Akt/mTOR mediated induction of bystander effect signaling in a nucleus independent manner in irradiated human lung adenocarcinoma epithelial cells

Cytoplasm is an important target for the radiation-induced bystander effect (RIBE). In the present work, the critical role of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in the generation of RIBE signaling after X-ray irradiation and the rapid phosphorylation of Akt and mTOR was observed in the cytoplasm of irradiated human lung adenocarcinoma epithelial (A549) cells. Targeting A549 cytoplasts with individual protons from a microbeam showed that RIBE signal(s) mediated by the Akt/mTOR pathway were generated even in the absence of a cell nucleus. These results provide a new insight into the mechanisms driving the cytoplasmic response to irradiation and their impact on the production of RIBE signal(s).</p

Effects of blood pressure level management on maternal and perinatal outcomes in pregnant women with mild to moderate gestational hypertension

Objectives: This study aims to investigate the effects of blood pressure control level on maternal and perinatal outcomesin pregnant women with mild to moderate gestational hypertension (GHp).Material and methods: A total of 344 pregnant women who initially diagnosed as mild to moderate gestational hypertensionwere recruited in this study. They were divided into 4 groups according to the stabilized blood pressure level (BPL)during pregnancy. The clinical parameters and the incidence of adverse pregnancy outcomes were compared among thefour groups. The association between blood pressure levels and relative factors were analyzed using the χ2 test. Multivariatelogistic regression analysis was adopted for risk factors associated with adverse pregnancy outcomes.Results: The results showed the prevalence of obesity was significantly associated with blood pressure levels of mild-moderateGHp pregnant women (p = 0.029). The incidence of severe GHp, SPE in group A, group B, and group C were statisticallysignificant (p &lt; 0.001, p = 0.041, respectively). In the patients who used drugs to control BPL, the incidence of severe GHphas a significant association with the initial blood pressure levels (p = 0.004). However, no significant difference was foundin the incidence of sPE, PE + Upro, and SGA (all p &gt; 0.05). Multivariate logistic regression analyses results showed that thegestational factor BPL was an independent risk factor for the incidence of sGHp. The AMA, primigravida, gestational BPL, andedema were risk factors for the incidence of preeclampsia with proteinuria. To the incidence of sPE, gestational BPL is theindependent risk factor. Finally, preeclampsia anamnesis and FGR trend are the high-risk parameters to the incidence of SGA.Conclusions: Timely management and control of blood pressure in pregnant women with mild to moderate GHp werebeneficial to reduce the occurrence of severe GHp and sPE, but the incidence of SGA does not affected

Regulation of retrotranslocation by p97-associated deubiquitinating enzyme ataxin-3

Misfolded proteins of the endoplasmic reticulum undergo retrotranslocation to enter the cytosol where they are degraded by the proteasome. Retrotranslocation of many substrates requires an ATPase complex consisting of the p97 ATPase and a dimeric cofactor, Ufd1-Npl4. We report that efficient elimination of misfolded ER proteins also involves ataxin-3 (atx3), a p97-associated deubiquitinating enzyme mutated in type-3 spinocerebellar ataxia. Overexpression of an atx3 mutant defective in deubiquitination inhibits the degradation of misfolded ER proteins and triggers ER stress. Misfolded polypeptides stabilized by mutant atx3 are accumulated in part as polyubiquitinated form, suggesting an involvement of its deubiquitinating activity in ER-associated protein degradation regulation. We demonstrate that atx3 transiently associates with the ER membrane via p97 and the recently identified Derlin–VIMP complex, and its release from the membrane appears to be governed by both the p97 ATPase cycle and its own deubiquitinating activity. We present evidence that atx3 may promote p97-associated deubiquitination to facilitate the transfer of polypeptides from p97 to the proteasome

Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model

BACKGROUND: Epigenetic regulation has emerged to be the critical steps for tumorigenesis and metastasis. Multiple histone methyltransferase and demethylase have been implicated as tumor suppressors or oncogenes recently. But the key epigenomic events in cancer cell transformation still remain poorly understood. METHODS: A breast cancer transformation model was established via stably expressing three oncogenes in primary breast epithelial cells. Chromatin immunoprecipitation followed by the next-generation sequencing of histone methylations was performed to determine epigenetic events during transformation. Western blot, quantitative RT-PCR, and immunostaining were used to determine gene expression in cells and tissues. RESULTS: Histones H3K9me2 and me3, two repressive marks of transcription, decrease in in vitro breast cancer cell model and in vivo clinical tissues. A survey of enzymes related with H3K9 methylation indicated that KDM3A/JMJD1A, a demethylase for H3K9me1 and me2, gradually increases during cancer transformation and is elevated in patient tissues. KDM3A/JMJD1A deficiency impairs the growth of tumors in nude mice and transformed cell lines. Genome-wide ChIP-seq analysis reveals that the boundaries of decreased H3K9me2 large organized chromatin K9 modifications (LOCKs) are enriched with cancer-related genes, such as MYC and PAX3. Further studies show that KDM3A/JMJD1A directly binds to these oncogenes and regulates their transcription by removing H3K9me2 mark. CONCLUSIONS: Our study demonstrates reduction of histones H3K9 me2 and me3, and elevation of KDM3A/JMJD1A as important events for breast cancer, and illustrates the dynamic epigenomic mechanisms during breast cancer transformation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-016-0201-x) contains supplementary material, which is available to authorized users

Dead center position of planar mechanism based on constraint normal line

ObjectiveTo address the issues of low efficiency and difficult operation in determining dead center position for complex planar mechanisms, a method for identifying dead center position based on constraint normal line was proposed.MethodsFirstly, the definition and representation method of constraint normal line for the target component in planer mechanism were established. Secondly, the dead center identification criterion was proposed, and its proof was provided. Subsequently, a Stephenson-Ⅲ six-bar linkage was selected for analysis. Its analysis was compared with that of the same type of linkage in relevant literature, leading to discrepant results. An in-depth analysis was then conducted on these discrepancies.ResultsThis case validation demonstrates that the new method is straightforward, intuitive, easy to grasp, and exhibits quite broad applicability

The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation

AbstractThe zinc finger-containing protein A20 is a negative regulator of TNF-induced JNK (c-Jun-N-terminal kinase) and NFκB (nuclear factor κB) signaling. A20 is an unusual enzyme that contains both ubiquitinating and deubiquitinating activities. Although A20 is mostly localized in the cytosol, our recent studies reveal that a fraction of A20 can associate with a lysosome-interacting compartment in a manner that requires its carboxy terminal zinc fingers, but independent of its ubiquitin modifying activities. Whether the lysosome-associated A20 has a function in cellular signaling is unclear. Here, we demonstrate that A20 is capable of targeting an associated signaling molecule such as TRAF2 to the lysosomes for degradation. This process is dependent on the membrane tethering zinc finger domains of A20, but does not require A20 ubiquitin modifying activity. Our findings suggest a novel mode of A20 action that involves lysosomal targeting of signal molecules bound to A20