Upregulation of UCP2 by Adiponectin: The Involvement of Mitochondrial Superoxide and hnRNP K

Background: The adipocyte-derived hormone adiponectin elicits protective functions against fatty liver diseases and hepatic injuries at least in part by stimulating the expression of a mitochondrial inner membrane transporter, uncoupling protein 2 (UCP2). The present study was designed to investigate the cellular and molecular mechanisms underlying adiponectin-induced UCP2 expression. Methodology/Principal Findnigs: Mice were treated with adiponectin and/or different drug inhibitors. Parenchymal (PCs) and nonparenchymal (NPCs) cells were fractionated from the liver tissues for mitochondria isolation, Western blotting and quantitative PCR analysis. Mitochondrial superoxide production was monitored by MitoSOX staining and flow cytometry analysis. Compared to control mice, the expression of UCP2 was significantly lower in NPCs, but not PCs of adiponectin knockout mice (AKO). Both chronic and acute treatment with adiponectin selectively increased the mRNA and protein abundance of UCP2 in NPCs, especially in the enriched endothelial cell fractions. The transcription inhibitor actinomycin D could not block adiponectin-induced UCP2 expression, whereas the protein synthesis inhibitor cycloheximide inhibited the elevation of UCP2 protein but not its mRNA levels. Mitochondrial content of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a nucleic acid binding protein involved in regulating mRNA transportation and stabilization, was significantly enhanced by adiponectin, which also evoked a transient elevation of mitochondrial superoxide. Rotenone, an inhibitor of mitochondrial respiratory complex I, abolished adiponectin-induced superoxide production, hnRNP K recruitment and UCP2 expression. Conclusions/Significance: Mitochondrial superoxide production stimulated by adiponectin serves as a trigger to initiate the translocation of hnRNP K, which in turn promotes UCP2 expressions in liver. © 2012 Zhou et al.published_or_final_versio

RNA Sequencing (RNA-Seq) Analysis Reveals Liver Lipid Metabolism Divergent Adaptive Response to Low- and High-Salinity Stress in Spotted Scat (<i>Scatophagus argus</i>)

Spotted scat (Scatophagus argus) can tolerate a wide range of salinity fluctuations. It is a good model for studying environmental salinity adaptation. Lipid metabolism plays an important role in salinity adaptation in fish. To elucidate the mechanism of lipid metabolism in the osmoregulation, the liver transcriptome was analyzed after 22 d culture with a salinity of 5 ppt (Low-salinity group: LS), 25 ppt (Control group: Ctrl), and 35 ppt (High-salinity group: HS) water by using RNA sequencing (RNA-seq) in spotted scat. RNA-seq analysis showed that 1276 and 2768 differentially expressed genes (DEGs) were identified in the LS vs. Ctrl and HS vs. Ctrl, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the pathways of steroid hormone biosynthesis, steroid biosynthesis, glycerophospholipid metabolism, glycerolipid metabolism, and lipid metabolism were significantly enriched in the LS vs. Ctrl. The genes of steroid biosynthesis (sqle, dhcr7, and cyp51a1), steroid hormone biosynthesis (ugt2a1, ugt2a2, ugt2b20, and ugt2b31), and glycerophospholipid metabolism (cept1, pla2g4a, and ptdss2) were significantly down-regulated in the LS vs. Ctrl. The pathways related to lipid metabolisms, such as fatty acid metabolism, fatty acid biosynthesis, peroxisome proliferator-activated receptor (PPAR) signaling pathway, adipocytokine signaling pathway, fatty acid degradation, and unsaturated fatty acid biosynthesis, were significantly enriched in the HS vs. Ctrl. The genes of unsaturated fatty acid biosynthesis (scd1, hacd3, fads2, pecr, and elovl1) and adipocytokine signaling pathway (g6pc1, socs1, socs3, adipor2, pck1, and pparα) were significantly up-regulated in the HS vs. Ctrl. These results suggest that the difference in liver lipid metabolism is important to adapt to low- and high-salinity stress in spotted scat, which clarifies the molecular regulatory mechanisms of salinity adaptation in euryhaline fish

Numerical simulation of fire flooding for heavy oil reservoirs after steam injection: A case study on Block H1 of Xinjiang Oilfield, NW China

With the 3a pilot area in Block H1 of Xinjiang Oilfield as an example, a basic model for accurate numerical simulation of fire flooding is established combining with physical simulation and field performance, after oil components are divided reasonably, high temperature combustion formula is defined. This model is used to trace and simulate the fire flooding in Block H1. The main results are as follows: (1) secondary water generated after steam injection is mostly displaced by flue gas during initial combustion phase, and only a small fraction works for limited wet combustion; (2) the flooded reservoirs, from the gas injection well to the production well, are divided into burnt zone, fire wall, coking zone, high temperature condensed zone (added newly), oil bank, and residual oil zone; and (3) the fire flooding for reservoir after steam injection, unlike original reservoir, experiences a process of oil bank building and migration featuring “pit filled and bank built”, with bank shape related to the performance of adjacent production wells. Moreover, the field experiment indicates that the numerical simulation of fire flooding contributes to the prediction and management of flooding performance. Key words: heavy oil reservoir, fire flooding, numerical simulation, secondary water, oil bank, high temperature condensed zon

