Trace Selenium Doping for Improving the Reaction Kinetics of ZnS Cathode for Aqueous Zn-S Batteries.

Aqueous Zinc-sulfur (Zn-S) batteries are promising for the field of energy storage due to their low cost, high theoretical capacity, and safety. However, the large volume expansion and the inherently poor conductivity of sulfur would result in electrode cracking and sluggish reaction kinetics, limiting the practical application of Zn-S batteries. Herein, commercial zinc sulfide (ZnS) is employed instead of S as cathode and proposed a doping modification strategy to solve the above problems. The designed ZnS0.93Se0.07 cathode shows good cycle stability and much-improved reaction kinetics, which is due to the smaller bandgap of ZnS0.93Se0.07 (1.40 eV) compared to ZnS (1.86 eV). As a result, the obtained ZnS0.93Se0.07 cathode exhibits a high specific capacity of 552 mAh g-1 (1672.6 mAh g-1 based on S) at 0.1 A g-1 and 330 mAh g-1 (1000 mAh g-1 based on S) at 2 A g-1. Moreover, the ZnS0.93Se0.07 cathode can provide a high areal capacity of 3.8 mAh cm-2 at a high mass loading of 10 mg cm-2 and limited electrolyte (4 µL mg-1). This work provides a simple and effective cathode modification strategy, which is conducive to promoting the practical application of Zn-S batteries.

Transarterial chemoembolization versus percutaneous microwave coagulation therapy for recurrent unresectable intrahepatic cholangiocarcinoma: Development of a prognostic nomogram.

BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) are commonly used to treat intrahepatic recurrent liver cancers. However, there is no information regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma (ICC) after resection. METHODS: A total of 275 patients with localized recurrent ICC who received either TACE (n = 183) or PMCT (n = 92) were studied. A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT. Prognostic factors for TACE and PMCT were identified respectively. Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values. RESULTS: Both TACE and PMCT provided curativeness in partial patients (5-year overall survival: 21.4% and 6.1%, respectively), but TACE provided better survival benefit in both overall patients (hazard ratio [HR] = 0.71; 95% confidence interval [CI]: 0.50-0.97; P = 0.034) and propensity score matching analysis (HR = 0.69; 95% CI: 0.47-0.98; P = 0.041). Independent prognostic factors for TACE were tumor size >5 cm, poor differentiation, and major resection, whereas poor differentiation, hepatitis B virus infection, cholelithiasis, and lymph node metastasis were identified for PMCT. Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70, respectively. CONCLUSIONS: TACE provided better survival benefits compared to PMCT. However, there was a disparity in prognostic factors, suggesting evaluation of the two nomograms may be supportive in modality selection. Further prospective validation studies are required for the results to be applied in clinical medicine.

Interleukin-1ß/Iinterleukin-1 receptor-associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis.

UNLABELLED: Hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up-regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)-1ß was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL-1ß/interleukin-1 receptor-associated kinase 1 (IRAK-1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho-IRAK-1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real-time polymerase chain reaction, or immunoblotting further confirmed the up-regulation of Gankyrin by IL-1ß/IRAK-1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF-Y) family members, which can recruit histone acetyltransferase coactivator E1A-binding protein p300 (p300) or CREB-binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF-Y, p300, or CBP inhibits Gankyrin expression. IL-1ß stimulation causes sequential phosphorylation of IRAK-1, c-Jun N-terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition of phospho-JNK impairs IL-1ß/IRAK-1 signaling-mediated up-regulation of Gankyrin. CONCLUSION: The finding of IL-1ß/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis.

The tyrosine kinase c-Met contributes to the pro-tumorigenic function of the p38 kinase in human bile duct cholangiocarcinoma cells.

Pro-tumorigenic function of the p38 kinase plays a critical role in human cholangiocarcinogenesis. However, the underlying mechanism remains incompletely understood. Here, we report that c-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), contributes to the pro-tumorigenic ability of p38 in human cholangiocarcinoma cells. Both p38 and c-Met promote the proliferation and invasion of human cholangiocarcinoma cells. Importantly, inhibition or knockdown of p38 decreased the basal activation of c-Met. Tyrosine phosphatase inhibitor studies revealed that p38 promotes the activity of c-Met, at least in part, by inhibiting dephosphorylation of the receptor. Moreover, density enhanced phosphatase-1 (DEP-1) is involved in p38-mediated inhibiting dephosphorylation of c-Met. Furthermore, p38 inhibits the degradation of c-Met. Taken together, these data provide a potential mechanism to explain how p38 promotes human cholangiocarcinoma cell proliferation and invasion. We propose that the link between p38 and c-Met is implicated in the progression of human cholangiocarcinoma.

