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Objectives. The efficacy of tivantinib may have some potential in treating MET-high hepatocellular carcinoma, and we aim to compare tivantinib with placebo for the treatment of MET-high hepatocellular carcinoma. Methods. Several databases including PubMed, Cochrane Library, Web of Science, EBSCO, and EMbase have been systematically searched through March 2022, and we included studies regarding the treatment of MET-high hepatocellular carcinoma by using tivantinib versus placebo. Results. We finally include three RCTs. In comparison with placebo for MET-high hepatocellular carcinoma, tivantinib reveals no significant influence on overall survival ( P = 0.21 ), progression-free survival ( P = 0.13 ), time to progression ( P = 0.38 ), or grade ≥3 anemia ( P = 0.50 ) but increases the incidence of grade ≥3 neutropenia ( P = 0.04 ). Conclusions. Tivantinib may provide no additional benefits for MET-high hepatocellular carcinoma.

Graves' disease (GD) is one of the most common autoimmune conditions, but the mechanisms underlying the associated induction of autoimmunity are not known. We explored the role of peripheral lymphocyte subpopulations in disease pathogenesis.In total, 32 patients and 40 age- and sex-matched healthy controls were recruited in this study. Peripheral levels of T, B, NK, CD4The absolute numbers of circulating Th17 cells (0.45 ± 1.16, p 0.05) between GD patients and healthy controls were not significantly different. However, the percentage of Th17 cells was significantly increased (0.25 ± 0.11, p 0.05). The absolute numbers and percentages of circulating Tregs in GD patients were significantly decreased compared with those in healthy participants (11.61 ± 2.75, p 0.05). There was a significant difference in Treg absolute numbers between the untreated and drug-treated groups. Furthermore, we found that the Treg percentage in untreated patients (mean=4.78) was not significantly different from that in the drug-treated group (mean=4.81). In addition, circulating Treg absolute numbers in GD patients with exophthalmos were significantly lower than those in GD patients without exophthalmos (9.96 ± 4.16, p 0.05). A similar trend was observed in GD patients with weight loss (11.97 ± 3.28, p 0.05).GD pathogenesis was associated with a lower Treg population and an increased Th17/Treg ratio (T helper cell 17/ regulatory T cells). Th17 cells in this study were not related to the disease. Furthermore, anti-thyroid drug therapy improved immune-mediated system disorders. Finally, we found lower absolute numbers of circulating Tregs in GD patients with certain positive signs, such as exophthalmos and/or weight loss. Thus, immune changes are correlated with partial clinical manifestations.

The sinterability, microstructure, and mechanical properties of pure TiB2- and CrB2-doped ZrB2 prepared by spark plasma sintering were investigated. The solid solutions were synthesized by the complete borothermal reduction to form (Zr0.95Ti0.05)B2 and (Zr0.95Cr0.05)B2. The results showed that the solid solution of (Zr0.95Ti0.05)B2 yielded the smaller particle size than that of (Zr0.95Cr0.05)B2. The sinterability was also improved with the use of the solid solutions, as evidenced by an increase of relative density but at the cost of coarsened microstructure. Overall, (Zr0.95Cr0.05)B2 possessed significantly higher relative density and Vickers hardness than ZrB2 and (Zr0.95Ti0.05)B2.

Starting from ZrO2 and boron (molar ratio: 1:4), four ZrB2 powders were synthesized by borothermal reduction method, three of which were designed to introduce minor modifications by combining solid solution with Ti and/or water-washing. The sinterability, microstructures, mechanical properties and thermal conductivity were investigated. In comparison with the conventional borothermal reduction, the modified methods offered significant improvement in terms of densification of ZrB2 ceramics, particularly the mixture that included water-washing. Owing to the refined particle size and boron residues, ZrB2 ceramics from the modified borothermal reduction which included water-washing demonstrated nearly full densification, Vickers hardness of 14.0 GPa and thermal conductivity of 82.5 W/m K after spark plasma sintering at 2000 °C for 10 min. It was revealed that the properties of ZrB2 ceramics could be enhanced utilizing the proposed minor modification, starting from the same raw materials and adopting the same sintering conditions.

Silicon carbide ceramics were pressureless joined by using Ti foil and Si powder, which generated Ti3SiC2 phase as the interlayer. The phase composition, microstructure and the shear strength were investigated. It was revealed that the SiC assembly after joining at 1500oC showed the high shear strength of 76.2 ± 19.5 MPa. The secondary phase of TiC within the interlayer was expected to contribute to densification improvement of Ti3SiC2 phase and thermal stress reduction.

Microstructure evolution of MeB2 (Me = Zr, Ti) powders prepared by borothermal reduction of the corresponding oxides with boron under vacuum was investigated after heat-treatment at different temperature. The existence of the by-product B2O3 resulted in the coarsening of faceted ZrB2 particles at 1550 °C or below, whereas B2O3 showed almost no effect on the size and morphology of TiB2 or Zr0·98Ti0·02B2 particles. It could be concluded that the coarsening of ZrB2 in the temperature range of 1000 °C–1550 °C was caused by the dissolution-reprecipitation mechanism. While, few effects on TiB2 or Zr0·98Ti0·02B2 was found in this temperature range. When subject to higher temperature in B2O3-free environment, the growth was inversely evidenced on TiB2 and Zr0·98Ti0·02B2 but the growth of ZrB2 particle could be retained, indicative of the surface diffusion, which controlled the particle growth at high temperature.

