Papillary renal cell carcinoma (pRCC) is a heterogeneous disease containing multifocal or solitary tumors with an aggressive phenotype. Increasing evidence has indicated the involvement of aberrant splicing variants in renal cell cancer, while systematic profiling of aberrant alternative splicing (AS) in pRCC was lacking and largely unknown. In the current study, comprehensive profiling of AS events were performed based on the integration of pRCC cohort from the Cancer Genome Atlas database and SpliceSeq software. With rigorous screening and univariate Cox analysis, a total of 2077 prognoses AS events from 1642 parent genes were identified. Then, stepwise least absolute shrinkage and selection operator method-penalized Cox regression analyses with 10-fold cross-validation followed by multivariate Cox regression were used to construct the prognostic AS signatures within each AS type. And a final 21 AS event-based signature was proposed which showed potent prognostic capability in stratifying patients into low- and high-risk subgroups (P < .0001). Furthermore, time-dependent receiver operating characteristics curves confirmed that the final AS signature was effective and robust in predicting overall survival for pRCC patients with the area under the curve above 0.9 from 1 to 5 years. In addition, splicing correlation network was built to uncover the potential regulatory pattern among prognostic splicing factors and candidate AS events. Besides, gene set enrichment analysis revealed the involvement of these candidates AS events in tumor-related pathways including extracellular matrix organization, oxidative phosphorylation, and P53 signaling pathways. Taken together, our results could contribute to elucidating the underlying mechanism of AS in the oncogenesis process and broaden the novel field of prognostic and clinical application of molecule-targeted approaches in pRCC. 相似文献
HIV preferentially infects activated CD4+ T cells. Current antiretroviral therapy cannot eradicate the virus. Viral infection of other cells such as macrophages may contribute to viral persistence during antiretroviral therapy. In addition to cell-free virus infection, macrophages can also get infected when engulfing infected CD4+ T cells as innate immune sentinels. How macrophages affect the dynamics of HIV infection remains unclear. In this paper, we develop an HIV model that includes the infection of CD4+ T cells and macrophages via cell-free virus infection and cell-to-cell viral transmission. We derive the basic reproduction number and obtain the local and global stability of the steady states. Sensitivity and viral dynamics simulations show that even when the infection of CD4+ T cells is completely blocked by therapy, virus can still persist and the steady-state viral load is not sensitive to the change of treatment efficacy. Analysis of the relative contributions to viral replication shows that cell-free virus infection leads to the majority of macrophage infection. Viral transmission from infected CD4+ T cells to macrophages during engulfment accounts for a small fraction of the macrophage infection and has a negligible effect on the total viral production. These results suggest that macrophage infection can be a source contributing to HIV persistence during suppressive therapy. Improving drug efficacies in heterogeneous target cells is crucial for achieving HIV eradication in infected individuals.
Mycopathologia - Candida albicans is an important opportunistic fungal pathogen, and its pathogenicity is closely related to its ability to form hyphae. ESCRT system was initially discovered as a... 相似文献
The emerging role of microRNAs (miRNAs) have been deeply explored in multiple diseases including neuropathic pain. miR-194 was widely reported to be a tumor suppressor and was related to the inflammatory response. The critical role of neuroinflammation on neuropathic pain leads to a thinking about the relationship between miR-194 and neuropathic pain. However, the function of miR-194 in neuropathic pain remains unknown. This study was aimed to explore the relationship between miR-194 and neuropathic pain progression by chronic sciatic nerve injury (CCI). miR-194 abnormally downregulated in the CCI model rat and its overexpression significantly alleviates neuroinflammation in vivo. We predict Forkhead box protein A1 (FOXA1) as a direct target of miR-194, whose restoration can markedly reverse the effects of miR-194 on neuropathic pain. Overall, our study demonstrated a novel mechanism of neuropathic pain progression that miR-194 alleviates neuropathic pain via targeting FOXA1 and preventing neuroinflammation by downregulating inflammatory cytokines containing cyclooxygenase 2, interleukin 6 (IL-6), and IL-10 in vivo, which can be reversed by the overexpression of FOXA1. 相似文献
