Long Noncoding RNA HOXA-AS2 Promotes Papillary Thyroid Cancer Progression by Regulating miR-520c-3p/S100A4 Pathway

Background/Aims: Thyroid cancer is one of the most prevalent endocrine tumors. The present study examined the effects of lncRNA HOXA cluster antisense RNA2 (HOXA-AS2) on the progression of papillary thyroid cancer (PTC), and explored the underlying molecular mechanisms. Methods: Quantitative real-time PCR was used to detect HOXA-AS2, miR-520c-3p and S100 calcium-binding protein A4 (S100A4) expression. Furthermore, the effects of HOXA-AS2 silencing and overexpression on cell proliferation, migration, and invasion were assessed in PTC in vitro by CCK8 and transwell assay. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in PTC. Results: We observed that HOXA-AS2 was up-regulated in PTC tissues. In vitro experiments revealed that HOXA-AS2 knockdown significantly inhibited cell growth in PTC in vitro and in vivo. Further functional assays indicated that HOXA-AS2 significantly promoted PTC cell migration and invasion by promoting EMT. Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c-3p at 3’-UTR with complementary binding sites, which was validated using luciferase reporter assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in PTC cells. MiR-520c-3p was down-regulated in PTC tissues, and S100A4 was predicted as a downstream target of miR-520c-3p, which was confirmed by luciferase reporter assay. Conclusion: In summary, our results suggested that the HOXA-AS2/miR-520c-3p/S100A4 axis may play an important role in the regulation of PTC progression, which provides us with new insights into understanding the PTC

Gender forgery of faces by fusing wavelet shortcut connection generative adversarial network

The mainstream methods in the field of facial attribute manipulation had the following two defects due to data and model architecture limitations.First, the bottleneck structure of the autoencoder model results in the loss of feature information, and the traditional method of continuously injected styles to the source domain features during the decoding process makes the generated image too referential to the target domain while losing the identity information and fine-grained details.Second, differences in facial attributes composition between images, such as gender, ethnicity, or age can cause variations in frequency domain information.And the current unsupervised training methods do not automatically adjust the proportion of source and target domain information in the style injection stage, resulting in artifacts in generated images.A facial gender forgery model based on generative adversarial networks and image-to-image translation techniques, namely fused wavelet shortcut connection generative adversarial network (WscGAN), was proposed to address the these issues.Shortcut connections were added to the autoencoder structure, and the outputs of different encoding stages were decomposed at the feature level by wavelet transform.Attention mechanism was employed to process them one by one, to dynamically change the proportion of source domain features at different frequencies in the decoding process.This model could complete forgery of facial images in terms of gender attributes.To verify the effectiveness of the model, it was conducted on the CelebA-HQ dataset and the FFHQ dataset.Compared with the existing optimal models, the method improves the FID and LPIPS indices by 5.4% and 11.2%, and by 1.8% and 6.7%, respectively.Furthermore, the effectiveness of the proposed method in improving the gender attribute conversion of facial images is fully demonstrated by the results based on qualitative visual comparisons

Prognostic costimulatory molecule-related signature risk model correlates with immunotherapy response in colon cancer

Abstract Costimulatory molecules can promote the activation and proliferation of T cells and play an essential role in immunotherapy. However, their role in the prognosis of colon adenocarcinoma remains elusive. In this study, the expression data of costimulatory molecules and clinicopathological information of 429 patients with colon adenocarcinoma were obtained from The Cancer Genome Atlas database. The patients were divided into training and verification cohorts. Correlation, Cox regression, and Lasso regression analyses were performed to identify costimulatory molecules related to prognosis. After mentioning the construction of the risk mode, a nomogram integrating the clinical characteristics and risk scores of patients was constructed to predict prognosis. Eventually, three prognostic costimulatory molecules were identified and used for constructing a risk model. High expression of these three molecules indicated a poor prognosis. The predictive accuracy of the risk model was verified in the GSE17536 dataset. Subsequently, multivariate regression analysis showed that the signature based on the three costimulatory molecules was an independent risk factor in the training cohort (HR = 2.12; 95% CI = 1.26, 3.56). Based on the risk model and clinicopathological data, the AUC values for predicting the 1-, 3-, and 5-year survival probability of patients with colon adenocarcinoma were 0.77, 0.77, and 0.71, respectively. To the best of our knowledge, this study is the first to report a risk signature constructed based on the costimulatory molecules TNFRSF10c, TNFRSF13c, and TNFRSF11a. This risk signature can serve as a prognostic biomarker for colon adenocarcinoma and is related to the immunotherapeutic response of patients