By using nano-infiltration and transient eutectic (NITE) phase with nanosized SiC and the addition of CeO2–Al2O3 as joining material, liquid-phase-sintered SiC ceramics were joined at the relatively low temperature of 1500 °C and 1700 °C. For comparison purpose, Al2O3–Y2O3 and SiO2–Al2O3–Y2O3 were used as the additives to join SiC ceramics. The shear strength of SiC assembly with the interlayer thickness of ~70 μm and addition of CeO2–Al2O3 after joining at 1700 °C was measured to be 163.9 MPa but decreased to 57.4 MPa when joining at 1500 °C. It was revealed that the joining status could be improved by decreasing the thickness of the interlayer to ~35 μm and SiC joint finishing at 1500 °C possessed the comparatively high shear strength of 113.2 MPa. NITE phase containing other additives (Al2O3–Y2O3 and SiO2–Al2O3–Y2O3) showed the much lower shear strength after joining at 1500 °C.

Liquid-phase-sintered SiC ceramics (LPS-SiC) with the sintering additives of Y2O3–Al2O3 and Y2O3–Al2O3–TaB2 were prepared. The oxidation behaviours of these sintered SiC ceramics were studied after oxidation test at 1300 °C in air. In comparison with SiC ceramicwith Y2O3–Al2O3, the addition of TaB2 inhibited the formation of the secondary phase of Y3Al5O12 (YAG) and homogeneous distribution of Al element in the SiC matrix was evidenced. After oxidation at 1300 °C, SiC ceramic without TaB2 additive was found to possess a two-layer structure within the oxidation region. In contrast, SiC ceramic with TaB2 additive demonstrated the three-layer structure consisting of a dense intermediate layer of SiO2, which could protect the SiC matrix from further oxidation.

Pressureless joining of SiC ceramics at low temperature was developed using Ti powder interlayer. Phase assemblage and microstructure of SiC joint revealed that the products after diffusion bonding mainly consisted of Ti5Si3 and TiC owing to the comparatively low joining temperature. Additionally, Si and C elements were found to be with higher penetration depth in the Ti interlayer. Benefitting from the lower proportion of the brittle Ti5Si3 phase and porosity, shear strength reached a relatively higher value of 41 MPa after joining at 1200 °C for 30 min.

Suppressors of cytokine signaling (SOCS) are important molecules that mediates the regulation of glucose homeostasis. Here, we cloned and characterized the full-length cDNA sequences of nine genes of the SOCS family (SOCS1, 2, 3, 3b, 5, 5b, 6, 7 and CISH) from yellow catfish P. fulvidraco, explored their mRNA abundance across the tissues and their mRNA changes to dietary carbohydrate levels. Structural analysis indicated that the nine members shared conserved functional domains to the orthologues of the mammalian SOCS members, such as SRC homology 2 and the SOCS domains. Their mRNAs were constitutively expressed in various tissues but changed among the tissues. Their mRNA expression in response to dietary carbohydrate levels were explored in the liver, muscle, intestine, testis and ovary. Dietary carbohydrate addition showed significant effects on the mRNA levels of the nine SOCS members. Moreover, their mRNA expressions in response to dietary carbohydrate levels were also tissue-dependent. These indicated that SOCS members potentially mediated the utilization of dietary carbohydrate in yellow catfish.

Cerebral ischemia caused severe disability, and associated with a series of neurological events. Long non-coding RNA SNHG12 was found to be upregulated in mouse brain microvascular endothelial cells by cerebral ischemia. Moreover, it was reported that SNHG12 could directly interact with miR-199a and sirtuin 1 (SIRT1) as a direct target of miR-199a in other diseases. However, the function and mechanism of SNHG12 in cerebral ischemia and reperfusion (I/R) injury of neuronal cells remains unclear. The present study was thus designed to explore the potential effect of SNHG12 and to investigate the underlying mechanism in I/R neuronal cells. we found that SNHG12 was upregulated in primary neuronal cells and N2a cells and peaked at 12 h and 24 h after OGD/R treatment, respectively. Meanwhile, MTT assay showed that knockdown SNHG12 inhibited cell proliferation under OGD/R condition. And flow cytometry analyses revealed more apoptosis rate was caused by SNHG12 knockdown. Mechanistically, SNHG12 interacted with miR-199a and decreased the expression of miR-199a. Overexpression miR-199a largely inhibited the cell proliferation and induced the cell apoptosis. Meanwhile, SNHG12 was proven to target miR-199a and then activated SIRT1 expression, which finally led to activation of AMPK signaling pathway. In summary, we demonstrate SNHG12 targets miR-199a to upregulate SIRT1 expression, which attenuates cerebral ischemia/reperfusion injury through AMPK pathway activation. Our findings provide molecular mechanism by which SNHG12 attenuates cerebral I/R injury and facilitate development of therapeautical strategies for treating ischemia-induced stroke.

High dietary carbohydrate intake leads to lipid accumulation in the intestinal tract, but the molecular mechanism remains unknown. In the present study, using yellow catfish (Pelteobagrus fulvidraco) as a model, we found that (1) high carbohydrate diets (HCD) and high glucose (HG) increased lipid deposition, up-regulated lipogenesis and fatty acid β-oxidation, activated autophagy and induced oxidative stress in the intestinal tissues and intestinal epithelial cells (IECs); (2) lipophagy alleviated HG-induced lipid accumulation via the up-regulation of fatty acid β-oxidation; (3) Akt interacted directly with Beclin1; (4) HG suppressed Akt1 phosphorylation, downregulated Akt1-mediated phosphorylation of Beclin1, activated lipophagy and alleviated the increment of TG deposition induced by HG with S87 and S292 being the key phosphorylation residues of Beclin1 in response to HG; (5) ROS generation mediated HG-induced activation of lipophagy and HG-induced suppression of AKT phosphorylation, activated AMPK and alleviated HG-induced increase of TG deposition. Our study provides mechanistic evidence that high carbohydrate- and glucose-induced lipophagy in intestine and IECs is associated with ROS-AKT-Beclin1-dependent activation of autophagy, which alleviates glucose-induced lipid accumulation. Our findings are important since the regulation of autophagy can be used as potential molecular targets for the prevention and treatment of lipotoxicity in the intestine of vertebrates, including humans.