Disturbance of Ca2+ homeostasis converts pro-Met into non-canonical tyrosine kinase p190MetNC in response to endoplasmic reticulum stress in MHCC97 cells.

c-Met, the tyrosine-kinase receptor for hepatocyte growth factor, plays a critical role in the tumorigenesis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains incompletely understood. The mature c-Met protein p190Met(αß) (consists of a α subunit and a ß subunit) is processed from pro-Met. Here we show that pro-Met is processed into p190Met(NC) by sarco/endoplasmic reticulum calcium-ATPase (SERCA) inhibitor thapsigargin. p190Met(NC) compensates for the degradation of p190Met(αß) and protects human HCC cells from apoptosis mediated by endoplasmic reticulum (ER) stress. In comparison with p190Met(αß), p190Met(NC) is not cleaved and is expressed as a single-chain polypeptide. Thapsigargin-initiated p190Met(NC) expression depends on the disturbance of ER calcium homeostasis. Once induced, p190Met(NC) is activated independent of hepatocyte growth factor engagement. p190Met(NC) contributes to sustained high basal activation of c-Met downstream pathways during ER calcium disturbance-mediated ER stress. Both p38 MAPK-promoted glucose-regulated protein 78 (GRP78) expression and sustained high basal activation of PI3K/Akt and MEK/ERK are involved in the cytoprotective function of p190Met(NC). Importantly, the expression of p190Met(NC) is detected in some HCC cases. Taken together, these data provide a potential mechanism to explain how c-Met promotes HCC cells survival in response to ER stress. We propose that context-specific processing of c-Met protein is implicated in HCC progression in stressful microenvironments.

p28(GANK) prevents degradation of Oct4 and promotes expansion of tumor-initiating cells in hepatocarcinogenesis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), although little is known about their stem cell-like properties. METHODS: We quantified levels of p28(GANK) (Gankyrin), OV6, and Oct4 in 130 human HCC samples using immunohistochemistry. Magnetic-activated cell sorting was used to isolate OV6+ HCC cells. T-IC properties were evaluated by quantitative reverse-transcription polymerase chain reaction, flow cytometry, and spheroid formation. We used a coimmunoprecipitation assay to study interactions among p28(GANK), Oct4, and WWP2. Tumorigenicity and pulmonary metastasis were examined in nonobese diabetic and severe combined immunodeficient mice. RESULTS: In HCC samples, high levels of p28(GANK) correlated with expansion of OV6+ tumor cells; the combination of high levels of p28(GANK) and OV6 was associated with progression of HCC. p28(GANK) was predominantly expressed in liver T-ICs, isolated by magnetic sorting, and undifferentiated primary HCC spheroids. Increased levels of p28(GANK) in T-ICs increased their percentages in HCC samples, expression of stem cell genes, self-renewal potential, chemoresistance in vitro, and tumorigenicity and ability to develop into pulmonary metastases in mice. Conversely, knockdown of p28(GANK) reduced their T-IC properties. p28(GANK) likely activates liver T-ICs by impeding ubiquitination and degradation of the transcription factor Oct4 by WWP2. In support of this concept, levels of p28(GANK) correlated with those of Oct4 in HCC samples. CONCLUSIONS: p28(GANK) activates and maintains liver T-ICs in HCCs by preventing degradation of Oct4. Inhibitors of p28(GANK) might therefore be developed to inactivate T-ICs and slow tumor progression.

High expression of proline-rich tyrosine kinase 2 is associated with poor survival of hepatocellular carcinoma via regulating phosphatidylinositol 3-kinase/AKT pathway.

