Kinase-independent function of RIP1, critical for mature T-cell survival and proliferation.

The death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses. However, the function of RIP1 in the adult lymphoid system has not been well understood, primarily owing to perinatal lethality in mice lacking the entire RIP1 protein in germ cells. This current study investigated the requirement for RIP1 in the T lineage using viable RIP1 mutant mice containing a conditional and kinase-dead RIP1 allele. Disabling the kinase activity of RIP1 had no obvious impact on the T-cell compartment. However, T-cell-specific deletion of RIP1 led to a severe T-lymphopenic condition, owing to a dramatically reduced mature T-cell pool in the periphery. Interestingly, the immature T-cell compartment in the thymus appeared intact. Further analysis showed that mature RIP1(-/-) T cells were severely defective in antigen receptor-induced proliferative responses. Moreover, the RIP1(-/-) T cells displayed greatly increased death and contained elevated caspase activities, an indication of apoptosis. In total, these results revealed a novel, kinase-independent function of RIP1, which is essential for not only promoting TCR-induced proliferative responses but also in blocking apoptosis in mature T cells

Validation of the GALAD model and establishment of a new model for HCC detection in Chinese patients

BackgroundGALAD model is a statistical model used to estimate the possibility of hepatocellular carcinoma (HCC) in patients with chronic liver disease. Many studies with other ethnic populations have shown that it has high sensitivity and specificity. However, whether this model can be used for Chinese patients remains to be determined. Our study was conducted to verify the performance of GALAD model in a Chinese cohort and construct a new model that is more appropriately for Chinese populations.MethodsThere are total 512 patients enrolled in the study, which can be divided into training set and validation set. 80 patients with primary liver cancer, 139 patients with chronic liver disease and 87 healthy people were included in the training set. Through the ROC(receiver operating characteristic) curve analysis, the recognition performance of GALAD model for liver cancer was evaluated, and the GAADPB model was established by logistic regression, including gender, age, AFP, DCP, total protein, and total bilirubin. The validation set (75 HCC patients and 130 CLD patients) was used to evaluate the performance of the GAADPB model.ResultThe GALAD and GAADPB achieved excellent performance (area under the receiver operating characteristic curve [AUC], 0.925, 0.945), and were better than GAAP, Doylestown, BALAD-2, aMAP, AFP, AFP-L3%, DCP and combined detection of AFP, AFP-L3 and DCP (AUCs: 0.894, 0.870, 0.648, 0.545, 0.879, 0.782, 0.820 and 0.911) for detecting HCC from CLD in the training set. As for early stage of HCC (BCLC 0/A), GAADPB had the best sensitivity compared to GALAD, ADP and DCP (56.3%, 53.1%, 40.6%, 50.0%). GAADPB had better performance than GALAD in the test set, AUC (0.896 vs 0.888).ConclusionsThe new GAADPB model was powerful and stable, with better performance than the GALAD and other models, and it also was promising in the area of HCC prognosis prediction. Further study on the real-world HCC patients in China are needed

Progress and trends in non-tool rock breaking theory and technology

With the gradual implementation of China’s deep-earth engineering strategy, deep resource extraction and underground space construction have brought in some new opportunities, but they also face many challenges, with extreme geological conditions such as high geopathic stresses, high ground temperatures and hard rock bodies popping up all the time. Rock breaking technology is the main engineering activity for all resource extraction and underground space construction, and it is the main factor determining the construction process and engineering efficiency. Under extreme geological conditions, tool-based rock breaking technology has become a key technical bottleneck to affect the smooth implementation of deep-earth engineering strategy due to fast tool wear and low rock breaking efficiency. In order to solve the problem of high-efficiency rock breaking in deep-earth and to guarantee the smooth implementation of deep-earth engineering strategy, there is an urgent need for a revolutionary rock breaking technology. As an important supplement to the tool-based breaking technology, the non-tool rock breaking technology is a feasible solution to break through the bottleneck of the tool-based breaking technology. To this end, the non-tool rock breaking technology is summarized into three types of technological systems, namely, impact rock breaking, thermal stress rock breaking and erosion and abrasion rock breaking. Sixteen types of rock breaking technologies, such as water jets, lasers and abrasive air jets, etc., are systematically analyzed. Also, the history of the development of each technology and their technical principles are summarized, and the advantages of the rock breaking and the technological bottlenecks are analyzed. It is concluded that the main reasons why the current non-tool rock-breaking technologies are not widely used in resource extraction and underground space construction are high energy consumption, poor adoptability and complex technical equipment. Compared with tool-based breaking, non-tool breaking technology has a lower energy utilization rate for breaking rock. The specific energy consumption of water jet breaking is 40−70 times that of a tool breaking. Microwave, laser and plasma technologies require high-standard operation environment and cannot be applied in drilling, tunneling and other restricted and harsh environments. In order to solve the problem of rock breaking in extreme geological conditions, the idea of synergistic rock breaking by multiple non-tool rock breaking technologies is proposed, giving full play to the technological advantages of each non-tool rock breaking technology. The rock breaking concept of unloading high geo-stress by jet slit and breaking hard rock by particle impact volume is constructed to minimize the energy consumption of rock breaking, simplify the system equipment, and provide a theoretical support for the development of non-tool rock breaking technology