Background Amino acid-chelated zinc (Zn) can increase anabolism of animals. However, the underlying mechanisms are unclear. We aimed to examine how autophagy impact anabolism following a diet containing methionine-chelated Zn (ZnMet) compared with inorganic Zn (ZnSO4). Methods Yellow catfish (weight: 4.02 ± 0.08 g) were fed two diets containing ZnSO4 or ZnMet for 8 wk. The differences in transcriptional responses and corresponding biological profiles were compared between the livers of fish fed the two Zn sources of diets. Hepatocytes of yellow catfish were incubated for 48 h in medium containing ZnSO4 (10 μM ZnSO4) or ZnMet (10 μM ZnMet) after 2 h pretreated with or without pathway inhibitors. Intracellular Zn, TG and protein contents, lipid droplet and autophagic vesicles were detected. Ultrastructural observation, enzymatic activities, qPCR assays, western blot and immunofluorescence analysis were conducted. Results ZnMet up-regulated the expression of genes associated with anabolism and autophagy. The differentially expressed genes (DEG) analysis indicated that both mTOR and autophagy pathways were activated. ZnMet-induced activation of autophagy was mTOR-independent. In this process, forkhead box class O was deacetylated and activated, and induced autophagy, which provided substrates for energy generation. Conclusions ZnMet increased anabolism through integrating mTOR signal and autophagy pathway in yellow catfish. The present study unravels a novel mechanism for amino acid-chelated minerals improving anabolism.

Objective To explore the clinical value of serum IgM and IgG to SARS‐CoV‐2 in COVID‐19. Methods 105 COVID‐19 patients were enrolled as the disease group. 197 non‐COVID‐19 patients served as the control group. Magnetic chemiluminescent immunoassay (MCLIA) was used to detect the IgM and IgG. Results The peak of positive rates of SARS‐CoV‐2 IgM was about 1 week earlier than that of IgG. It reached to peak within 15–21 days and then began a slowly decline. The positive rates of IgG were increased with the disease course and reached the peak between 22 and 39 days. The differences in sensitivity of the three detection modes (IgM, IgG, and IgM + IgG) were statistically significant. The largest group of test cases (illness onset 15–21 days) showed that the positive rate of IgG was higher than IgM. Also, the sensitivity of IgM combined with IgG was higher than IgM or IgG. IgM and IgG were monitored dynamically for 16 patients with COVID‐19, the results showed that serological transformation of IgM was carried out simultaneously with IgG in seven patients, which was earlier than IgG in four patients and later than IgG in five patients. Conclusion The detection of SARS‐CoV‐2 IgM and IgG is very important to determine the course of COVID‐19. Nucleic acid detection combined with serum antibody of SARS‐CoV‐2 may be the best laboratory indicator for the diagnosis of SARS‐CoV‐2 infection and the phrase and predication for prognosis of COVID‐19., Antibody response to SARS‐CoV‐2 in 105 COVID‐19 patients. (A) The positive rate of SARS‐CoV‐2 antibody in 105 patients. (B) The changes of antibody titers to SARS‐CoV‐2 in 105 patients.

Dysregulation in hepatic lipid synthesis by excess dietary carbohydrate intake is often relevant with the occurrence of fatty liver; therefore, the thorough understanding of the regulation of lipid deposition and metabolism seems crucial to search for potential regulatory targets. In the present study, we examined TAG accumulation, lipid metabolism-related gene expression, the enzyme activities of lipogenesis-related enzymes, the protein levels of transcription factors or genes involving lipogenesis in the livers of yellow catfish fed five dietary carbohydrate sources, such as glucose, maize starch, sucrose, potato starch and dextrin, respectively. Generally speaking, compared with other carbohydrate sources, dietary glucose promoted TAG accumulation, up-regulated lipogenic enzyme activities and gene expressions, and down-regulated mRNA expression of genes involved in lipolysis and small ubiquitin-related modifier (SUMO) modification pathways. Further studies found that sterol regulatory element binding protein 1 (SREBP1), a key transcriptional factor relevant to lipogenic regulation, was modified by SUMO1. Mutational analyses found two important sites for SUMOylation modification (K254R and K264R) in SREBP1. Mutant SREBP lacking lysine 264 up-regulated the transactivation capacity on an SREBP-responsive promoter. Glucose reduced the SUMOylation level of SREBP1 and promoted the protein expression of SREBP1 and its target gene stearoyl-CoA desaturase 1 (SCD1), indicating that SUMOylation of SREBP1 mediated glucose-induced hepatic lipid metabolism. Our study elucidated the molecular mechanism of dietary glucose increasing hepatic lipid deposition and found that the SREBP-dependent transactivation was regulated by SUMO1 modification, which served as a new target for the transcriptional programmes governing lipid metabolism.

