UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage.

The transcription factor nuclear factor erythroid 2 like 1 (NFE2L1 or NRF1) regulates constitutive and inducible expression of proteasome subunits and assembly chaperones. The precursor of NRF1 is integrated into the endoplasmic reticulum (ER) and can be retrotranslocated from the ER to the cytosol where it is processed by ubiquitin-directed endoprotease DDI2. DDI2 cleaves and activates NRF1 only when NRF1 is highly polyubiquitinated. It remains unclear how retrotranslocated NRF1 is primed with large amount of ubiquitin and/or very long polyubiquitin chain for subsequent processing. Here, we report that E3 ligase UBE4A catalyzes ubiquitination of retrotranslocated NRF1 and promotes its cleavage. Depletion of UBE4A reduces the amount of ubiquitin modified on NRF1, shortens the average length of polyubiquitin chain, decreases NRF1 cleavage efficiency and causes accumulation of non-cleaved, inactivated NRF1. Expression of a UBE4A mutant lacking ligase activity impairs the cleavage, likely due to a dominant negative effect. UBE4A interacts with NRF1 and the recombinant UBE4A can promote ubiquitination of retrotranslocated NRF1 in vitro. In addition, knocking out UBE4A reduces transcription of proteasomal subunits in cells. Our results indicate that UBE4A primes NRF1 for DDI2-mediated activation to facilitate expression of proteasomal genes.

Scenario simulation of the EU carbon price and its enlightenment to China.

Through exploring price characteristics of carbon futures products in EU ET, this paper aims to provide China's policy makers with meaningful materials and references for understanding how a carbon trading market can be established and well regulated. Based on the dataset comprising of multiple sources including Euro stoxx600 index, coal and crude oil prices, natural gas prices and European clean energy company stock prices, etc., this paper uses BP neural network model to simulate the long-term trends of carbon futures prices in six scenarios that represent the typical features of a carbon trading market. The results show that: (1) the magnitude of economic development's effect on carbon price is the largest among other factors, with the shortest duration; (2) in comparison, the effect of black energy consumption is weaker, but its lasting duration is the longest; (3) the impact of clean energy development on carbon price is similar to that of black energy, but the effect magnitude and lasting duration are relatively smaller. These findings suggest three viable directions for the development of China's carbon trading market in future i.e. adjusting total quotas in accordance with economic development, establishing market price stabilization mechanism, and developing clean energy. The novelty of this paper is to simulate the long-term trend of carbon prices by constructing a carbon price prediction system.

Study on serviceability and efficiency of seven pilot carbon trading exchanges in China.

Carbon trading has become a major innovation for many countries to cope with climate change, where in China the 7 pilot markets have been running for over 6 years with different performances shown. Being the actual venue where buyers and sellers trade carbon permits, how well and efficient a carbon trading exchange is designed directly affects whether the market can fulfill its environmental purpose. This paper selects 13 sub-indicators from three dimensions of main settings, risk prevention & control, and regional cooperation to evaluate the serviceability of the 7 exchanges in pilot carbon markets in China. Using which as input indicator and market operational effect as output indicator that represented by 5 sub-indicators including percentage of valid trading days, dispersion of trading volume etc., the study attempts to analyze how the serviceability of exchanges affect market operation. By applying the SUP-CCR-DEA (Super-efficiency CCR Data Envelope Analyze) model on 7 exchanges' trading data from 2013 to 2017, the study finds that the serviceability of the exchanges varies significantly, with Shanghai being the best and Shenzhen ranks the second. Obvious stratification is detected but with small changes during the four years observed, differences in main settings and transaction management system being the primary cause. It is found that the serviceability has a direct and significant impact on the market performance for all 6 exchanges except for Tianjin, and for those top-ranked exchanges, strong enforcement system and legally binding agreements contribute to their high service efficiency.

Correlation and expression analysis of hypoxia-inducible factor 1α, glucose transporter 1 and lactate dehydrogenase 5 in human gastric cancer.

