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

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

Effect of Fiber Content on Sound Absorption, Thermal Conductivity, and Compression Strength of Straw Fiber-filled Rigid Polyurethane Foams

Rigid polyurethane (PUR) foam is one of the most important insulating materials used today in the construction industry and is the main insulation material used in the global appliances industry. This study developed rice straw fiber-filled PUF (RPUF) and wheat straw fiber-filled PUF (WPUF) and explored the morphology, sound absorption properties, heat transfer, and compressive strength of the PUF composites. The results indicated that, with the higher fiber content, more open cells were observed in SEM images of the composites. The average sound absorption coefficients (ASAC) of both WPUF and RPUF were significantly increased when 5 per hundred polyols (php) by weight and 10 php fiber contents were added. When fiber contents of 15 php and 20 php were utilized, ASAC reduced due to the tortuosity of cells and large holes in the foam. The sound absorption coefficient (SAC) first increased, then decreased, and increased finally as the sound frequency increased from 100 to 2000 Hz for the two composites. The thermal conductivities of both WPUF and RPUF first decreased and then increased as the fiber content increased from 0 to 20 php. When 5 and 10 php straw contents was added, the thermal conductivities were reduced by 25% to 50% compared to that of the pure PU form (0 php), indicating that the improved thermal insulation ability was obtained. The composite compressive strength was reduced by 19% to 28% due to the fiber addition