Transcription in eukaryotic genomes generates an extensive array of non-protein-coding RNA, the functional significance of which is mostly unknown. We are investigating the link between non-coding ...RNA and chromatin regulation through analysis of FLC — a regulator of flowering time in Arabidopsis and a target of several chromatin pathways. Here we use an unbiased strategy to characterize non-coding transcripts of FLC and show that sense/antisense transcript levels correlate in a range of mutants and treatments, but change independently in cold-treated plants. Prolonged cold epigenetically silences FLC in a Polycomb-mediated process called vernalization. Our data indicate that upregulation of long non-coding antisense transcripts covering the entire FLC locus may be part of the cold-sensing mechanism. Induction of these antisense transcripts occurs earlier than, and is independent of, other vernalization markers and coincides with a reduction in sense transcription. We show that addition of the FLC antisense promoter sequences to a reporter gene is sufficient to confer cold-induced silencing of the reporter. Our data indicate that cold-induced FLC antisense transcripts have an early role in the epigenetic silencing of FLC, acting to silence FLC transcription transiently. Recruitment of the Polycomb machinery then confers the epigenetic memory. Antisense transcription events originating from 3′ ends of genes might be a general mechanism to regulate the corresponding sense transcription in a condition/stage-dependent manner.
Noncoding RNA is emerging as an important regulator of gene expression in many organisms. We are characterizing RNA-mediated chromatin silencing of the Arabidopsis major floral repressor gene, FLC. ...Through suppressor mutagenesis, we identify a requirement for CstF64 and CstF77, two conserved RNA 3'-end-processing factors, in FLC silencing. However, FLC sense transcript 3' processing is not affected in the mutants. Instead, CstF64 and CstF77 are required for 3' processing of FLC antisense transcripts. A specific RNA-binding protein directs their activity to a proximal antisense polyadenylation site. This targeted processing triggers localized histone demethylase activity and results in reduced FLC sense transcription. Targeted 3' processing of antisense transcripts may be a common mechanism triggering transcriptional silencing of the corresponding sense gene.
Hepatorenal syndrome is a severe complication of advanced liver diseases with a dismal prognosis.
This systematic review and meta-analysis aims to explore the efficacy and safety of transjugular ...intrahepatic portosystemic shunt for the treatment of hepatorenal syndrome.
Publications were searched via PubMed and EMBASE databases. The pooled proportion and mean difference were calculated by using a random-effect model.
Nine publications were included, in which 128 patients with hepatorenal syndrome were treated with transjugular intrahepatic portosystemic shunt. The pooled short-term and 1-year survival rates were 72% and 47% in type 1 hepatorenal syndrome and 86% and 64% in type 2 hepatorenal syndrome. No lethal procedure-related complications were observed. The pooled rate of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt was 49%. The pooled rate of renal function improvement after transjugular intrahepatic portosystemic shunt was 93% in type 1 hepatorenal syndrome and 83% in any type of hepatorenal syndrome. After transjugular intrahepatic portosystemic shunt, serum creatinine, blood urea nitrogen, serum sodium, sodium excretion, and urine volume were significantly improved; by comparison, serum bilirubin slightly increased, but the difference was not statistically significant.
Limited evidence suggested a potential survival benefit of transjugular intrahepatic portosystemic shunt in patients with hepatorenal syndrome but with a high incidence of hepatic encephalopathy.
The basis of quantitative regulation of gene expression is still poorly understood. In Arabidopsis thaliana, quantitative variation in expression of FLOWERING LOCUS C (FLC) influences the timing of ...flowering. In ambient temperatures, FLC expression is quantitatively modulated by a chromatin silencing mechanism involving alternative polyadenylation of antisense transcripts. Investigation of this mechanism unexpectedly showed that RNA polymerase II (Pol II) occupancy changes at FLC did not reflect RNA fold changes. Mathematical modeling of these transcriptional dynamics predicted a tight coordination of transcriptional initiation and elongation. This prediction was validated by detailed measurements of total and chromatin-bound FLC intronic RNA, a methodology appropriate for analyzing elongation rate changes in a range of organisms. Transcription initiation was found to vary ∼25-fold with elongation rate varying ∼8- to 12-fold. Premature sense transcript termination contributed very little to expression differences. This quantitative variation in transcription was coincident with variation in H3K36me3 and H3K4me2 over the FLC gene body. We propose different chromatin states coordinately influence transcriptional initiation and elongation rates and that this coordination is likely to be a general feature of quantitative gene regulation in a chromatin context.