The development and identification of novel potential targeting sites for intervention therapy are essential in the search for improved treatment methods for gastric cancer (GC). Previously, it has been reported that hypoxia inducible factor-1α (HIF-1α) is a potential target gene involved in the endogenous hypoxic response and bioenergetic metabolism of GC cells. In the present study, with the assumption of a close interplay among HIF-1α, glucose transporter 1 (GLUT1) and lactate dehydrogenase-5 (LDH-5), 85 patients with GC were recruited and the protein and gene expression levels of HIF-1α, GLUT1 and LDH-5 in tumor tissues were evaluated in order to assess clinical correlations and co-expression patterns, using Immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction. The results demonstrated that the protein and gene expression levels of HIF-1α were significantly associated with the depth of invasion, nodal metastasis, clinical stage, differentiation and distant metastasis. Consistent with the protein expression results, the mRNA expression levels of the genes coding for GLUT1 and LDH-5 were clearly associated with tumor size, depth of invasion, distant metastasis, clinical stage and differentiation. Correlation analysis of HIF-1α with GLUT1 and LDH-5 at the protein and mRNA expression levels in gastric carcinoma indicated that HIF-1α expression was positively correlated with the expression of GLUT1 (P<0.01, r=0.765 for mRNA expression; P<0.01, r=0.697 for protein expression) and LDH-5 (P<0.01, r=0.892 for mRNA expression; P<0.01, r=0.783 for protein expression) at the mRNA and protein levels. Therefore, it may be concluded that HIF-1α, GLUT1 and LDH-5 are potential target genes involved in the endogenous tumor response to hypoxia and the inhibition of tumor energy metabolism, highlighting a novel therapeutic target for GC.

Transjugular intrahepatic portosystemic shunt for the prevention of recurrent esophageal variceal bleeding in patients with cavernous transformation of portal vein.

BACKGROUND: Treatment options for patients with cavernous transformation of portal vein (CTPV) are limited. This study aimed to evaluate the feasibility, efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) to prevent recurrent esophageal variceal bleeding in patients with CTPV. METHODS: We retrospectively analyzed 67 consecutive patients undergone TIPS from January 2011 to December 2016. All patients were diagnosed with CTPV. The indication for TIPS was a previous episode of variceal bleeding. The data on recurrent bleeding, stent patency, hepatic encephalopathy and survival were retrieved and analyzed. RESULTS: TIPS procedure was successfully performed in 56 out of 67 (83.6%) patients with CTPV. TIPS was performed via a transjugular approach alone (n = 15), a combined transjugular/transhepatic approach (n = 33) and a combined transjugular/transsplenic approach (n = 8). Mean portosystemic pressure gradient (PSG) decreased from 28.09 ±â€¯7.28 mmHg to 17.53 ±â€¯6.12 mmHg after TIPS (P < 0.01). The probability of the remaining free recurrent variceal bleeding was 87.0%. The probability of TIPS patency reached 81.5%. Hepatic encephalopathy occurrence was 27.8%, and survival rate was 88.9% until the end of follow-up. Four out of 11 patients who failed TIPS died, and 4 had recurrent bleeding. CONCLUSIONS: TIPS should be considered a safe and feasible alternative therapy to prevent recurrent esophageal variceal bleeding in patients with CTPV, and to achieve clinical improvement.

Secretion of pro- and mature Rhizopus arrhizus lipases by Pichia pastoris and properties of the proteins.

The lipases of Rhizopus spp. share a high 1,3-regiospecificity toward triacylglycerols, which makes them important enzymes in lipid modification. In the present study, the extracellularly active production of recombinant Rhizopus arrhizuslipase was carried out with genes encoding the mature region (mRAL) and the mRAL having the prosequence (ProRAL) in Pichia pastoris. Two transformed P. pastoris clones containing the multicopy of mRAL and ProRAL genes were separately selected for the production of recombinant enzymes. In a fed-batch cultivation, where methanol feeding was controlled by an on-line methanol analyzer, the supernatant contained 91 mg/L recombinant pro-form lipase (rProRAL) and 80 mg/L recombinant mature lipase (rRAL) after 92 h of cultivation. rProRAL and rRAL were purified by ultrafiltration, SP-Sepharose Fast Flow chromatography, and Butyl-Sepharose Fast Flow chromatography. Molecular weights of rProRAL and rRAL are 32 kDa and 29 kDa, respectively. The amino-terminal analysis showed that the 32-kDa protein was mRAL attached with 28 amino acids of the carboxy-terminal part of the prosequence (rPro28RAL). The specific lipase activities of mRAL attached with 28 amino acids of the carboxy-terminal part of the prosequence (rPro28RAL) and rRAL were 1543 U/mg and 2437 U/mg. The rPro28RAL was more stable than rRAL at pH 4.0-7.0, whereas rRAL was more stable at pH 7.0-10.0. The rPro28RAL had the highest lipase activity toward tributyrin (C4), whereas rRAL had the highest lipase activity toward tricaprylin (C8).