The Ets Transcription Factor GABP Is a Component of the Hippo Pathway Essential for Growth and Antioxidant Defense

这是周大旺教授继2009年首次发现了Hippo信号通路在哺乳动物中控制器官大小及肿瘤发生具有重要作用后的又一重大研究成果，该研究系统阐述了 YAP基因在转录调控水平上的的调控机理，进一步完善了人们对Hippo信号通路的认识，也为由YAP调控异常所引发的癌症提供了一个潜在的治疗靶点。 该论文的第一作者为博士生吴黉坦和硕士生肖玉波和张世浩, 通讯作者是周大旺教授和陈兰芬副教授，该工作是与厦门市中医院、中山医院和医学高等专科学校等单位合作完成的。周大旺教授是中央首批“青年千人计划”入选者并获得国家首批“优秀青年科学基金”资助。The transcriptional coactivator Yes-associated protein (YAP) plays an important role in organ-size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell-cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced glutathione depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects against acetaminophen-induced liver injury. Similar to its effects on YAP, Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP

Identification of miRs-143 and -145 that Is Associated with Bone Metastasis of Prostate Cancer and Involved in the Regulation of EMT

The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone. MicroRNAs (miRNAs) play a crucial role in many tumor metastases. The importance of miRNAs in bone metastasis of PCa has not been elucidated to date. We investigated whether the expression of certain miRNAs was associated with bone metastasis of PCa. We examined the miRNA expression profiles of 6 primary and 7 bone metastatic PCa samples by miRNA microarray analysis. The expression of 5 miRNAs significantly decreased in bone metastasis compared with primary PCa, including miRs-508-5p, -145, -143, -33a and -100. We further examined other samples of 16 primary PCa and 13 bone metastases using real-time PCR analysis. The expressions of miRs-143 and -145 were verified to down-regulate significantly in metastasis samples. By investigating relationship of the levels of miRs-143 and -145 with clinicopathological features of PCa patients, we found down-regulations of miRs-143 and -145 were negatively correlated to bone metastasis, the Gleason score and level of free PSA in primary PCa. Over-expression miR-143 and -145 by retrovirus transfection reduced the ability of migration and invasion in vitro, and tumor development and bone invasion in vivo of PC-3 cells, a human PCa cell line originated from a bone metastatic PCa specimen. Their upregulation also increased E-cadherin expression and reduced fibronectin expression of PC-3 cells which revealed a less invasive morphologic phenotype. These findings indicate that miRs-143 and -145 are associated with bone metastasis of PCa and suggest that they may play important roles in the bone metastasis and be involved in the regulation of EMT Both of them may also be clinically used as novel biomarkers in discriminating different stages of human PCa and predicting bone metastasis

Dissipative quadratizations of polynomial ODE systems

Quadratization refers to a transformation of an arbitrary system of polynomial ordinary differential equations to a system with at most quadratic right-hand side. Such a transformation unveils new variables and model structures that facilitate model analysis, simulation, and control and offers a convenient parameterization for data-driven approaches. Quadratization techniques have found applications in diverse fields, including systems theory, fluid mechanics, chemical reaction modeling, and mathematical analysis. In this study, we focus on quadratizations that preserve the stability properties of the original model, specifically dissipativity at given equilibria. This preservation is desirable in many applications of quadratization including reachability analysis and synthetic biology. We establish the existence of dissipativity-preserving quadratizations, develop an algorithm for their computation, and demonstrate it in several case studies