To explore the clinical application value of serum light chain (sLC) in the diagnosis and therapeutic efficacy evaluation for multiple myeloma.46 patients with newly diagnosed multiple myeloma were selected as MM group and 50 healthy persons as control group. Rate scattering immunoturbidimetry was used to detect serum light chain and immunoglobulin (Ig) in two groups, serum protein electrophoresis was used to detect M protein by agarose gel. Then, the sensitivity and specificity of the two methods in MM diagnosis were analyzed and compared, and the significance of sLC detection in MM diagnosis were discussed. In addition, 15 MM patients after received conventional therapy were tracked, sLC levels in five different therapentic times were recorded, and the effect of sLC in efficacy evaluation of MM was analyzed.There were 11 cases of IgA type, 15 cases of IgG type, 8 cases of light chain κ type, 8 cases of light chain λ type, 2 cases of IgD type, and 2 cases of non-secretion type. The sLC-κ, sLC-λ and their ratio (including light chain type and double clone type), IgA and IgG (except IgD type), as well as albumin, beta-globulin and gamma-globulin levels showed statistically significant differences (P＜0.05) compared with the control group. The sensitivity of serum protein electrophoresis, Ig quantification, sLC and its ratio in the diagnosis of multiple myeloma were 57%, 76% and 65%, and their specificity were 83%, 61% and 90%, respectively. After the second or third chemotherapy, the sLC-κ/λ ratio gradually approached the normal range as the disease reliefes, and the sLC-κ/λ ratio continued to be on or off the line at outliers or further away from the reference value as the disease progresses in MM patients with κ type or λ type.sLC detection shows positive significance in early diagnosis of multiple myeloma, SLC monitoring can be used for the efficacy evaluation for treatment of MM patients.血清轻链在多发性骨髓瘤中的诊断及疗效评价中的价值.探讨血清轻链（sLC）在多发性骨髓瘤（MM）中的临床诊断和疗效评估中的应用价值.以临床初诊为MM的46例多发性骨髓瘤患者作为MM组，50例健康人作为正常对照组，对2组对象分别采用速率散射免疫比浊法检测血清轻链和免疫球蛋白（Ig），同时利用琼脂糖凝胶进行血清蛋白电泳检测M蛋白，分析比较2种方法对MM诊断的敏感度、特异度，探讨sLC检测在MM诊断中的意义；同时，对接受常规治疗的15例MM患者进行随访跟踪，记录5次不同治疗时间的sLC水平，分析sLC在MM疗效评估中的作用.IgA型11例，IgG型15例，轻链κ型8例，轻链λ型8例，IgD型2例，不分泌型2例。多发性骨髓瘤患者组与正常对照组比较，sLC-κ、sLC-λ及其比值（包括轻链型和双克隆型），IgA、IgG（免疫球蛋白除IgD型外），白蛋白、β-球蛋白、γ-球蛋白水平均有统计学差异（P＜0.05）。血清蛋白电泳、Ig定量、sLC及其比值诊断多发性骨髓瘤的灵敏度依次为：57%，76%和65%，特异度依次为：83%，61%和90%。κ型和λ型患者在第2或第3次化疗后，随着病情的缓解sLC-κ/λ逐渐趋近于正常范围，而当病情进展时，sLC-κ/λ持续在异常值或更远离于参考值的上线或下线.sLC检测对多发性骨髓瘤的诊断具有辅助作用，通过分析sLC水平及其比值的变化有助于对MM的疗效评估.

Lipid metabolism could be used as a biomarker for environmental monitoring of metal pollution, including Cu. Given the potential role of the Wnt/β-catenin signaling pathway and acetylation in lipid metabolism, the aim of this study was to investigate the mechanism of Wnt signaling and acetylation mediating Cu-induced lipogenesis. Grass carp Ctenopharyngodon idella, widely distributed freshwater teleost, were used as the model. We found that waterborne Cu exposure increased the accumulation of Cu and lipid, up-regulated lipogenesis, suppressed Wnt signaling, reduced β-catenin protein level and its nuclear location, reduced the sirt1 mRNA levels and up-regulated the β-catenin acetylation level. Further investigation found that Cu up-regulated lipogenesis through Wnt/β-catenin pathway; Cu regulated the β-catenin acetylation, and K311 was the key acetylated residue after Cu incubation. SIRT1 mediated Cu-induced changes of acetylated β-catenin and played an essential role in nuclear accumulation of β-catenin and Cu-induced lipogenesis. Cu facilitated lipid accumulation via the regulation of Wnt pathway by SIRT1. For the first time, our study uncovered the novel mechanism for Wnt/β-catenin pathway and β-catenin acetylation levels mediating Cu-induced lipid deposition, which provided insights into the association between Cu exposure and lipid metabolism in fish and had important environmental implications for monitoring metal pollution in the water by using new biomarkers involved in lipid metabolism.