BACKGROUND: The peritumoral environment has been implicated to be important in the process of metastasis and recurrence in hepatocellular carcinoma (HCC). Our aims were to assess the prognostic value of proline-rich tyrosine kinase 2 (Pyk2) in HCC and investigate related molecular mechanism. METHODS: Expression of Pyk2 was tested by immunohistochemistry in tissue microarrays containing 141 paired HCC samples. Correlation between Pyk2 and vascular endothelial growth factor (VEGF) expression in clinical samples was analyzed by Spearman rank correlation. Matrigel invasion, anchorage-independent growth assay and immunoblotting were performed to study the effect of Pyk2 on the invasion and progression of HCC cells and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. RESULTS: Higher Pyk2 density in both tumor and peritumor was associated with lower overall survival (P = 0.044; P = 0.041, respectively), serum AFP levels > 1,000 ng/ml (P = 0.013; P = 0.032, respectively) and postoperative distant metastasis (both P < 0.001). However, only higher peritumoral Pyk2 density was related to lower disease-free survival (P = 0.014) and vascular invasion (P = 0.035). A significant correlation between Pyk2 and VEGF density in tumor or peritumoral liver tissue was observed (r = 0. 3133, P = 0.0002; r = 0.5176, P < 0.0001, respectively). Immunoblotting showed that Pyk2 activated PI3K-AKT pathway to upregulate VEGF expression in HL-7702, SMMC-7721 and HepG2 cells. CONCLUSIONS: High Pyk2, especially peritumoral Pyk2 was associated with poor survival, disease recurrence, and metastasis in HCC. PI3K-AKT pathway was involved in Pyk2-mediated VEGF expression during HCC progression and invasion.

Phase Engineering of Nonstoichiometric Cu2-xSe as Anode for Aqueous Zn-Ion Batteries.

Aqueous zinc-ion batteries (AZIBs) are receiving widespread attention due to their abundant resources, low material cost, and high safety. However, the susceptibility of Zn metal anodes to corrosion and hydrogen evolution limits their further practical applications. Replacing Zn metal with intercalation-type anode material and constructing rocking-chair-type batteries could be an effective way to significantly prolong the cycle life of AZIBs. Herein, we present copper selenide with different crystal phase structures through a facile redox reaction as an anode for AZIBs. By comparing and analyzing different copper selenide phases, it is found that the cubic Cu2-xSe shows superior structural stability and highly reversible Zn2+ storage. Theoretical calculation results further demonstrate that the cubic Cu2-xSe possesses an increased electrical conductivity, higher Zn2+ adsorption energy, and reduced diffusion barrier, thereby promoting the storage reversibility and (de)intercalation kinetics of the Zn2+ ion. Thus, the Cu2-xSe anode delivers a long-term service life of over 15 000 cycles and impressive cumulative capacity. Furthermore, the full-cells assembled with the MnO2/CNT cathode operate stably for over 1500 cycles at 6 mA cm-2 at a negative/positive (N/P) capacity ratio of ∼1.53. This work provides a more ideal Zn-metal-free anode, which helps to push the practical applications of AZIBs.

p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways.

UNLABELLED: The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular mechanisms underlying HCC progression and aggressiveness are unclear. Here, we report that increased expression of p28(GANK) (Gankyrin, PSMD10, or p28) in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and intrahepatic or distant metastasis, expressed high levels of p28(GANK) . Invasive tumors overexpressing p28(GANK) were featured by active epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with vascular endothelial growth factor overexpression, whereas silencing p28(GANK) expression attenuated EMT and motility/invasion of tumor cells. The p28(GANK) activates phosphoinositide 3-kinase (PI3K)-V-akt Murine Thymoma Viral Oncogene Homolog (AKT)-hypoxia-inducible factor 1α (HIF-1α) signaling to promote TWIST1, vascular endothelial growth factor, and metalloproteinase 2 expression. Suppression of the PI3K-AKT-HIF-1α pathway interfered with p28(GANK) -mediated EMT and invasion. Consistently, we detected a significant correlation between p28(GANK) expression and p-AKT levels in a cohort of HCC biopsies, and the combination of these two parameters is a more powerful predictor of poor prognosis. CONCLUSION: These results present novel mechanistic insight into a critical role of p28(GANK) in HCC progression and metastasis.

Arsenic Accumulation and Physiological Response of Three Leafy Vegetable Varieties to As Stress.