RIP1/RIP3 Binding to HSV-1 ICP6 Initiates Necroptosis to Restrict Virus Propagation in Mice

文章简介细胞坏死是一种由受体相互作用蛋白3(RIP3)和1(RIP1)介导的程序性死亡方式。本研究发现在RIP3缺失的小鼠细胞中,Ⅰ型单纯疱疹病毒(HSV-1)的繁殖效率远远高于在野生型细胞中的繁殖效率。这一结果表明:在小鼠细胞中,RIP3对于抵抗HSV-1的感染起到了非常重要的作用。进一步的研究发现,在感染HSV-1的小鼠细胞中,RIP1/3能够和HSV-1编码的ICP6蛋白发生相互作用;这一相互作用激活了RIP3介导的坏死信号,进一步引起细胞坏国家自然科学基金委重点项目;; 科技部973项目的资

Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis

National Basic Research Program of China (973 Program) [2009CB522201]; National Natural Science Foundation of China [91029304, 30830092, 30921005, 81061160512]; Hi-Tech Research and Development Program of China (863 program) [2012AA02A201]; 111 Project [B12001]; Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University [SKLCSB2012KF003]Mixed lineage kinase domain-like protein (Mlkl) was recently found to interact with receptor interacting protein 3 (Rip3) and to be essential for tumor necrosis factor (TNF)-induced programmed necrosis (necroptosis) in cultured cell lines. We have generated Mlkl-deficient mice by transcription activator-like effector nucleases (TALENs)-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell development. Mlkl-deficient mouse embryonic fibroblasts (MEFs) and macrophages both showed resistance to necrotic but not apoptotic stimuli. Mlkl-deficient MEFs and macrophages were indistinguishable from wild-type cells in their ability to activate NF-kappa B, ERK, JNK, and p38 in response to TNF and lipopolysaccharides (LPS), respectively. Consistently, Mlkl-deficient macrophages and mice exhibited normal interleukin-1 beta (IL-1 beta), IL-6, and TNF production after LPS treatment. Mlkl deficiency protects mice from cerulean-induced acute pancreatitis, a necrosis-related disease, but has no effect on polymicrobial septic shock-induced animal death. Our results provide genetic evidence for the role of Mlkl in necroptosis

Diverse Sequence Determinants Control Human and Mouse Receptor Interacting Protein 3 (RIP3) and Mixed Lineage Kinase domain-Like (MLKL) Interaction in Necroptotic Signaling

973 program Grant [2009CB522201]; National Science Foundation of China [91029304, 31221065, 81061160512, 91229201]; 863 program Grant [2012AA02A201]; 111 Project [B12001]; Chinese National Scientific and Technological Major Project Grant [2013ZX10002002]; Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University [SKLCSB2012KF003]Receptor interacting protein 3 (RIP3) is a protein kinase essential for TNF-induced necroptosis. Phosphorylation on Ser227 in human RIP3 (hRIP3) is required for its interaction with human mixed lineage kinase domain-like (MLKL) in the necrosome, a signaling complex induced by TNF stimulation. RIP1 and RIP3 mediate necrosome aggregation leading to the formation of amyloid-like signaling complexes. We found that TNF induces Thr-231 and Ser-232 phosphorylation in mouse RIP3 (mRIP3) and this phosphorylation is required for mRIP3 to interact with mMLKL. Ser-232 in mRIP3 corresponds to Ser-227 in hRIP3, whereas Thr-231 is not conserved in hRIP3. Although the RIP3-MLKL interaction is required for necroptosis in both human and mouse cells, hRIP3 does not interact with mMLKL and mRIP3 cannot bind to hMLKL. The species specificity of the RIP3-MLKL interaction is primarily determined by the sequence differences in the phosphorylation sites and the flanking sequence around the phosphorylation sites in hRIP3 and mRIP3. It appears that the RIP3-MLKL interaction has been selected as an evolutionarily conserved mechanism in mediating necroptosis signaling despite that differing structural and mechanistic bases for this interaction emerged simultaneously in different organisms. In addition, we further revealed that the interaction of RIP3 with MLKL prevented massive abnormal RIP3 aggregation, and therefore should be crucial for formation of the amyloid signaling complex of necrosomes. We also found that the interaction between RIP3 and MLKL is required for the translocation of necrosomes to mitochondria-associated membranes. Our data demonstrate the importance of the RIP3-MLKL interaction in the formation of functional necrosomes and suggest that translocation of necrosomes to mitochondria-associated membranes is essential for necroptosis signaling