Zinc (Zn) deficiency is the most consistently discovered nutritional manifestations of fatty liver disease. Although Zn is known to stimulate hepatic lipid oxidation, little is known about its underlying mechanism of action in lipolysis. Given the potential role of lipophagy in lipid metabolism, the purpose of this study was to test the hypothesis that Zn attenuates hepatic lipid accumulation by modulating lipophagy. The present study indicated that Zn is a potent promoter of lipophagy. Zn administration significantly alleviated hepatocellular lipid accumulation and increased the release of free fatty acids in association with enhanced fatty acid oxidation and inhibited lipogenesis, which was accompanied by activation of autophagy. Moreover, Zn reduced lipid accumulation and stimulated lipolysis by autophagy-mediated lipophagy. Zn-induced up-regulation of autophagy and lipid depletion is free Zn2+-dependent in the cytosols. Zn-induced autophagy and lipid turnover involved up-regulation of the calcium/calmodulin-dependent protein kinase kinase-β (Ca2+/CaMKKβ)/AMPK pathway. Meanwhile, Zn2+-activated autophagy and lipid depletion were via enhancing metal response element-binding transcription factor (MTF)-1 DNA binding at PPARα promoter region, which in turn induced transcriptional activation of the key genes related to autophagy and lipolysis. Zn activated the pathways of Zn2+/MTF-1/ Peroxisome proliferator-activated receptor (PPAR)α and Ca2+/CaMKKβ/AMPK, resulting in the up-regulation of lipophagy and accordingly reduced hepatic lipid accumulation. Our study, for the first time, provided innovative evidence of the direct relationship between metal elements (Zn) and lipid metabolism. The present study also indicated the novel mechanism for Zn-induced lipolysis by the activation of Zn2+/MTF-1/PPARα and Ca2+/CaMKKβ/AMPK pathways, which induced the occurrence of lipophagy. These results provide new insight into Zn nutrition and its potential beneficial effects on the prevention of fatty liver disease in vertebrates.-Wei, C.-C., Luo, Z., Hogstrand, C., Xu, Y.-H., Wu, L.-X., Chen, G.-H., Pan, Y.-X., Song, Y.-F. Zinc reduces hepatic lipid deposition and activates lipophagy via Zn2+/MTF-1/PPARα and Ca2+/CaMKKβ/AMPK pathways.

Si 3 N 4 -ZrB 2 ceramics were hot-pressed at 1500 °C using self-synthesized fine ZrB 2 powders containing 2.0 wt% B 2 O 3 together with MgO-Re 2 O 3 (Re = Y, Yb) additives. Both Si 3 N 4 and ZrB 2 grains in the hot-pressed ceramics were featured with elongated and equiaxed morphology. The presence of elongated Si 3 N 4 and ZrB 2 grains led to the partial texture of the ceramics under the applied pressure. Vickers hardness and fracture toughness of Si 3 N 4 -ZrB 2 ceramics with MgO-Re 2 O 3 additives prepared at low temperature were about 19–20 GPa and 9–11 MPa m 1/2 , respectively, higher than the reported values of Si 3 N 4 -based ceramics prepared at high temperature (1800 °C or above) under the same test method.

Ischemic stroke is a leading cause of death and disability worldwide, and autophagy may be involved in the pathological process of cerebral ischemia/reperfusion injury. Hydrogen sulfide (H2S) is an endogenous gasotransmitter with protective effects against multiple diseases. Here, we tested the effect of H2S on cerebral ischemia/reperfusion injury in rats. Sodium hydrosulfide (NaHS), an H2S donor, improved neurological function and reduced the size of the infarcts induced by transient middle cerebral artery occlusion (MCAO) followed by reperfusion in rats. NaHS treatment reduced the lactate dehydrogenase (LDH) activity in the serum (a marker of cellular membrane integrity) and the expression of cleaved caspase-3 (a marker for apoptosis) in the brains of MCAO rats. We also found that autophagy was overactivated in the brains of MCAO rats, as indicated by an increased ratio of LC3 II to I, decreased expression of p62, and transmission electron microscope detection. NaHS treatment significantly inhibited the autophagic activity in the brains of MCAO rats. Furthermore, PC12 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic MCAO in vitro. We found that NaHS treatment reduced cellular injury and suppressed overactivated autophagy induced by OGD/R in PC12 cells. An autophagy stimulator (rapamycin) eliminated the protective effect of NaHS against LDH release and caspase-3 activity induced by OGD/R in PC12 cells. An autophagy inhibitor (3-methyladenine, 3-MA) also reduced the cellular injury induced by OGD/R in PC12 cells. In conclusion, the results indicate that overactivated autophagy accelerates cellular injury after MCAO in rats and that exogenous H2S attenuates cerebral ischemia/reperfusion injury via suppressing overactivated autophagy in rats.

Sintered reaction-bonded Si3N4 ceramics with equiaxed microstructure were prepared with TiO2–Y2O3–Al2O3 additions by rapid nitridation at 1400°C for 2 hours and subsequent post-sintering at 1850°C for 2 hours under N2 pressure of 3 MPa. It was found that α–Si3N4, β–Si3N4, Si2N2O, and TiN phases were formed by rapid nitridation of Si powders with single TiO2 additives. However, the combination of TiO2 and Y2O3–Al2O3 additives led to the formation of 100% β–Si3N4 phase from the nitridation of Si powders at such low temperature (1400°C), and the removal of Si2N2O phase. As a result, dense β–Si3N4 ceramics with equiaxed microstructure were obtained after post-sintering at high temperature.

Flexible synthesis of ultra-fine ZrB2 powders was achieved by borothermal reduction in a mixture of ZrO2, boron, and TiO2. Without TiO2 additive, coarse ZrB2 powders with particle size of 0.81 μm were obtained, presumably due to good wettability and solubility of ZrB2 in the byproduct B2O3. It was found that the particle growth of ZrB2 was effectively inhibited by the solid solution of TiB2 (≥1 mol%). The refinement mechanism was that the solid solution of in situ formed TiB2 presumably lowered the wettability and solubility of ZrB2 in the B2O3 liquid and significantly inhibited the coarsening of ZrB2. The average particle size of resulting powders decreased to 0.37 μm with the addition of 10 mol% TiO2.

