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Previous studies have shown that microRNA-1304 （miR-1304） is dysregulated in certain types of cancers, including non-small cell lung cancer （NSCLC）, and might be involved in tumor survival and/or growth. In this study we investigated the direct target of miR-1304 and its function in NSCLC in vitro. Human lung adenocarcinoma cell lines （A549 and NCI-H1975） were studied. The cell proliferation and survival were investigated via cell counting, MTT and colony-formation assays. Cell apoptosis and cell cycle were examined using annexin V-PE/7-AAD and PI staining assays, respectively. The dual-luciferase reporter assay was used to verify post-transcriptional regulation of heme oxygenase-1 （HO-1） by miR-1304. CRISPR/Cas9 was used to deplete endogenous miR-1304. Overexpression of MiR-1304 significantly decreased the number and viability of NSCLC cells and colony formation, and induced cell apoptosis and Go/ G~ phase cell cycle arrest. HO-1 was demonstrated to be a direct target of miR-1304 in NSCLC cells. Restoration of HO-1 expression by hemin （20 IJmol/L） abolished the inhibition of miR-1304 on cell growth and rescued miR-1304-induced apoptosis in A549 cells. Suppression of endogenous miR-1304 with anti-1304 significantly increased HO-1 expression and promoted cell growth and survival in A549 cells. In 17 human NSCLC tissue samples, miR-1304 expression was significantly decreased, while HO-1 expression was significantly increased as compared to normal lung tissues. MicroRNA-1304 is a tumor suppressor and HO-1 is its direct target in NSCLC. The results suggest the potential for miR-1304 as a therapeutic target for NSCLC.

Blockade of the immunosuppressive checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed death 1 (PD-1) and its cognate ligand, programmed death 1 ligand (PD-L1), has altered the landscape of anti-tumor immunotherapy. B7 family and tumor necrosis factor receptor (TNFR) superfamily play a crucial role in T cell activation, tolerance, and anergy through co-stimulatory and inhibitory signal transduction. Investigating the immune molecular landscapes of the B7 and TNFR families is critical in defining the promising responsive candidates. Herein, we performed comprehensive alteration analysis of the B7 and TNFR family genes across six hepatocellular carcinoma (HCC) datasets with over 1000 patients using cBioPortal TCGA data. About 16% of patients had both B7 and TNFR gene alterations. TNFR gene amplifications were relatively more common (1.73–8.82%) than B7 gene amplifications (1.61–2.94%). Analysis of 371 sequenced samples revealed that all genes were upregulated: B7 and TNFR mRNA were upregulated in 23% of cases (86/371) and 28% of cases (105/371), respectively. Promoter methylation analysis indicated an epigenetic basis for B7 and TNFR gene regulation. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. B7-H6 expression was significantly associated with worse overall survival, and B7-H6 mRNA was increased gradually in cases with gene copy number alterations. B7-H6 overexpression was associated with aggressive clinicopathologic features and poor prognosis in HCC. Downregulation of B7-H6 in HCC cells significantly inhibited cell adhesion, proliferation, migration, and invasion. Knockdown of B7-H6 in HCC cells inhibited tumor growth and metastasis in vivo. B7-H6 promoted HCC metastasis via induction of MMP-9 expression and STAT3 activation. B7-H6 and STAT3 performed functional overlapping roles on enhancing the MMP-9 promoter activity in HCC cells. These results suggest that alterations of the immunologic co-stimulator B7 and TNFR families correlate with HCC metastasis and prognosis, and especially B7-H6 plays a critical role in promoting metastasis of HCC.

Dicer1 is an enzyme essential for microRNA （miRNA） maturation. The loss of miRNAs resulted from Dicer1 deficiency greatly contributes to the progression of many diseases, including lipid dysregulation, but its role in hepatic accumulation of free cholesterol （FC） that is critical in the development of non-alcoholic steatohepatitis （NASH） remains elusive, In this study, we used the liver-specific Dicerl-knockout mice to identify the miRNAs involved in hepatic FC accumulation. In a widely used dietary NASH model, mice were fed a methionine-choline-deficient （MCD） diet for 3 weeks, which resulted in significant increase in hepatic FC levels as well as decrease of Dicer1 mRNA levels in livers. The liver-specific Dicerl-knockout induced hepatic FC accumulation at 5-6 weeks, accompanied by increased mRNA and protein levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase （HMGCR）, a rate-limiting enzyme of cholesterol synthesis in livers. Eleven predicted miRNAs were screened, revealing that miR-29a/b/c significantly suppressed HMGCR expression by targeting the HMGCR mRNA 3＇-UTR. Overexpression of miR-29a in SMMC-7721 cells, a steatosis hepatic cell model, significantly decreased HMGCR expression and the FC level. Furthermore, the expression levels of miR-29a were inversely correlated with HMGCR expression levels in the MCD diet mouse model in vivo and in 2 steatosis hepatic cell models （SMMC-7721 and HL-7702 cells） in vitro. Our results show that Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse NASH, and miR-29 may serve as an important regulator of hepatic cholesterol homeostasis. Thus, miR-29a could be utilized as a potential therapeutic target for the treatment of non-alcoholic fatty liver disease as well as for other liver diseases associated with FC accumulation.

