DRAIC mediates hnRNPA2B1 stability and m6A-modified IGF1R instability to inhibit tumor progression.

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N6-methyladenosine (m6A) of IGF1R remains unclear. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitination and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-IGF1R, leading to inhibition of ccRCC progression. Moreover, four m6A modification sites are identified to be responsible for the mRNA degradation of IGF1R. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA stability in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.

circRNA_8521 promotes Senecavirus A infection by sponging miRNA-324 to regulate LC3A.

Senecavirus A (SVA) causes outbreaks of vesicular disease in pigs, which imposes a considerable economic burden on the pork industry. As current SVA prevention measures are ineffective, new strategies for controlling SVA are urgently needed. Circular (circ)RNA is a newly characterized class of widely expressed, endogenous regulatory RNAs, which have been implicated in viral infection; however, whether circRNAs regulate SVA infection remains unknown. To investigate the influence of circRNAs on SVA infection in porcine kidney 15 (PK-15) cells, RNA sequencing technology was used to analyze the circRNA expression profiles of SVA-infected and uninfected PK-15 cells, the interactions between circRNAs, miRNAs, and mRNAs potentially implicated in SVA infection were predicted using bioinformatics tools. The prediction accuracy was verified using quantitative real-time (qRT)-PCR, Western blotting, as well as dual-luciferase reporter and RNA pull-down assays. The results showed that 67 circRNAs were differentially expressed as a result of SVA infection. We found that circ_8521 was significantly upregulated in SVA-infected PK-15 cells and promoted SVA infection. circ_8521 interacted with miR-324. miR-324 bound to LC3A mRNA which inhibited the expression of LC3A. Knockdown of LC3A inhibited SVA infection. However, circ_8521 promoted the expression of LC3A by binding to miR-324, thereby promoting SVA infection. We demonstrated that circ_8521 functioned as an endogenous miR-324 sponge to sequester miR-324, which promoted LC3A expression and ultimately SVA infection.

The porcine piRNA transcriptome response to Senecavirus a infection.

Introduction: Senecavirus A (SVA) belongs to the genus Senecavirus in the family Picornaviridae. PIWI-interacting RNAs (piRNAs) are a class of small Ribonucleic Acids (RNAs) that have been found in mammalian cells in recent years. However, the expression profile of piRNAs in the host during SVA infection and their roles are poorly understood. Methods: Here, we found the significant differential expression of 173 piRNAs in SVA-infected porcine kidney (PK-15) cells using RNA-seq and 10 significant differentially expressed (DE) piRNAs were further verified by qRT-PCR. Results: GO annotation analysis showed that metabolism, proliferation, and differentiation were significantly activated after SVA infection. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that significant DE piRNAs were mainly enriched in AMPK pathway, Rap1 pathway, circadian rhythm and VEGF pathway. It was suggested that piRNAs may regulated antiviral immunity, intracellular homeostasis, and tumor activities during SVA infection. In addition, we found that the expression levels of the major piRNA-generating genes BMAL1 and CRY1 were significantly downregulated after SVA infection. Discussion: This suggests that SVA may affect circadian rhythm and promote apoptosis by inhibiting the major piRNA-generating genes BMAL1 and CRY1. The piRNA transcriptome in PK-15 cells has never been reported before, and this study will further the understanding of the piRNA regulatory mechanisms underlying SVA infections.

LCDR regulates the integrity of lysosomal membrane by hnRNP K-stabilized LAPTM5 transcript and promotes cell survival.

Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation-regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.

Incidence and prevalence of moyamoya disease in urban China: a nationwide retrospective cohort study.

BACKGROUND AND OBJECTIVE: Moyamoya disease (MMD) is an increasingly recognised cause of stroke, mainly described in East Asia. China is the largest nation in Asia, but few studies reported the epidemiology of MMD, especially at a national level. We aimed to estimate the incidence and prevalence of MMD in China. METHODS: We performed a population-based study using data from the national databases of Urban Basic Medical Insurance between 2013 and 2016, covering approximately 0.50 billion individuals. MMD cases were identified by diagnostic code (International Classification of Diseases, 10th Revision I67.5) or related diagnostic text. RESULTS: A total of 1987 MMD patients (mean age 44.45±14.30 years, female-to-male ratio 1.12) were identified, representing a national crude incidence of 0.59 (95% CI: 0.49 to 0.68) and a prevalence of 1.01 (95% CI: 0.81 to 1.21) per 100 000 person-years in 2016. Rates were higher in females than in males for the incidence (0.66 vs 0.52) and prevalence (1.05 vs 0.90). And the age-specific rates showed a bimodal distribution, with the highest peak in middle-aged group and the second peak in child group. CONCLUSIONS: Our results confirm that MMD is relatively common in East Asians, but the rates in China were lower than those in other East Asian countries such as Japan and Korea. The unique epidemiological features, including a relatively weak female predominance and a shift in the highest peak of incidence from children to adults, revealed new sight into MMD. Further research is expected to explore the potential pathogenesis of MMD.

DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression.

Aberrant N 6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation-deregulated and RNA m6A reader-cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1-S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. SIGNIFICANCE: This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.

Fault Diagnosis for Rotating Machinery Using Multiscale Permutation Entropy and Convolutional Neural Networks.

In view of the limitations of existing rotating machine fault diagnosis methods in single-scale signal analysis, a fault diagnosis method based on multi-scale permutation entropy (MPE) and multi-channel fusion convolutional neural networks (MCFCNN) is proposed. First, MPE quantitatively analyzes the vibration signals of rotating machine at different scales, and obtains permutation entropy (PE) to construct feature vector sets. Then, considering the structure and spatial information between different sensor measurement points, MCFCNN constructs multiple channels in the input layer according to the number of sensors, and each channel corresponds to the MPE feature sets of different monitored points. MCFCNN uses convolutional kernels to learn the features of each channel in an unsupervised way, and fuses the features of each channel into a new feature map. At last, multi-layer perceptron is applied to fuse multi-channel features and identify faults. Through the health monitoring experiment of planetary gearbox and rolling bearing, and compared with single channel convolutional neural networks (CNN) and existing CNN based fusion methods, the proposed method based on MPE and MCFCNN model can diagnose faults with high accuracy, stability, and speed.

Up-regulation of long noncoding RNA CCAL predicts poor patient prognosis and promotes tumor metastasis in osteosarcoma.

BACKGROUND: Long noncoding RNAs (lncRNAs) play essential roles in tumor progression. Aberrant colorectal cancer-associated lncRNA (CCAL) has been found in colorectal cancer. However, the function of lncRNA CCAL in osteosarcoma (OS) remains unclear. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to measure CCAL expression in OS tissues and adjacent nontumor tissues. The correlation betweent CCAL expression and clinicopathological features and prognosis was also analyzed. In addition, the function of CCAL was further evaluated by cell proliferation, migration and invasion assays. RESULTS: We showed that CCAL was significantly up-regulated in OS tissues compared with adjacent nontumor tissues. Increased expression of CCAL was correlated with advanced TNM stage and metastasis. Kaplan-Meier analysis demonstrated that patients with high CCAL expression had lower overall survival than those with low CCAL expression. Multivariate Cox regression analysis indicated that CCAL expression might be an independent prognostic factor for OS patients. In addition, functional assays showed that decreased CCAL expression could inhibit OS cell proliferation, migration and invasion ability. CONCLUSIONS: Our findings suggested that CCAL plays critical roles in OS progression and could act as a therapeutic target in the treatment of OS.