Phase compositions, densification, microstructures, thermal conductivities, and mechanical properties of sintered reaction-bonded Si 3 N 4 (SRBSN) and sintered Si 3 N 4 (SSN) using the same additives and procedure were compared. The present results showed that the density of SRBSN with MgO-Y 2 O 3 additives was much lower than that of SSN with the same additives. The Eu 2 O 3 -MgO-Y 2 O 3 additives inhibited the densification, while the ZrO 2 -MgO-Y 2 O 3 additives promoted the densification. The SRBSN with relative density of 99.5% and thermal conductivity of 66.5 Wm −1 K −1 was rapidly prepared using ZrO 2 -MgO-Y 2 O 3 as aids. The SSN with relative density of 99.0% and thermal conductivity of 56.8 Wm −1 K −1 was fabricated using ZrO 2 -MgO-Y 2 O 3 additives. The comparable density and higher thermal conductivity made the SRBSN prepared rapidly from low cost Si starting powder superior over the SSN. This study suggested that the SRBSN route with a combination of nitridation catalyst and densification aids provided a promising route to fabricate cost-effective Si 3 N 4 ceramics.

Early molecular events after the exposure of heavy metals, such as aberrant DNA methylation, suggest that DNA methylation was important in regulating physiological processes for animals and accordingly could be used as environmental biomarkers. In the present study, we found that copper (Cu) exposure increased lipid content and induced the DNA hypermethylation at the whole genome level. Especially, Cu induced hypermethylation of glucose-regulated protein 78 (grp78) and peroxisome proliferator-activated receptor gamma coactivator-1α (pgc1α). CCAAT/enhancer binding protein α (C/EBPα) could bind to the methylated sequence of grp78, whereas C/EBPβ could not bind to the methylated sequence of grp78. These synergistically influenced grp78 expression and increased lipogenesis. In contrast, DNA methylation of PGC1α blocked the specific protein 1 (SP1) binding and interfered mitochondrial function. Moreover, Cu increased reactive oxygen species (ROS) production, activated endoplasmic reticulum (ER) stress and damaged mitochondrial function, and accordingly increased lipid deposition. Notably, we found a new toxicological mechanism for Cu-induced lipid deposition at DNA methylation level. The measurement of DNA methylation facilitated the use of these epigenetic biomarkers for the evaluation of environmental risk.

Among various Zn transport proteins, SLC30A/ZnTs help Zn efflux from the cells and Zn compartmentation into the organelles, and so play important roles in the control of Zn homeostasis. The present study was conducted to clone and characterize six members (ZnT2, ZnT4, ZnT6, ZnT8, ZnT9 and ZnT10) of ZnT family and determine their expression patterns from yellow catfish Pelteobagrus fulvidraco. The influences of zinc oxide nanoparticles (ZnO NPs) in the diets on their mRNA expression were determined in several tissues, such as spleen, kidney, muscle and gill of yellow catfish. Six members (ZnT2, ZnT4, ZnT6, ZnT8, ZnT9 and ZnT10) of ZnT family of yellow catfish share similar domains to other fish and mammals. Their mRNAs were expressed in nine tissues (heart, liver, brain, spleen, kidney, muscle, mesenteric fat, intestine and gill), but at different levels. Dietary ZnO NPs addition increased Zn content in the spleen, kidney and gills, but not in the muscle. N,N,N′,N′-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN, Zn chelator) addition did not significantly influence Zn contents of four tested tissues of yellow catfish after high ZnO NPs feeding. The influences of dietary ZnO NPs addition on their mRNA levels in spleen, kidney, muscle and gill of yellow catfish were tissue-dependent. Our study, for the first time, identified and characterized six ZnT family members, found their ubiquitious expression among the tissues and elucidated their responses in yellow catfish fed ZnO NPs-added diet, indicating that these ZnT proteins act in tissue-specific manners in the control of Zn homeostasis.

Effects of ZrO 2 particle size (~50 nm and ~2 µm) on synthesis of ZrB 2 powders via conventional or new borothermal reduction were investigated. The conventional process was a one-step heat treatment at 1600 °C in vacuum. The newly developed process consisted of two-step heat treatment (first-step at 1000 °C and second-step at 1600 °C) plus intermediate step of water washing. Micron-sized ZrB 2 powders were prepared by conventional process, independent of initial ZrO 2 particle size. Based on new process, submicrometric ZrB 2 powders were synthesized using nano-size ZrO 2 . However, submicrometric ZrB 2 could also be synthesized using micron-size ZrO 2 by prolonging the holding time during first-step heat treatment. Therefore, results of present study suggested that fine ZrB 2 powders could be synthesized by controlling the time of first-step heat treatment of the new borothermal reduction process by converting ZrO 2 as completely as possible independent of initial particle size.

B 4 C–ZrB 2 ceramics were reactively hot pressed by three-step process using B and C with Zr (C–B–Zr mixtures) or ZrO 2 (C–B–ZrO 2 mixtures) as raw materials. Based on thermodynamic analysis and experimental results, the C–B–Zr or C–B–ZrO 2 mixtures were firstly held at 1000 °C, then held at 1650 °C, and finally held at 2000 °C under 30 MPa. B 4 C–ZrB 2 ceramics were obtained by using the three-step process and controlling the reaction sequence. The ZrB 2 grains in B 4 C–ZrB 2 ceramics from C–B–Zr mixtures had a bimodal grain size distribution including fine grains with size of 1–2 μm and large agglomeration-like grains with size of 10–30 μm, while that in the ceramics from C–B–ZrO 2 mixtures showed homogeneous distribution with small grain size of 1–2 μm. The B 4 C–ZrB 2 ceramics from C–B–ZrO 2 mixtures showed higher relative density, more homogeneous and fine-grained microstructure, higher hardness (33.0 ± 1.3 GPa), and comparable toughness (4.1 ± 0.2 MPam 1/2 ), compared with the ceramics from C–B–Zr mixtures.