Arsenic (As) in leafy vegetables may harm humans. Herein, we assessed As accumulation in leafy vegetables and the associated physiological resistance mechanisms using soil pot and hydroponic experiments. Garland chrysanthemum (Chrysanthemum coronarium L.), spinach (Spinacia oleracea L.), and lettuce (Lactuca sativa L.) were tested, and the soil As safety threshold values of the tested leafy vegetables were 91.7, 76.2, and 80.7 mg kg−1, respectively, i.e., higher than the soil environmental quality standard of China. According to growth indicators and oxidative stress markers (malondialdehyde, the ratio of reduced glutathione to oxidized glutathione, and soluble protein), the order of As tolerance was: GC > SP > LE. The high tolerance of GC was due to the low transport factor of As from the roots to the shoots; the high activity of superoxide dismutase, glutathione peroxidase, and catalase; and the high content of phytochelatin in the roots. Results of this work shed light on the use of As-contaminated soils and plant tolerance of As stress.

Zinc finger protein ZBTB20 expression is increased in hepatocellular carcinoma and associated with poor prognosis.

BACKGROUND: Our previous studies showed that ZBTB20, a new BTB/POZ-domain gene, could negatively regulate α feto-protein and other liver-specific genes, concerning such as bio-transformation, glucose metabolism and the regulation of the somatotropic hormonal axis. The aim of this study is to determine the potential clinical implications of ZBTB20 in hepatocellular carcinoma (HCC). METHODS: Quantitative real-time RT-PCR and Western blot analyses were used to detect expression levels of ZBTB20 in 50 paired HCC tumorous and nontumorous tissues and in 20 normal liver tissues. Moreover, expression of ZBTB20 was assessed by immunohistochemistry of paired tumor and peritumoral liver tissue from 102 patients who had undergone hepatectomy for histologically proven HCC. And its relationship with clinicopathological parameters and prognosis was investigated. RESULTS: Both messenger RNA and protein expression levels of ZBTB20 were elevated significantly in HCC tissues compared with the paired non-tumor tissues and normal liver tissues. Overexpressed ZBTB20 protein in HCC was significantly associated with vein invasion (P=0.016). Importantly, the recurrence or metastasis rates of HCCs with higher ZBTB20 expression were markedly greater than those of HCCs with lower expression (P=0.003, P=0.00015, respectively). Univariate and multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. The disease-free survival period and over-all survival period in patients with overexpressed ZBTB20 in HCC was significantly reduced. CONCLUSIONS: The expression of ZBTB20 is increased in HCC and associated with poor prognosis in patients with HCC, implicating ZBTB20 as a candidate prognostic marker in HCC.

Corrosion behavior of high nitrogen nickel-free austenitic stainless steel in the presence of artificial saliva and Streptococcus mutans.

High nitrogen nickel-free austenitic stainless steels (HNSs) have great potentials to be used in dentistry owing to its exceptional mechanical properties, high corrosion resistance, and biocompatibility. In this study, HNSs with nitrogen of 0.88 wt% and 1.08 wt% displayed much lower maximum pit depths than 316L stainless steel (SS) after 21 d of immersion in abiotic artificial saliva (2.2 µm and 1.7 µm vs. 4.5 µm). Microbiologically influenced corrosion (MIC) evaluations revealed that Streptococcus mutans biofilms led to much severer corrosion of 316L SS than HNSs. Corrosion current densities of HNSs were two orders of magnitude lower than that of 316L SS after incubation of 7 d (37.5 nA/cm2 and 29.9 nA/cm2 vs. 5.63 µA/cm2). The pitting potentials of HNSs were at least 550 mV higher than that of 316L SS in the presence of S. mutans, confirming the better MIC resistance of HNSs. Cytotoxicity assay confirmed that HNSs were not toxic to MC3T3-E1 cells and allowed better sessile cell growth on them than on 316L SS. It can be concluded that HNSs are more suitable dental materials than the conventional 316L SS.

An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity.