Osteosarcoma (OS) is the most common primary solid malignant bone tumor, and its metastasis is a prominent cause of high mortality in patients. In this study, a prognosis risk signature was constructed based on metastasis-associated genes. Four microarrays datasets with clinical information were downloaded from Gene Expression Omnibus, and 256 metastasis-associated genes were identified by limma package. Further, a protein-protein interaction network was constructed, and survival analysis was performed using data from the Therapeutically Applicable Research to Generate Effective Treatments data matrix, identifying 19 genes correlated with prognosis. Six genes were selected by the least absolute shrinkage and selection operator regression for multivariate cox analysis. Finally, a three-gene (MYC, CPE, and LY86) risk signature was constructed, and datasets GSE21257 and GSE16091 were used to validate the prediction efficiency of the signature. The survival times of low- and high-risk groups were significantly different in the training set and validation set. Additionally, gene set enrichment analysis revealed that the genes in the signature may affect the cell cycle, gap junctions, and interleukin-6 production. Therefore, the three-gene survival risk signature could potentially predict the prognosis of patients with OS. Further, proteins encoded by CPE and LY86 may provide novel insights into the prediction of OS prognosis and therapeutic targets. 相似文献
By investigating the expression profiles of miR-19a and metalloproteinases (MMP13) in human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) and HFL cells lines, this study intends to confirm the directly target connection between them and reveal the effect of suppressing MMP13 on HLFS-RA migration, invasion and apoptosis. After screening the abnormal expressed messenger RNAs and microRNAs in synovial tissues of patients with RA, the underlying pathway was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The HFLS-RA cell line was transfected for the following experiments with pcDNA3.1(+) served as vector. The directly target association between miR-19a and MMP13 was confirmed by Luciferase reporter assay. Microarray analysis suggested that MMP13 was upregulated while miR-19a was downregulated in HFLS of RA tissues compared with the healthy control group. MMP13 was related to many proteins in protein-protein interaction network, which might be the main influencing factor of RA. KEGG pathway analysis identified that interleukin (IL)-17 pathway was activated in the regulation of MMP13 in the development of RA. Through observing the alteration of luciferase activity, miR-19a could indeed bind to the 3′UTR of the downstream of MMP13, the target association was then confirmed. The proliferation and invasion of HFLS-RA were promoted by overexpressing MMP13 protein. miR-19a could function as a suppressor of MMP13 and thereby retard the severity of RA. The results showed that miR-19a could regulate the expression of MMP13 in HFLS-RA by mediating the proliferation and invasion of HFLS-RA through IL-17 signaling pathway, thereby participating in the degradation of chondrocytes in the progression of RA. 相似文献
Plant Molecular Biology Reporter - Previously, we cloned the full sequence of masson pine (Pinus massoniana) phosphate transporter gene (PmPT1) from a phosphorus (Pi) deficiency tolerant strain. To... 相似文献
Plant Molecular Biology Reporter - Low temperature is among the most significant abiotic stresses restricting geographical distribution of plants and reducing crop productivity. However, the... 相似文献
AbstractThe emergent need for new treatment methods for multi-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) has focused attention on novel potential tools like nanoparticles (NPs). In the present study, a drug-free cationic nanoparticles (CNPs) system was developed and its anti-MRSA effects were firstly investigated. The results showed that CNPs (261.7?nm, 26.1?mv) showed time- and concentration-dependent activity against MRSA growth, killing ~ 90% of planktonic bacterial cells in 3?h at 400?μg ml?1, and completely inhibiting biofilm formation at 1000?μg ml?1. Moreover, CNPs at 400?μg ml?1 reduced the minimum inhibitory concentration (MIC) of vancomycin on inhibition of planktonic MRSA growth (~ 25%) and biofilm formation (~ 50%). The CNPs–bacteria interaction force was up to 22 nN. Overall, these data suggest that CNPs have a good potential in clinical applications for the prevention and treatment of MRSA infection. 相似文献