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1.
Transforming growth factor-β (TGF-β) signaling plays an important role in regulation of a wide variety of cellular processes. Canonical TGF-β signaling is mediated by Smads which were further regulated by several factors. We previously reported that E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein, also named Stub1) controlled the sensitivity of TGF-β signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. Here, we present evidence that Hsp70 and Hsp90 regulate the complex formation of Smad3/CHIP. Furthermore, we observed that over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3, which finally enhances TGF-β signaling. In contrast, over-expressed Hsp90 antagonizes CHIP mediated Smad3 ubiquitination and degradation and desensitizes cells in response to TGF-β signaling. Taken together, our data reveal an opposite role of Hsp70 and Hsp90 in regulating TGF-β signaling by implicating CHIP-mediated Smad3 ubiquitination and degradation. This study provides a new insight into understanding the regulation of the TGF-β signaling by chaperones.  相似文献   
2.
It has been shown that cholesterol modulates activity of protein kinase C (PKC), and PKC phosphorylates connexin 43 (Cx43) to regulate its function, respectively. However, it is not known whether cholesterol modulates function of Cx43 through regulating activity of PKC. In the present study, we demonstrated that cholesterol enrichment reduced the dye transfer ability of Cx43 in cultured H9c2 cells. Western blot analysis indicated that cholesterol enrichment enhanced the phosphorylated state of Cx43. Immunofluorescent images showed that cholesterol enrichment made the Cx43 distribution from condensed to diffused manner in the interface between the cells. In cholesterol enriched cells, PKC antagonists partially restored the dye transfer ability among the cells, downregulated the phosphorylation of Cx43 and redistributed Cx43 from the diffused manner to the condensed manner in the cell interface. In addition, reduction of cholesterol level suppressed PKC activity to phosphorylate Cx43 and restored Cx43 function in PKC agonist-treated cells. Furthermore, we demonstrated that cholesterol enrichment upregulated the phosphorylated state of Cx43 at Ser368, while PKC antagonists reversed the effect. Taken together, cholesterol level in the cells plays important roles in regulating Cx43 function through activation of the PKC signaling pathway.  相似文献   
3.
KPC-producing Klebsiella pneumoniae isolates have emerged as important pathogens of nosocomial infections, and tigecycline is one of the antibiotics recommended for severe infections caused by KPC-producing K. pneumoniae. To identify the susceptibility profile of KPC-producing K. pneumoniae to tigecycline and investigate the role of efflux pumps in tigecycline resistance, a total of 215 KPC-producing K. pneumoniae isolates were collected. The minimum inhibitory concentration (MIC) of tigecycline was determined by standard broth microdilution tests. Isolates showing resistance to tigecycline underwent susceptibility test with efflux pump inhibitors. Expression levels of efflux pump genes (acrB and oqxB) and their regulators (ramA, marA, soxS and rarA) were examined by real-time PCR, and the correlation between tigecycline MICs and gene expression levels were analysed. Our results show that the tigecycline resistance rate in these isolates was 11.2%. Exposure of the tigecycline-resistant isolates to the efflux pump inhibitor NMP resulted in an obvious decrease in MICs and restored susceptibility to tigecycline in 91.7% of the isolates. A statistically significant association between acrB expression and tigecycline MICs was observed, and overexpression of ramA was found in three tigecycline-resistant isolates, further analysis confirmed ramR mutations existed in these isolates. Transformation of one mutant with wild-type ramR restored susceptibility to tigecycline and repressed overexpression of ramA and acrB. These data indicate that efflux pump AcrAB, which can be up-regulated by ramR mutations and subsequent ramA activation, contributed to tigecycline resistance in K. pneumoniae clinical isolates.  相似文献   
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Astragaloside IV (AGS-IV) is a main active ingredient of Astragalus membranaceus Bunge, a medicinal herb prescribed as an immunostimulant, hepatoprotective, antiperspirant, a diuretic or a tonic as documented in Chinese Materia Medica. In the present study, we employed a high-throughput comparative proteomic approach based on 2D-nano-LC-MS/MS to investigate the possible mechanism of action involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. Differential proteins were identified, among which 13 proteins survived the stringent filter criteria and were further included for functional discussion. Two proteins (vimentin and Gap43) were randomly selected, and their expression levels were further confirmed by western blots analysis. The results matched well with those of proteomics. Furthermore, network analysis of protein-protein interactions (PPI) and pathways enrichment with AGS-IV associated proteins were carried out to illustrate its underlying molecular mechanism. Proteins associated with signal transduction, immune system, signaling molecules and interaction, and energy metabolism play important roles in neuroprotective effect of AGS-IV and Raf-MEK-ERK pathway was involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. This study demonstrates that comparative proteomics based on shotgun approach is a valuable tool for molecular mechanism studies, since it allows the simultaneously evaluate the global proteins alterations.  相似文献   
6.
Accurate prediction of complex traits based on whole-genome data is a computational problem of paramount importance, particularly to plant and animal breeders. However, the number of genetic markers is typically orders of magnitude larger than the number of samples (p >> n), amongst other challenges. We assessed the effectiveness of a diverse set of state-of-the-art methods on publicly accessible real data. The most surprising finding was that approaches with feature selection performed better than others on average, in contrast to the expectation in the community that variable selection is mostly ineffective, i.e. that it does not improve accuracy of prediction, in spite of p >> n. We observed superior performance despite a somewhat simplistic approach to variable selection, possibly suggesting an inherent robustness. This bodes well in general since the variable selection methods usually improve interpretability without loss of prediction power. Apart from identifying a set of benchmark data sets (including one simulated data), we also discuss the performance analysis for each data set in terms of the input characteristics.  相似文献   
7.