Hepatocellular carcinoma (HCC) is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy. A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs (ceRNAs) bind to the same microRNAs. However, the contribution of such mechanisms in HCC has not been well studied. Herein, potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages, identifying the mTORC2 component RICTOR as a potential HMGB1 ceRNA in HBV+ early stage HCC. Indeed, elevated HMGB1 mRNA was found to promote the expression of RICTOR mRNA through competitively binding with the miR-200 family, especially miR-429. Functional assays employing overexpression or interference strategies demonstrated that the HMGB1 and RICTOR 3'untranslated regions (UTR) epigenetically promoted the malignant proliferation, self-renewal, and tumorigenesis in HCC cells. Intriguingly, interference against HMGB1 and RICTOR in HCC cells promoted a stronger anti-PD-L1 immunotherapy response, which appeared to associate with the production of PD-L1+ exosomes. Mechanistically, the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms, activating a positive feedback loop involving mTORC2-AKT-C-MYC to upregulate glutamine synthetase (GS) expression, and inducing mTORC1 signaling to derepress SIRT4 on glutamate dehydrogenase (GDH). Meanwhile, this crosstalk network could impede the efficacy of immunotherapy through mTORC1-P70S6K dependent PD-L1 production and PD-L1+ exosomes activity. In conclusion, our study highlights the non-coding regulatory role of HMGB1 with implications for RNA-based therapeutic targeting together with a prediction of anti-PD-L1 immunotherapy in HCC.

Nickel-free austenitic stainless steels for medical applications.

The adverse effects of nickel ions being released into the human body have prompted the development of high-nitrogen nickel-free austenitic stainless steels for medical applications. Nitrogen not only replaces nickel for austenitic structure stability but also much improves steel properties. Here we review the harmful effects associated with nickel in medical stainless steels, the advantages of nitrogen in stainless steels, and emphatically, the development of high-nitrogen nickel-free stainless steels for medical applications. By combining the benefits of stable austenitic structure, high strength and good plasticity, better corrosion and wear resistances, and superior biocompatibility compared to the currently used 316L stainless steel, the newly developed high-nitrogen nickel-free stainless steel is a reliable substitute for the conventional medical stainless steels.

Concentrations of polycyclic aromatic hydrocarbons in street dust from bus stops in Qingyang city: Estimates of lifetime cancer risk and sources of exposure for daily commuters in Northwest China.

Lifetime cancer risk and exposure of daily commuters to polycyclic aromatic hydrocarbons (PAHs) in cities of Northwest China were determined from a study of street dust samples obtained from bus stops in Qingyang city. The sum of 16 priority PAHs (Σ16 PAHs) concentrations in the dust samples ranged from 0.8 to 18.3 mg kg-1 (mean 3.0 mg kg-1) and the distribution of individual, carcinogenic, combustion specific, low (2-3 rings) and high molecular weight (4-6 rings) PAHs was determined. The benzo[a]pyrene toxic equivalents of Σ16 PAHs ranged from 0.01 to 12.2 mg kg-1 (mean 0.8 mg kg-1). Incremental lifetime cancer risk from exposure to PAHs in dust at bus stops in Qingyang city was estimated at 1.9 × 10-6 for adults and 3.5 × 10-6 for children (confidence limit ≥ 95%). Emission source analysis of PAHs in bus stop dust showed that they were mainly derived from residential coal, oil and biomass combustion, e.g. from boilers, traffic vehicles, and Kang heaters. Higher concentrations of PAHs were obtained at bus stops near transport hubs, commercial districts, and administrative institutions.

Deep-learning-based information mining from ocean remote-sensing imagery.

With the continuous development of space and sensor technologies during the last 40 years, ocean remote sensing has entered into the big-data era with typical five-V (volume, variety, value, velocity and veracity) characteristics. Ocean remote-sensing data archives reach several tens of petabytes and massive satellite data are acquired worldwide daily. To precisely, efficiently and intelligently mine the useful information submerged in such ocean remote-sensing data sets is a big challenge. Deep learning-a powerful technology recently emerging in the machine-learning field-has demonstrated its more significant superiority over traditional physical- or statistical-based algorithms for image-information extraction in many industrial-field applications and starts to draw interest in ocean remote-sensing applications. In this review paper, we first systematically reviewed two deep-learning frameworks that carry out ocean remote-sensing-image classifications and then presented eight typical applications in ocean internal-wave/eddy/oil-spill/coastal-inundation/sea-ice/green-algae/ship/coral-reef mapping from different types of ocean remote-sensing imagery to show how effective these deep-learning frameworks are. Researchers can also readily modify these existing frameworks for information mining of other kinds of remote-sensing imagery.

Biomechanical compatibility of high strength nickel free stainless steel bone plate under lightweight design.