Early detection of human papillomavirus (HPV) is important for the clinical diagnosis of cervical cancer. However, to date, the pathogenesis of cervical cancer is still unclear. Autophagy is a dynamic process that contributes to the maintenance of cellular homeostasis. Here, we investigate whether variants of autophagy genes affect the occurrence of cervical cancer. In this study, our results indicate that single nucleotide polymorphisms (SNPs) of autophagy-related protein 4 (ATG4), including rs4036579, rs5973822, rs807181, rs807182 and rs807183, have a significant relationship with cervical cancer risk. Furthermore, stratified analysis suggests that the homozygous variant genotype could decrease the risk of cervical cancer and should be considered when investigating the role of HPV in cervical cancer. We aim to investigate whether SNPs of ATG4A contribute to HPV infection in the population of Southwestern China. The association of both single SNPs and SNP-SNP interactions with HPV was evaluated in a sample of cancer cases and healthy control subjects. The interaction of rs807181 and rs807183 was associated with HPV infection in case and control subjects (combined P=2.00×10−3 and 3.22×10−2, respectively). This result showed that ATG4A SNP interactions may affect HPV infection in the population of Southwestern China. Notably, the autophagy gene ATG4A may contribute to cervical cancer.

Chemical reactivity of hot-pressed Si 3 N 4 –ZrB 2 ceramics at 1500–1700 °C under N 2 and Ar atmosphere is investigated by X-ray diffraction, thermodynamic calculation, and phase diagram. Results show that there are chemical reactions in Si 3 N 4 –ZrB 2 ceramics. The chemical reactions accelerate the decomposition and phase transformation of Si 3 N 4 . The reaction products include ZrN, BN, ZrSi 2 , SiC or Si, which strongly depend on the atmosphere or temperature. The source of N 2 for ZrN and BN products is both atmosphere and decomposition of Si 3 N 4 at 1600 °C or above, whereas that is only atmosphere at 1500 °C. There is no reaction in Si 3 N 4 –ZrB 2 ceramics at 1500 °C under Ar. The MgO–Lu 2 O 3 sintering adds lead to the significant increase of relative density of Si 3 N 4 –ZrB 2 from 48% to 94% at 1500 °C in Ar. Therefore, it is possible that dense Si 3 N 4 –ZrB 2 ceramics with no reaction could be achieved at 1500 °C or below in Ar.

A novel poly(amide-urethane@imide) reverse osmosis (RO) composite membrane with chlorine-tolerant property was prepared on a polysulfone supporting film through two-step interfacial polymerization. The crosslinking agent – 5-choroformyloxyisophaloyl chloride (CFIC) was first reacted with 4-methyl-phenylenediamine (MMPD) via interfacial polymerization to get the nascent poly(amide-urethane) base membrane (CFIC–MMPD) without curing treatment. Then the resultant base membrane contacted again with the second aqueous solution containing functional secondary amine – N,N′-dimethyl-m-phenylenediamine (DMMPD) to obtain the poly(amide-urethane@imide) TFC RO membrane (MMPD–CFIC@CFIC–DMMPD). X-ray photoelectronic spectroscopy (XPS) was combined with attenuated total reflectance infrared (ATR-IR) to verify that the ultrathin polyimide film (CFIC–DMMPD) has been successfully grafted on the surface of the MMPD–CFIC base membrane. The images of scanning electronic microscopy (SEM) and atomic force microscope (AFM) showed that the poly(amide-urethane@imide) membrane has much smoother, more hydrophilic surface than the poly(amide/imide-urethane) membrane (MMPD/DMMPD–CFIC) prepared by conventional one-step interfacial polymerization of CFIC and composite MMPD/DMMPD. However, the permeation experiment revealed that the poly(amide-urethane@imide) membrane has a slight loss in both salt rejection and water flux than the poly(amide/imide-urethane) membrane and conventional commercialized polyamide membrane (MPD–TMC), but exhibits better chlorine-tolerant property due to the introduction of ultrathin polyimide film (CFIC–DMMPD) on the outmost surface of the TFC RO membrane, and the combination of IR and XPS analyses shows a good agreement with the chlorine exposure results of membranes.

Effect of TiO2 additives on nitridation of Si powders at 1300 °C and 1400 °C was studied by combining X-ray diffraction, thermogravimetric analysis, and thermodynamic calculations. Weak Si3N4 phase was detected in pure Si powders after nitridation at 1300 °C, whereas no Si3N4 phase was found in TiO2-doped Si powders and only secondary TiN phase was observed in addition to main Si phase. The TiO2 demonstrated an inhibiting effect on nitridation of Si powders at 1300 °C. However, the TiO2 led to the rapid nitridation of Si powders at 1400 °C by circulating reaction mechanism between TiO2 and TiN, and promoted α-to β-Si3N4 phase transformation. In addition to TiN phase, secondary Si2N2O phase was observed in the TiO2-doped Si powders. The present study suggested that TiO2 additives exhibited effectively nitridation enhancing effect on the formation of reaction-bonded Si3N4 at 1400 °C.

