The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs and were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14-high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. .
The distinctive differentiated states of the CD4+ T helper cells are determined by the set of transcription factors and the genes transcribed by the transcription factors. In vitro induction models, the major determinants of the cytokines present during the T-cell receptor (TCR)-mediated activation process. IL-12 and IFN-γ make Naive CD4+ T cells highly express T-bet and STAT4 and differentiate to TH1 cells, while IL-4 make Naive CD4+ T cells highly express STAT6 and GATA3 and differentiated to TH2 cells. Even through T-bet and GATA3 are master regulators for TH1/TH2 cells differentiation. There are many other transcription factors, such as RUNX family proteins, IRF4, Dec2, Gfi1, Hlx, and JunB that can impair TH1/TH2 cells differentiation. In recent years, noncoding RNAs (microRNA and long noncoding RNA) join in the crowd. The leukocytes should migrate to the right place to show their impact. There are some successful strategies, which are revealed to targeting chemokines and their receptors, that have been developed to treat human immune-related diseases.
Genome editing techniques such as the zinc-finger nucleases (ZFNs), transcription activator-like effecter nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system Cas9 can induce efficient DNA double strand breaks (DSBs) at the target genomic sequence and result in indel mutations by the error-prone non-homologous end joining (NHEJ) DNA repair system. Several methods including sequence specific endonuclease assay, T7E1 assay and high resolution melting curve assay (HRM) etc have been developed to detect the efficiency of the induced mutations. However, these assays have some limitations in that they either require specific sequences in the target sites or are unable to generate sequencing-ready mutant DNA fragments or unable to distinguish induced mutations from natural nucleotide polymorphism. Here, we developed a simple PCR-based protocol for detecting indel mutations induced by TALEN and Cas9 in zebrafish. We designed 2 pairs of primers for each target locus, with one putative amplicon extending beyond the putative indel site and the other overlapping it. With these primers, we performed a qPCR assay to efficiently detect the frequencies of newly induced mutations, which was accompanied with a T-vector-based colony analysis to generate single-copy mutant fragment clones for subsequent DNA sequencing. Thus, our work has provided a very simple, efficient and fast assay for detecting induced mutations, which we anticipate will be widely used in the area of genome editing.
The solid electrolyte interface (SEI) is a passivation layer formed on the surface of lithium-ion battery (LIB) anode materials produced by electrolyte decomposition.
BACKGROUND & AIMS: Activation of TGFB (transforming growth factor b) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS:We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1 Dhep ). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl 4 ) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with av integrins Gastroenterology 2019;157:1352-1367 BASIC AND TRANSLATIONAL LIVER * Authors share co-first authorship.Abbreviations used in this paper: AAV, adeno-associated virus; CLD, chronic liver disease; CCl 4 , carbon tetrachloride; ECM1, extracellular matrix protein 1; ECM1 D;hep , hepatocyte-specific deletion of extracellular matrix protein 1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase;
CD4+ T helper cells regulate appropriate cellular and humoral immune responses to a wide range of pathogens and get involved in many diseases progress. The balance of the earliest determined CD4+ T helper cell subsets, Th1 and Th2, play an important role in allergy and autoimmune diseases. During the research, Animal models in immunology research are necessary and always the powerful tools for the basic scientific research. With the new sequence technologies, the finding of key gene mutation in Th1/Th2 cells has been proved to be related to human diseases. Here, we review four animal models about four key genes in Th1/Th2 cells to introduce the balance between Th1/Th2 cells. Furthermore, the related genetic mutations in human diseases and the new therapies are reviewed in this chapter, which show the importance of Th1/Th2 cells in human diseases further.
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