High nitrogen nickel-free stainless steel (HNNFSS) has excellent mechanical properties, corrosion resistance and biocompatibility, but its strength advantage is not fully used even though with one time higher than that of the conventional 316 L stainless steel. In this work, the lightweight design of HNNFSS bone plate was studied using finite element analysis, and the effect of lightweight plate fixation on histological and biomechanical behavior of healing bone were also researched on fractured rabbit femur. The finite element analysis results showed that the lightweight plate within 18.2% thickness reduction had higher bending strength and more homogeneous stress distribution compared with 316 L stainless steel plate. There was no obvious difference in radiography, histology analysis of callus and expression pattern of insulin like growth factor-1(IGF-1) of callus between the lightweight HNNFSS plate group and 316 L stainless steel plate group in animal test, and the IGF-1 concentrations of callus and the biomechanical bending test results also showed no statistical significance (p > 0.05), even though the data of the lightweight HNNFSS plate group were relatively better than that of 316 L stainless steel plate group. Therefore, the high nitrogen nickel-free stainless steel has the lightweight potential to keep good fixing function and improve bone healing compared with 316 L stainless steel plate.

Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3.

BACKGROUND AND PURPOSE: Necroptosis is a form of programmed, caspase-independent, cell death, mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan-Raf inhibitor TAK-632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK-632 by targeting RIPK1 and RIPK3. EXPERIMENTAL APPROACH: Cell viability was measured by MTT, propidium staining, or CellTiter-Glo luminescent assays. Effects of TAK-632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK-632 were identified by a drug affinity responsive target stability assay and a pull-down assay with biotinylated TAK-632. A mouse model of TNF-α-induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK-632 in protecting against necroptosis-associated inflammation in vivo. KEY RESULTS: TAK-632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK-632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK-632 alleviated TNF-induced SIRS. Furthermore, we performed a structure-activity relationship analysis of TAK-632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3. CONCLUSIONS AND IMPLICATIONS: TAK-632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3.

p28GANK knockdown-derived reactive oxygen species induces apoptosis through mitochondrial dysfunction mediated by p38 in HepG2 cells.

Oncoprotein p28GANK knockdown by RNA interference (RNAi) can induce hepatoma cells apoptosis. However, the mechanisms have not been well defined yet. In the present study the p28GANK knockdown-induced apoptosis in HepG2 cells was prevented by caspase-9 inhibitor (Z-LEHD-FMK). During the knockdown of p28GANK, mitochondrial translocation of Bax, loss of mitochondrial transmembrane potential (DeltaPsim) and release of cytochrome c were observed. In this study, the activation of p38 was found to be critical for the p28GANK knockdown-induced apoptosis, as suggested by the finding that pharmacological inhibition of p38 with SB203580 suppressed the redistribution of Bax, the loss of DeltaPsim and the apoptosis. Moreover, generation of reactive oxygen species (ROS) contributed to the cell death because N-acetyl-L-cystenine (NAC), a ROS scavenger, suppressed the phosphorylation of p38 and the apoptosis. Our studies established the signaling pathway of p28GANK knockdown-induced apoptosis in HepG2 cells, namely, mitochondrial dysfunction mediated by p38 downstream of intracellular ROS generation.

[Effects of copper content on the antibacterial performance and corrosion resistance of CoCrMoCu alloy].

OBJECTIVE: This study aimed to determine the effects of copper content on the corrosion resistance of CoCrMoCu alloy and its in vitro antibacterial performance. METHODS: CoCrMoCu specimens with different Cu contents (2%, 3%, 5%, and 7%) were prepared by vacuum melting method. CoCrMo without Cu served as control. The corrosion resistance of the specimens was measured by electrochemistry. The antibacterial effects of the specimens on Staphylococcus aureus and Escherichia coli were analyzed by coating-film method. RESULTS: Compared with CoCrMo without Cu, the addition of 2%-5% Cu to CoCrMo improved the pitting and uniform corrosion of CoCrMo alloy and decreased the corrosion current density. The antibacterial performance of CoCrMoCu alloy increased with increased Cu content. The antibacterial rate of alloy was 99% when Cu content exceeded 5%. CONCLUSIONS: Cu addition had a statistically significant influence on the corrosion resistance and antibacterial performance of CoCrMoCu. CoCrMoCu has better corrosion resistance and antibacterial performance when Cu content is 5%.