Parkinson's disease (PD) is age-related neurodegenerative disorder by a progressive loss of dopaminergic(DA) neurons in the substantia nigra (SN) and striatum, which is at least partly associated with α-synuclein protein accumulation in these neurons. Hydrogen sulfide (H2S) plays an important role in the nervous system. Studies have shown that H2S has a protective effect on PD. However, as a kind of gas molecules, H2S is lively, volatile, and not conducive to scientific research and clinical application. Cystathionine-beta-synthase(CBS) is the main enzymes of synthesis of H2S in the brain. In order to examine the neuroprotective effects of CBS on PD, we detected the effects of CBS overexpression on 6-Hydroxydopamine (6-OHDA)-lesioned PD rats using lentivirus-mediated gene transfection techniques. In the injured SN of 6-OHDA-induced PD rats, the CBS expression and the endogenous H2S level markedly decreased, while administration of lentivirus-mediated CBS overexpression increased the CBS expression and the endogenous H2S production.CBS overexpression dramatically reversed apomorphine-induced rotation of the 6-OHDA model rats, decreased the number of TUNEL-positive neurons and the loss of the nigral DA neurons，specifically inhibited 6-OHDA-induced oxidase stress injury, and down-regulated the expression of α-synuclein(α-SYN) in the injured SN. NaHS (an H2S donor) had similar effects to CBS overexpression, while Amino-oxyacetate(AOAA, a CBS inhibitor) had opposite effects on PD rats. In summary, we demonstrated that CBS overexpression was able to provide neuroprotective on PD rats and improving the expression of CBS may be a potential therapeutic method for PD.

The autophagy-lysosome pathway, which involves many crucial genes and proteins, plays crucial roles in the maintenance of intracellular homeostasis by the degradation of damaged components. At present, some of these genes and proteins have been identified but their specific functions are largely unknown. This study was performed to clone and characterize the full-length cDNA sequences of nine key autolysosome-related genes (vps11, vps16, vps18, vps33b, vps41, lamp1, mcoln1, ctsd1 and tfeb) from yellow catfish Pelteobagrus fulvidraco. The expression of these genes and the transcriptional responses to a high-fat diet and fatty acids (FAs) (palmitic acid (PA) and oleic acid (OA)) were investigated. The mRNAs of these genes could be detected in heart, liver, muscle, spleen, brain, mesenteric adipose tissue, intestine, kidney and ovary, but varied with the tissues. In the liver, the mRNA levels of the nine autolysosome-related genes were lower in fish fed a high-fat diet than those fed the control, indicating that a high-fat diet inhibited formation of autolysosomes. Palmitic acid (a saturated FA) significantly inhibited the formation of autolysosomes at 12 h, 24 h and 48 h incubation. In contrast, oleic acid (an unsaturated FA) significantly induced the formation of autolysosomes at 12 h, but inhibited them at 24 h. At 48 h, the effects of OA incubation on autolysosomes were OA concentration-dependent in primary hepatocytes of P. fulvidraco. The results of flow cytometry and laser confocal observations confirmed these results. PA and OA incubation also increased intracellular non-esterified fatty acid (NEFA) concentration at 12 h, 24 h and 48 h, and influenced mRNA levels of fatty acid binding protein (fabp) and fatty acid transport protein 4 (fatp4) which facilitate FA transport in primary hepatocytes of P. fulvidraco. The present study demonstrated the molecular characterization of the nine autolysosome-related genes and their transcriptional responses to fat and FAs in fish, which provides the basis for further exploring their regulatory mechanism in vertebrates.

Glioblastoma is the most common primary central nervous system malignancy and its unique invasiveness hinders effective treatment. Its high invasiveness may be controlled partly by microRNAs (miRNAs, miRs) and their target genes. In the present study, we found that increased miR-223 expression and reduced PAX6 expression coexisted in glioblastoma as detected by quantitative PCR or tissue microarrays. We confirmed that miR-223 directly targets PAX6 through binding to its 3'-UTR using dual luciferase reporter assay. In U251 and U373 glioblastoma cells, overexpression of miR-223 decreased PAX6 mRNA and protein expression; however, inhibition of miR-223 increased PAX6 mRNA and protein expression. Moreover, overexpression of miR-223 led to effects similar to those of PAX6 knockdown: increased cell viability, increased percentage of cells in the G1 phase and increased cell invasiveness parallel with increased MMP2, MMP9 and VEGFA expression. In addition, inhibition of miR-223 resulted in effects similar to those of PAX6 overexpression: decreased cell viability, decreased percentage of cells in the G1 phase and decreased cell invasiveness parallel with reduced MMP2, MMP9 and VEGFA expression. The data presented here suggest that miR-223 promotes the growth and invasion of U251 and U373 glioblastoma cells by targeting PAX6, which serves as a tumor suppressor in glioblastoma exerting the functions of inhibition of cell cycle transition, and the expression of MMP2, MMP9 and VEGFA. In conclusion, the present study supports miR-223 and PAX6 as novel therapeutic targets for glioblastoma.

Chemotherapy is a standard strategy for glioma, while chemoresistance remains a major therapeutic challenge in current clinical practice. Our present study was aimed to determine whether inhibition of the miR-223/paired box 6 (PAX6) pathway could increase the sensitivity of glioma to Temozolomide. An elevated level of miR-223 was observed in glioma tissues. Exogenous miR-223 promoted cell survival when exposed to Temozolomide (TMZ), while miR-223 inhibition could reverse this process. The RNA and protein levels of PAX6 were significantly decreased by exogenous miR-223, and the 3'-untranslated region of PAX6 was shown to be a target of miR-223. Besides, it has also been reported that PI3K/Akt signaling pathway is pivotal to regulate glioma growth and proliferation. In the present study, we revealed that miR-223/PAX6 axis regulated the growth, invasion, and chemo resistance of glioblastoma stem cells to TMZ via regulating PI3K/Akt signaling pathway, which present a novel potential therapy for intervention of glioblastoma. Taken together, our findings shed new light on the miR-223/PAX6 pathway in glioma and this pathway might modulate the sensitivity of glioma to TMZ via regulating PI3K/Akt signaling pathway. J. Cell. Biochem. 118: 3452-3461, 2017. © 2017 Wiley Periodicals, Inc.