NLR family pyrin domain containing 3 (NLRP3) inflammasome accompanies chronic liver injury and is a critical mediator of inflammation-driven liver fibrosis. Sphingosine 1-phosphate (S1P)/S1P Receptor ...(S1PR) signaling participates in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophage (BMM) activation. However, the relationship between S1P/S1PR signaling and NLRP3 inflammasome in BMMs remains unclear. Here, we found significantly elevated gene expression of NLRP3 inflammasome components (NLRP3, pro-interleukin-1β, and pro-interleukin-18) and the activation of NLRP3 inflammasome significantly elevated during murine chronic liver injury induced by a bile duct ligation operation, a methionine-choline-deficient and high-fat diet, or carbon tetrachloride intraperitoneal injection. Moreover, the increased expression of sphingosine kinase 1 (SphK1), the rate-limiting synthetic enzyme of S1P, was positively correlated with NLRP3 inflammasome components in both patients and mouse model livers. Flow cytometry analysis and immunofluorescence staining showed BMMs contributed to the significant proportion of NLRP3
cells in murine inflammatory livers, but not Kupffer cells, dendritic cells, endothelial cells, T cells, and hepatocytes. Focusing on macrophages, S1P promoted NLRP3 inflammasome priming and activation in a dose-dependent manner. Blockade of S1PR
by JTE-013 (antagonist of S1PR
) or S1PR
-siRNA inhibited S1P-induced NLRP3 inflammasome priming and inflammatory cytokine (interleukin-1β and interleukin-18) secretion, whereas blockade of S1PR
or S1PR
had no such effect.
, a β1,3-d-glucan-encapsulated siRNA particle (GeRP) delivery system is capable of silencing genes in macrophages specifically. Treatment with S1PR
siRNA-GeRPs markedly reduced NLRP3 inflammasome priming and activation and attenuated liver inflammation and fibrosis. Together, the conclusions indicated that targeting macrophage S1PR
retarded liver inflammation and fibrogenesis via downregulating NLRP3 inflammasome, which may represent an effective therapeutic strategy for chronic liver injury.
Objective
To investigate the prognostic value of baseline magnetic resonance imaging (MRI) texture analysis of hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization ...(TACE) and microwave ablation (MWA).
Methods
MRI was performed on 102 patients with HCC before receiving TACE combined with MWA in this retrospective study. The best 10 texture features were screened as a feature group for each MRI sequence by MaZda software using mutual information coefficient (MI), nonlinear discriminant analysis (NDA) and other methods. The optimal feature group with the lowest misdiagnosis rate was achieved on one MRI sequence between two groups dichotomized by 3-year survival, which was used to optimize the significant texture features with the optimal cutoff values. The Cox proportional hazards model was generated for the significant texture features and clinical variables to determine the independent predictors of overall survival (OS). The predictive performance of the model was further evaluated by the area under the ROC curve (AUC). Kaplan–Meier and log-rank tests were performed for disease-free survival (DFS) and Local recurrence-free survival (LRFS).
Results
The optimal feature group with the lowest misdiagnosis rate of 8.82% was obtained on T2WI using MI combined with NDA feature analysis. For Cox proportional hazards regression models, the independent prognostic factors associated with OS were albumin (
P
= 0.047), BCLC stage (
P
= 0.001), Correlat
(1,− 1)T2
(
P
= 0.01) and SumEntrp
(3,0)T2
(
P
= 0.015), and the prediction efficiency of multivariate model is AUC = 0.876, 95%CI = 0.803–0.949. Kaplan–Meier analyses further demonstrated that BCLC (
P
< 0.001), Correlat
(1,− 1)T2
(
P
= 0.023) and SumEntrp
(3,0)T2
(
P
< 0.001) were associated with DFS, and BCLC (
P
= 0.007) related to LRFS.
Conclusions
MR imaging texture features may be used to predict the prognosis of HCC treated with TACE combined with MWA.
A repressor of the transition to flowering in Arabidopsis is the MADS box protein FLOWERING LOCUS C (FLC). FCA, an RNA-binding protein, and FY, a homolog of the yeast RNA 3′ processing factor Pfs2p, ...downregulate FLC expression and therefore promote flowering. FCA/FY physically interact and alter polyadenylation/3′ processing to negatively autoregulate FCA. Here, we show that FCA requires FLOWERING LOCUS D (FLD), a homolog of the human lysine-specific demethylase 1 (LSD1) for FLC downregulation. FCA also partially depends on DICER-LIKE 3, involved in chromatin silencing. fca mutations increased levels of unspliced sense FLC transcript, altered processing of antisense FLC transcripts, and increased H3K4 dimethylation in the central region of FLC. These data support a close association of FCA and FLD in mediating H3K4 demethylation and thus transcriptional silencing of FLC and reveal roles for antisense RNA processing and DCL3 function in this regulation.
