DOE) by 0.303MN/year was revealed.
Discussion and conclusion: The obtained data encourage us to consider MN as valuable markers for preventive medical screening of occupationally exposed groups. 相似文献
This paper examines age patterns of first marriage and motherhood and covariates of early marriage, delayed consummation of marriage and early motherhood in Nepal using data from the 2000 Nepal Adolescent and Young Adult Survey (NAYA). Both unmarried and married male and female youths (age 14-22) were included in the survey. The analysis is based on 2800 urban youths and 5075 rural youths with complete information on the variables examined. Proportional hazard models are used to estimate covariates of early marriage and early motherhood, and logistic regression models are used to estimate covariates of delayed consummation of marriage. The results show that early marriage and early motherhood are quite common among Nepalese women, especially in rural areas. Early marriage is much less common among men. Delayed consummation of marriage is common among very young brides, especially in rural areas. The main covariates associated with early marriage and early motherhood are respondent's education, region of residence and ethnicity. The main covariates of delayed consummation of marriage are age at first marriage, region of residence and ethnicity. The study highlights the need to focus on less educated female youths in the Terai region in order to reduce the reproductive and child health risks associated with early marriage and early childbearing. 相似文献
We examined whether behavioral sensitization to amphetamine is associated with redistribution of glutamate receptors (GluR) in the rat nucleus accumbens (NAc) or dorsolateral striatum (DLSTR). Following repeated amphetamine treatment and 21 days of withdrawal, surface and intracellular levels of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or NMDA receptor subunits were determined using a protein cross-linking assay. In contrast to our previous results in cocaine-sensitized rats, we did not observe redistribution of GluR1 or GluR2 to the cell surface in the NAc after amphetamine withdrawal, although a small increase in total GluR1 was found in the shell subregion. Nor did we observe activation of signaling pathways associated with cocaine-induced AMPA receptor trafficking or changes in NMDA receptor subunits. No significant changes were observed in the DLSTR. We also investigated the effect of administering a challenge injection of amphetamine to amphetamine-sensitized rats 24 h prior to biochemical analysis based on prior studies showing that cocaine challenge decreases AMPA receptor surface expression in the NAc of cocaine-sensitized rats. GluR1 and GluR2 were not significantly altered in either NAc or DLSTR, although a modest effect on GluR3 cannot be ruled out. Our results suggest that glutamate transmission in the NAc is dramatically different in rats sensitized to amphetamine versus cocaine. 相似文献