In order to improve the production efficiency of electroslag remelting process and the solidification quality of electroslag ingot, a novel electroslag furnace with electromagnetic stirring was designed and the effects of external magnetic field and different electrical parameters on electroslag remelting process were studied. The distribution of carbon, chromium, phosphorus and compactness in electroslag ingot was analyzed through original position analysis apparatus. Results show that the external magnetic field accelerates the remelting of consumable electrode. Under the condition of remelting voltage of 34 V and current of 1500 A, the remelting rate of metal consumable electrode increases from 20 to 27 mm min −1 when the magnetic induction intensity of 62 × 10 −4 and 108 × 10 −4  T is applied. However, the remelting current decreases from 1500 to 1100 A under the condition of constant remelting rate and remelting voltage, thereby reducing the energy consumption. The effect of external magnetic field on the segregation of different elements in electroslag ingot is different. Under the experimental conditions, the carbon segregation is unremarkable, but the phosphorus segregation is improved when the electromagnetic force generated by the interaction between the external magnetic field and the remelting current is small. However, the excessive electromagnetic force aggravates the segregation of carbon and phosphorus. With the increase in electromagnetic force, the chromium segregation gradually increases.

A novel inorganic-organic hybrid supramolecular macrocyclic compound, (4-nitroanilinium)(18-crown-6)(PF6)(1), was synthesized and characterized by infrared spectroscopy, thermogravimetric analysis, elemental analysis, differential scanning calorimetry (DSC), and single-crystal X-ray diffraction. Crystal 1 is found to comprise 1D C–H···F–P hydrogen-bonded chains of (4-nitroanilinium+)(18-crown-6) supramolecular cations and PF6− anions. DSC measurements confirm that 1 undergoes a reversible phase transition at 255 K with a hysteresis width of 6 K. A strong dielectric response is observed above 250 K at a low frequency (500 Hz), suggesting the occurrence of proton transfer in the C–H···F–P hydrogen bonds. A precise analysis on the main packing and structural differences, as well as the changes in the intermolecular interaction between the low- and high-temperature phases, reveals that C–H···F–P hydrogen bonds are the main factors affecting phase transition and dielectric behavior.

Biochar is widely considered as a soil amendment. This study aims to investigate the leaching of macronutrients (K, Mg and Ca) and organics from biochars produced from mallee biomass (wood, leaf, bark) in a fluidised-bed pyrolyser at 500 °C. Biochars were soaked in solutions of varying pH values and shaken for a pre-set period of time ranging from 1 h to 4 weeks. The initial pH values of the leaching solutions used (3.4, 5.5, 7 and 8.5) covered the pH range of the soils in the Wheatbelt region of Western Australia (WA). For these bark, leaf and wood biochars, we can conclude that the biochars have a liming capacity for the acid soils of the WA Wheatbelt, depending on the feedstock. The maximum leachabilities and leaching kinetics of the macronutrients K, Mg and Ca depend on the pH of the solution in which biochar was soaked. Apparently, Ca, K and Mg in biomass are converted into different species upon pyrolysis, and the biomass species are critical for the extent of the leachability of macronutrients. Further, the chemical form of each nutrient retained in the biochars will dictate the kinetics as a function of soil pH. This study’s GC/MS analysis of solvent extraction of the biochars showed potential toxicity due to the leaching of light organic compounds when biochars are added to soils. Furthermore, this study also showed the influence of pH on the leaching of large aromatic organics from the biochars. Apart from the pH of leaching solution, the influence of the biomass feedstock on the leaching kinetics of large aromatic organics from biochars was demonstrated. These leached aromatic organics were characterised by UV-fluorescence spectroscopy.

Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3 mice. Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.

Aim: Monocrotaline (MCT) in plants of the genus Crotalaria induces significant toxicity in multiple organs including the liver, lung and kidney. Metabolic activation of MCT is required for MCT-induced toxicity. In this study, we attempted to determine whether the toxicity of MCT in kidney was a consequence of the metabolic activation of MCT in the liver. Methods: Liver-specific cytochrome P450 reductase-null (Null) mice, wild-type (WT) mice and CYP3A inhibitor ketoconazole-pretreated WT (KET-WT) mice were examined. The mice were injected with MCT (300, 400, or 500 mg/kg, ip), and hepatotoxicity and nephrotoxicity were examined 24 h after MCT treatment. The levels of MCT and its metabolites in the blood, liver, lung, kidney and bile were determined using LC-MS analysis. Results: Treatment of WT mice with MCT increased the serum levels of alanine aminotransferase, hyaluronic acid, urea nitrogen and creatinine in a dose-dependent manner. Histological examination revealed that MCT (500 mg/kg) caused severe liver injury and moderate kidney injury. In contrast, these pathological abnormalities were absent in Null and KET-WT mice. After injection of MCT (400 and 500 mg/kg), the plasma, liver, kidney and lung of WT mice had significantly lower MCT levels and much higher N-oxide metabolites contents in compared with those of Null and KET-WT mice. Furthermore, WT mice had considerably higher levels of tissue-bound pyrroles and bile GSH-conjugated MCT metabolites compared with Null and KET-WT mice. Conclusion: Cytochrome P450s in mouse liver play a major role in the metabolic activation of MCT and thus contribute to MCT-induced renal toxicity.

Background：The location of facial port-wine stain （PWS） may be helpful for predicting some associated anomalies;high glaucoma incidence is found in patients with eyes close to PWS-affected areas （V1,ophthalmic branch area of the trigeminal nerve）.This study aimed to investigate the characteristics of glaucoma in V1-affected PWS.Methods：A total of 569 patients with V1 area-affected PWS were reviewed in the study.The large series was based on the referral system between the Department of Plastic and Reconstructive Surgery and the Department of Ophthalmology.All patients were screened for glaucoma with assessments of intraocular pressure,cup-to-disc ratio,comeal diameter （only for infants）,and axial length.Results：Of the 569 patients,110 （19.3%） patients had glaucoma.Among the patients,18.1% （76/420） had early-onset glaucoma （under 4-year-old group）.In the 4 to 18-year-old age group,29.3% （29/99） of the patients had glaucoma.Compared with right lateral and bilateral PWS,left-sided PWS had a lower risk of glaucoma in this study （odds ratio =0.432 [95% confidence interval,0.264-0.706],P =0.01）.The under 4-year-old group showed a slight predominance of males （61.8%） in glaucoma.Conclusions：High glaucoma incidence was observed in patients with eyes close to PWS.More attention should be paid to glaucoma screening for right lateral and bilateral PWS patients.The predominance of males in Sturge-Weber syndrome （SWS） early-onset glaucoma patients might be due to the limitation of the case number;however,it might also provide us a new clue of potential relationship between SWS and PCG.

Background： Auditory verbal hallucinations （AVHs） of schizophrenia have been associated with structural and functional alterations of some brain regions. However, the brain regional homogeneity （ReHo） alterations specific to AVHs of schizophrenia remain unclear. In the current study, we aimed to investigate ReHo alterations specific to schizophrenic AVHs. Methods： Thirty-five schizophrenic patients with AVH, 41 schizophrenic patients without AVHs, and fifty healthy subjects underwent resting-state functional magnetic resonance imaging. ReHo differences across the three groups were tested using a voxel-wise analysis. Results： Compared with the healthy control group, the two schizophrenia groups showed significantly increased ReHo in the right caudate and inferior temporal gyrus and decreased ReHo in the bilateral postcentral gyrus and thalamus and the right inferior occipital gyrus （false discovery rate corrected, P 〈 0.05）. More importantly, the AVH group exhibited significantly increased ReHo in the left precuneus compared with the non-AVH group. However, using correlation analysis, we did not find any correlation between the auditory hallucination rating scale score and the ReHo of brain regions. Conclusions： Our results suggest that increased ReHo in the left precuneus may be a pathological feature exclusive to schizophrenic AVHs.