Transcription termination is emerging as an important component of gene regulation necessary to partition the genome and minimize transcriptional interference. We have discovered a role for the ...Arabidopsis RNA silencing enzyme DICER-LIKE 4 (DCL4) in transcription termination of an endogenous Arabidopsis gene, FCA. DCL4 directly associates with FCA chromatin in the 3′ region and promotes cleavage of the nascent transcript in a domain downstream of the canonical poly A site. In a dcl4 mutant, the resulting transcriptional read-through triggers an RNA interference-mediated gene silencing of a transgene containing the same 3′ region. We conclude that DCL4 promotes transcription termination of the Arabidopsis FCA gene, reducing the amount of aberrant RNA produced from the locus.
To compare changes in spectral CT iodine densities of hepatic parenchyma and vessels before and after transjugular intrahepatic portosystemic shunt (TIPS) in hepatitis B virus (HBV)-related liver ...cirrhosis. Twenty-five patients with HBV-related liver cirrhosis who received TIPS for gastroesophageal varices bleeding were recruited. Each patient underwent three phases contrast CT before and after TIPS within 4 weeks, with the raw data reconstructed at 1.25-mm-thick slices. Iodine density (in milligrams per milliliter) was measured on iodine-based material decomposition image. Multiple regions of interest (ROIs) in liver parenchyma, aorta and portal vein were selected from three slices of images. Portal vein trunk was set as the central one, and mean liver parenchymal iodine densities from arterial phase (AP), venous phase (VP) and equilibrium phase (EP) were recorded. Quantitative indices of iodine density (ID), including normalized ID in liver parenchyma for arterial phase (NIDLAP), ID of liver parenchyma for venous phase (IDLVP), ID of portal vein in venous phase (IDPVP) and liver arterial iodine density fraction (AIF), were measured and compared before and after TIPS. Based on Child-Pugh stage, 4, 12 and 9 patients were classified as grade A, B, and C, respectively. Liver volume was comparable before and after TIPS (1110.5 ± 287.4 vs. 1092.0 ± 276.3, P = 0.28). After TIPS, ID was decreased in aorta (146.0 ± 34.5 vs. 120.9 ± 30.7, P < 0.01) whereas increased in liver parenchyma at arterial phase, as demonstrated by IDAP (9.3 ± 3.1 vs. 13.4 ± 4.4 mg/mL) and AIF (0.40 ± 0.11 vs. 0.58 ± 0.11, P < 0.01). For venous or equilibrium phase, quantitative indices remained stable (23.1 ± 4.5 vs. 23.0 ± 5.3, 19.8 ± 4.1 vs. 19.4 ± 4.6) mg/mL (Ps > 0.05). For portal vein, ID and NID were increased after TIPS (23.1 ± 11.7 vs. 36.5 ± 13.0, 16.4 ± 8.5 vs. 31.8 ± 12.8) (P < 0.01). No positive correlation between iodine density and preoperative Child-Pugh score was observed. Based on iodine density measurement, spectral CT as a noninvasive imaging modality may assess hepatic parenchyma and vascular blood flow changes before and after TIPS in HBV-related liver cirrhosis.Clinical registration number: ChiCTR- DDC-16009986.
It is of great significance to understand the particle distribution characteristics at different heights to effectively control particle pollution. Based on fractal theory, the fractal dimension of ...outdoor particles in a high-rise building in Xi’an and its relationship with the concentration of particles with different particle sizes are discussed and analyzed in this paper. The results indicate that the atmosphere in Xi’an is mainly composed of fine particles and that the average proportion of particles ranging from 0 to 1.0 µm is approximately 99.885% of the total particulates. The fractal dimension of particles in the atmosphere at different heights ranges from 5.014 to 5.764, with an average fractal dimension of 5.456. In summer, the fractal dimension of the outdoor particles on the 17th floor was the largest, at 5.764. The fractal dimension in summer is relatively high, being 0.158 higher than that in winter on average. The larger the fractal dimension, the higher the proportion of fine particles. In addition, the fractal dimension can characterize the adsorption of toxic and harmful gases by particles well. It provides parameter support for understanding particle distribution and the effective control of atmospheric particles at different heights and application values.
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