Background

The present study was designed to determine whether the Thinprep plus Papanicolaou stain (Thinprep) method is more sensitive than the Cytospin-coupled Wright-Giemsa (WG) stain (Cytospin) method in diagnosis of leptomeningeal metastasis (LM) from malignant solid tumors in cerebrospinal fluid (CSF). We also explored if the Thinprep method could be used in the differential diagnosis of the type of primary tumor cells based on the morphology of tumor cells in CSF samples.

Methods

The morphological features of tumor cells in fresh CSF samples were analyzed using both methods. The tumor cell detection rates were compared between the two methods.

Results

Using the Thinprep method, we found that each type of tumor cells in the CSF samples had specific identifiable morphological features linked to their primary cancer origins, such as adenocarcinomas originated from the lungs, breast, and stomach, and lung squamous cell carcinomas, small cell lung cancer, large-cell neuroendocrine lung cancer, hepatocellular carcinoma, and malignant melanoma. In a retrospective study with 88 LM patients, cancer cells were detected in 80 out of the 88 CSF samples. In the comparative study with 45 LM patients, the initial detection rate of the Thinprep method was significantly higher than that of the Cytospin method (73.3% vs. 57.8%, P<0.01). The cell morphology was better preserved and subcellular structures were clearer using the Thinprep method, compared to the Cytospin method.

Conclusions

The Thinprep method is more sensitive and suitable for LM diagnosis in CSF in patients with malignant solid tumors than the Cytospin method. The Thinprep method may facilitate primary tumor detection and help design early treatment regimens for LM patients with tumors of unknown primary origin.  相似文献   
8.
Climate change may shift interactions of invasive plants, herbivorous insects and native plants, potentially affecting biological control efficacy and non‐target effects on native species. Here, we show how climate warming affects impacts of a multivoltine introduced biocontrol beetle on the non‐target native plant Alternanthera sessilis in China. In field surveys across a latitudinal gradient covering their full distributions, we found beetle damage on A. sessilis increased with rising temperature and plant life history changed from perennial to annual. Experiments showed that elevated temperature changed plant life history and increased insect overwintering, damage and impacts on seedling recruitment. These results suggest that warming can shift phenologies, increase non‐target effect magnitude and increase non‐target effect occurrence by beetle range expansion to additional areas where A. sessilis occurs. This study highlights the importance of understanding how climate change affects species interactions for future biological control of invasive species and conservation of native species.  相似文献   
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