Genome-Wide Binding Site Analysis of FAR-RED ELONGATED HYPOCOTYL3 Reveals Its Novel Function in Arabidopsis Development

FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and its homolog FAR-RED IMPAIRED RESPONSE1 (FAR1), two transposase-derived transcription factors, are key components in phytochrome A signaling and the circadian clock. Here, we use chromatin immunoprecipitation–based sequencing (ChIP-seq) to identify 1559 and 1009 FHY3 direct target genes in darkness (D) and far-red (FR) light conditions, respectively, in the Arabidopsis thaliana genome. FHY3 preferentially binds to promoters through the FHY3/FAR1 binding motif (CACGCGC). Interestingly, FHY3 also binds to two motifs in the 178-bp Arabidopsis centromeric repeats. Comparison between the ChIP-seq and microarray data indicates that FHY3 quickly regulates the expression of 197 and 86 genes in D and FR, respectively. FHY3 also coregulates a number of common target genes with PHYTOCHROME INTERACTING FACTOR 3-LIKE5 and ELONGATED HYPOCOTYL5. Moreover, we uncover a role for FHY3 in controlling chloroplast development by directly activating the expression of ACCUMULATION AND REPLICATION OF CHLOROPLASTS5, whose product is a structural component of the latter stages of chloroplast division in Arabidopsis. Taken together, our data suggest that FHY3 regulates multiple facets of plant development, thus providing insights into its functions beyond light and circadian pathways

Reform and prospects of mining technology for large inclined coal seam in China

The steeply dipping coal seam is one of the main forms of coal storage in China. It is widely and regionally distributed. According to incomplete statistics, twenty-six provinces, autonomous regions and municipalities directly under the central government are involved in the mining of such coal seams, with abundant reserves, large production and high production concentration in the central and western regions. It shows diversity and complexity in terms of the conditions of existence, with different regions having different coal formation periods and different tectonic control processes, forming diverse and complex mining conditions and giving rise to different mining technology requirements. The mining of steeply dipping coal seam is technically difficult. The asymmetry of the movement and damage of the peripheral rock in the mining area affected by the inclination angle of the coal seam is obvious, and the difficulty of the stability control of the support system and equipment, the matching and coordination of the “three machines”, the layout and support of the mining roadway, and the safety guarantee of the “human-machine” environment at the working face has increased significantly, which seriously restricts the safe and efficient mining of the mine. This has seriously restricted the improvement of safe and efficient mining. The regional economic demand for the mining of steeply dipping coal seam is strong. This kind of coal seams and the production of more concentrated areas are mostly seen in the coal industry-based resource cities, the economic structure is relatively single, the safe and efficient development and utilization of coal resources for the regional energy supply, people’s livelihood, economic stability has the role of the bottom of the pocket, the demand is urgent. For a long time, mining technologies for the steeply dipping coal seam changes focus on solving the “difficult” and “need” contradiction. In the coal mining methods and techniques, strata control theory and technology, complete sets of equipment development and application of the three aspects of continuous improvement, innovation, development, to achieve the transformation from non-mechanized to fully-mechanized mining, the level of safety and production efficiency has increased dramatically, the personnel labor intensity has decreased dramatically, and the operating environment has improved significantly. In the mid-1990s, Lvshuidong Coal Mine of Sichuan Coal Industry Group Limited Liability Company successfully realized longwall fully-mechanized mining in steeply dipping coal seam with medium mining height for the first time, breaking through the "forbidden zone" in this filed. Under this demonstration, the three pioneering engineering practices of longwall fully-mechanical mining of steeply dipping coal seam with thick mining height, steeply dipping coal seam with large mining height, and longwall fully-mechanical mining of steeply dipping coal seam with thin mining height in pseudo-inclination have been successful successively, which innovated the non-linear limiting arrangement of the working face and the way of adjusting the slanting, established a multi-dimensional interactive control mode of the system stability of the “bracket-surrounding rock”, and researched and developed the “support and stability and heavy weight, high-strength and light-weight, safe and reliable, and matching synergistic” complete set of equipment of the working face, which has achieved good results, and the scope of application of the comprehensive mechanized mining technology has further been widened. At the same time, there are still many key scientific problems and technical bottlenecks that need to be broken through in the mining of steeply dipping coal seams, resulting in a large gap between the intelligence level and that of the flat/gently inclined coal seams. Research on the mining dynamics of coal and rock bodies in inclined bedded coal beds, revealing their control mechanisms on the disaster of the surrounding rocks in the mining field, and realizing quantitative characterization need to be further strengthened. It is necessary to further clarify the multi-dimensional dynamic process and law between the system of “rock-bearing structure - mining equipment group”, improve the theoretical and technological basis of “multi-dimensional dynamic multi-objective synergistic control of equipment and surrounding rock”, and realize the transformation and application of the technology. On the basis of breakthroughs in scientific issues, we will carry out systematic technological innovation and research and development of coal mining methods, mining techniques, rock formation control, and complete sets of equipment, so as to crack the bottleneck of the constraints on the double enhancement of “safety and efficiency” in the mining of steeply dipping coal seams, and make the upper limit of the inclination of the steeply dipping coal seams for comprehensive mechanized mining extend upward under the prerequisite of reliable technological safeguards, so as to lay the foundation for the realization of automated and intelligent mining

Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer

Abstract Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment