Manipulating the ordered oxygen complexes to achieve high strength and ductility in medium-entropy alloys.

Oxygen solute strengthening is an effective strategy to harden alloys, yet, it often deteriorates the ductility. Ordered oxygen complexes (OOCs), a state between random interstitials and oxides, can simultaneously enhance strength and ductility in high-entropy alloys. However, whether this particular strengthening mechanism holds in other alloys and how these OOCs are tailored remain unclear. Herein, we demonstrate that OOCs can be obtained in bcc (body-centered-cubic) Ti-Zr-Nb medium-entropy alloys via adjusting the content of Nb and oxygen. Decreasing the phase stability enhances the degree of (Ti, Zr)-rich chemical short-range orderings, and then favors formation of OOCs after doping oxygen. Moreover, the number density of OOCs increases with oxygen contents in a given alloy, but adding excessive oxygen (>3.0 at.%) causes grain boundary segregation. Consequently, the tensile yield strength is enhanced by ~75% and ductility is substantially improved by ~164% with addition of 3.0 at.% O in the Ti-30Zr-14Nb MEA.

Feeder delivery vehicle scheduling optimization of high-speed railway express based on trunk and branch intermodal transportation.

In view of the traditional branch line end express delivery centralized mode cannot adapt to the growing demand of high-speed rail (HSR) express, resulting in poor connection between trunk and branch line, high cost and poor timeliness. In this paper, the problem of scheduling optimization of branch-line flexible distribution vehicles relying on intermodal transportation of trunk and branch lines is proposed. Considering the number of vehicles, vehicle capacity, customer service time window and other constraints, an integer linear programming mathematical model with the minimum total cost of vehicle transportation cost, usage cost and time window penalty cost as the optimization objective is established. A two-level nested heuristic algorithm with two-level coding structure is proposed to solve the problem. Finally, a simulation example is given to verify the effectiveness of the model and the algorithm. The results show that the vehicle scheduling optimization problem studied in this paper can effectively improve the timeliness and accuracy of HSR express delivery, and can significantly reduce the total vehicle delivery cost.

HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1.

Human papillomaviruses (HPV), mainly HPV16 and HPV18, of high-risk classification are involved in cervical cancer carcinogenesis and progression. Octamer-binding transcription factor 4 (OCT4) is a key transcription factor that is increased in various cancer types. Cervical cancer patients with higher levels of OCT4 had worse survival rates. However, the definite mechanisms underlying its function in the development of cervical cancer still remain to be explicated. Here, our study demonstrated that OCT4 expression was slightly increased in cervical cancer tissues than in precancerous ones. However, OCT4 was significantly upregulated in HPV16-positive tissues, in contrast to the expression profiling for p53. Moreover, knockdown of HPV16 E6 in SiHa cells suppressed the expression of OCT4 with impaired activities of cell proliferation, migration, and invasion, while it recovered the expression of p53. Overexpression of OCT4 and p53 exerted opposite roles on cell proliferation, migration, invasion, and colony formation of cervical cancer cells. More importantly, the enforced expression of OCT4 augmented p53-inhibited cell migration, invasion, and colony formation in human cervical cancer by promoting EMT. Finally, we identified that OCT4 could bind to the p53 promoter region to repress p53 expression by recruiting co-repressor NCOR1 using luciferase, ChIP, and co-IP experiments. We further illustrated that OCT4 not only increased the lung metastasis of cervical cancer but also effectively reversed p53-inhibited lung metastasis. In conclusion, our results suggested that HPV16 E6 activated the expression of OCT4 and subsequently crippled the transcription of p53 via co-repressor NCOR1, which contributed to cervical cancer progression.

RuO2 electronic structure and lattice strain dual engineering for enhanced acidic oxygen evolution reaction performance.

Developing highly active and durable electrocatalysts for acidic oxygen evolution reaction remains a great challenge due to the sluggish kinetics of the four-electron transfer reaction and severe catalyst dissolution. Here we report an electrochemical lithium intercalation method to improve both the activity and stability of RuO2 for acidic oxygen evolution reaction. The lithium intercalates into the lattice interstices of RuO2, donates electrons and distorts the local structure. Therefore, the Ru valence state is lowered with formation of stable Li-O-Ru local structure, and the Ru-O covalency is weakened, which suppresses the dissolution of Ru, resulting in greatly enhanced durability. Meanwhile, the inherent lattice strain results in the surface structural distortion of LixRuO2 and activates the dangling O atom near the Ru active site as a proton acceptor, which stabilizes the OOH* and dramatically enhances the activity. This work provides an effective strategy to develop highly efficient catalyst towards water splitting.

Telocytes enhanced in vitro decidualization and mesenchymal-epithelial transition in endometrial stromal cells via Wnt/ß-catenin signaling pathway.

Decidualization of endometrial stromal cells (ESCs) is essential for preparing endometrium for embryo implantation. Telocytes (TCs), a novel type of interstitial cell, exist in the female reproductive tract and participate in the pathophysiology of diseases. This study further investigates the hypothesis that TCs, a source of Wnt, modulates decidualization and MET in ESCs. We had observed differential expression of Wnt ligands in primary mice ESCs and TCs by qPCR. TCM-induced decidualization and MET was assessed in ESCs. Changes in markers for decidualization (cyclin-D3, desmin, d/tPRP), stromal cells (N-cadherin), epithelial cells (E-cadherin), and the Wnt/ß-catenin pathway (ß-catenin, FOXO1) were quantified by western blot and RT-PCR. ß-catenin knockdown in ESCs decreased the degree of TCM-induced decidualization and MET, with significantly reversed expression profiles (P < 0.05). This is the first study to show that TCs can enhance decidualization and MET in ESCs through the Wnt/ß-catenin signaling-pathway. Therefore, we describe a promising cell therapy for gynecological conditions and related reproductive problems associated with defective decidualization.

Accessory ovary may be a treatment for infertility: Case report and review of current literatures.

Accessory ovary is a type of ovarian dysplasia, which is often defined as an ovarian tissue placed near and directly connected to the normal ovary or one of ovarian ligaments. It is often asymptomatic, mostly is found or diagnosed at laparotomy, laparoscopy or autopsy. Accessory ovary is often excised during surgery due to its potential malignant behavior. We report a case of endometriosis cyst occurred simultaneously in right side of orthotopic and accessory ovaries, together with torsion 180° of accessory ovarian cyst. Considering that the patient had not given birth and the large size of cysts, exploratory laparotomy was performed. During laparotomy, both site of ovarian cyst have been removed with orthotopic and accessory ovarian tissues preserved. After surgery, a large number of antral follicles were found both in right side of orthotopic and accessory ovaries by ultrasonography. Accessory ovary is considered to have physiological function, and can be preserved as a fertility protection measure for women who have fertility requirements. At present, the definition of ectopic ovary, accessory ovary and supernumerary ovary are very vague and rarely discussed separately. So, we proposed a new way to clarify the concepts of ectopic ovary, accessory ovary and supernumerary ovary. Moreover, we advocated that they should be discussed separately in terms of definition and management measures.

Study of the mechanism underlying hsa-miR338-3p downregulation to promote fibrosis of the synovial tissue in osteoarthritis patients.

Osteoarthritis (OA) is a degenerative joint disease characterized by the degradation of joint cartilage, the formation of osteophyma at joint margins, and synovial changes. Whereas lesions of the joint cartilage were the key point of the research and treatment of osteoarthritis before, a recent study showed that the synovium plays a crucial role in the pathological progress of OA. The inflammatory environment in the joints of OA patients always results in the overactivation of fibroblast-like synoviocytes (FLSs), which produce a multitude of inflammatory factors and media, not only leading to the degradation and injury of the cartilage tissue and promoting the development of osteoarthritis but also resulting in synovial fibrosis and joint stiffness. Therefore, the synovium has attracted increasing attention in the research of OA, and the study of the mechanism of activation of FLSs and the fibrosis of joint synovium may shed new light on OA treatment. By using high-throughput screening, we have identified that hsa-miR338-3p is significantly downregulated in the synovial tissue and joint effusion from OA patients. A functional study showed that overexpression of hsa-miR338-3p in the FLSs inhibited the TGF-ß1-induced overactivation of the TGF-ß/Smad fibrosis regulation pathway by suppressing TRAP-1 expression and thus reducing the TGF-ß1-induced activation of the FLSs and the expression of vimentin and collagen I, two fibrosis markers. Meanwhile, a mechanism study also showed that the upregulation of hsa-miR338-3p reduced Smad2/3 phosphorylation by suppressing TRAP-1 and thus inhibited the TGF-ß/Smad pathway and TIMP1, a downstream protein. The present study, for the first time, illustrates the role of hsa-miR338-3p in synovial fibrosis in OA patients and the related mechanism, which is of importance to the treatment of OA and its complications by targeting the FLSs and synovial tissue. Hsa-miR338-3p not only has the potential to be a target for the gene therapy of OA but also has the potential to be a new marker for the diagnosis of clinical progression in OA patients.

Discovering a First-Order Phase Transition in the Li-CeO2 System.

An in-depth understanding of (de)lithiation induced phase transition in electrode materials is crucial to grasp their structure-property relationships and provide guidance to the design of more desirable electrodes. By operando synchrotron XRD (SXRD) measurement and Density Functional Theory (DFT) based calculations, we discover a reversible first-order phase transition for the first time during (de)lithiation of CeO2 nanoparticles. The LixCeO2 compound phase is identified to possess the same fluorite crystal structure with FM3M space group as that of the pristine CeO2 nanoparticles. The SXRD determined lattice constant of the LixCeO2 compound phase is 0.551 nm, larger than that of 0.541 nm of the pristine CeO2 phase. The DFT calculations further reveal that the Li induced redistribution of electrons causes the increase in the Ce-O covalent bonding, the shuffling of Ce and O atoms, and the jump expansion of lattice constant, thereby resulting in the first-order phase transition. Discovering the new phase transition throws light upon the reaction between lithium and CeO2, and provides opportunities to the further investigation of properties and potential applications of LixCeO2.

Size- and temperature-dependent Young's modulus and size-dependent thermal expansion coefficient of thin films.

Nanomaterials possess a high surface/volume ratio and surfaces play an essential role in size-dependent material properties. In the present study, nanometer-thick thin films were taken as an ideal system to investigate the surface-induced size- and temperature-dependent Young's modulus and size-dependent thermal expansion coefficient. The surface eigenstress model was further developed with the consideration of thermal expansion, leading to analytic formulas of size- and temperature-dependent Young's modulus, and size-dependent thermal expansion coefficient of thin films. Molecular dynamics (MD) simulations on face-centered cubic (fcc) Ag, Cu, and Ni(001) thin films were conducted at temperatures ranging from 300 K to 600 K. The MD simulation results are perfectly consistent with the theoretical predictions, thereby verifying the theoretical approach. The newly developed surface eigenstress model will be able to attack similar problems in other types of nanomaterials.

Regulation of inflammatory response in human chondrocytes by lentiviral mediated RNA interference against S100A10.

OBJECTIVE: The aim of the present study was to evaluate the effects of S100A10 silencing on the inflammatory response in human chondrocytes (HCs).The inflammation induced by lipopolysaccharide (LPS) was investigated in HCs in which the S100A10 was blocked with a lentiviral shRNA vector. METHODS: A lentiviral shRNA vector targeting S100A10 was constructed and packaged to effectively block S100A10 expression in HCs. HCs were infected with the lentivirus. S100A10 expression levels in HCs were detected by western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was employed to evaluate the change of cytokine secretion levels. The effects of S100A10 silencing on the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathway were also determined by western blot analysis. In addition, fluo-3-AM was used to demonstrate the change in calcium mobilization. RESULTS: Lentivirus effectively infected the HCs and inhibited the expression of S100A10. HCs with downregulated S100A10 showed significantly decreased production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-10. S100A10 silencing markedly suppressed the activation of MAPKs induced by LPS. Furthermore, the calcium concentration increase in HCs stimulated by LPS was also inhibited by S100A10 knockdown. CONCLUSION: Our investigation demonstrated that S100A10 might be considered as a potential target for anti-inflammatory treatment.

Statins synergize dexamethasone-induced adipocyte fatty acid binding protein expression in macrophages.

OBJECTIVE: Macrophage adipocyte fatty acid binding protein (FABP4) plays an important role in the development of atherosclerosis. We previously reported that dexamethasone induces macrophage FABP4 mRNA expression. Statins inhibit FABP4 expression. However, it remains unknown that if statins can antagonise dexamethasone-induced macrophage FABP4 expression. METHODS AND RESULTS: We determined the effect of co-treatment of statins and dexamethasone on macrophage FABP4 expression. Unexpectedly, statins did not block the induction of macrophage FABP4 expression by dexamethasone. In contrast, statins synergized dexamethasone-induced FABP4 expression. In vivo, pitavastatin synergized dexamethasone-induced FABP4 expression in both peritoneal macrophages and adipose tissues. Cholesterol and mevalonate, but not farnesylation and geranylgeranylation, inhibited the synergistic induction. Promoter assay disclosed a putative negative glucocorticoid regulatory element (nGRE) in FABP4 gene. Pitavastatin had little effect on expression of glucocorticoid receptor (GR). However, pitavastatin enhanced dexamethasone-mediated GR nuclear translocation but inhibited the binding of GR with nGRE. CONCLUSION: Our study defines an important mechanism involved in the regulation of macrophage FABP4 expression by a glucocorticoid and statins.

Induction of macrophage scavenger receptor type BI expression by tamoxifen and 4-hydroxytamoxifen.

OBJECTIVE: Scavenger receptor type BI (SR-BI) is an HDL receptor that is expressed by macrophages. SR-BI expression is tightly linked to the development of atherosclerosis. Tamoxifen has been shown to be atheroprotective. However, the involved mechanisms have not been fully elucidated. METHODS AND RESULTS: In this study, we investigated the effect of tamoxifen and 4-hydroxytamoxifen on macrophage SR-BI expression. Macrophage cell lines and peritoneal macrophages isolated from wild-type mice were used to determine changes in SR-BI mRNA and protein expression in response to tamoxifen and 4-hydroxytamoxifen. We observed that tamoxifen and 4-hydroxytamoxifen increased SR-BI protein expression in a macrophage cell line derived from female mice (J774 cells) but not in a line derived from male mice (RAW cells). Similar observations were obtained in primary macrophages isolated from wild-type male and female mice. Thus, the induction of macrophage SR-BI expression by tamoxifen and 4-hydroxytamoxifen is sex-dependent. Furthermore, we observed that SR-BI expression was induced by activating the oestrogen receptor (ER, specifically ERα) but was inhibited by inactivating the ER. However, the increased macrophage SR-BI protein expression was independent of transcription because SR-BI mRNA expression and promoter activity were not influenced by tamoxifen and 4-hydroxytamoxifen. Instead, tamoxifen increased the stability of macrophage SR-BI protein. Tamoxifen administration to mice had no effect on hepatic SR-BI protein expression but improved the serum lipid profile. CONCLUSION: Our study demonstrates that tamoxifen and 4-hydroxytamoxifen induce macrophage SR-BI protein expression via a post-transcriptional mechanism.

Inhibition of ERK1/2 and activation of liver X receptor synergistically induce macrophage ABCA1 expression and cholesterol efflux.

ATP-binding cassette transporter A1 (ABCA1), a molecule mediating free cholesterol efflux from peripheral tissues to apoAI and high density lipoprotein (HDL), inhibits the formation of lipid-laden macrophage/foam cells and the development of atherosclerosis. ERK1/2 are important signaling molecules regulating cellular growth and differentiation. The ERK1/2 signaling pathway is implicated in cardiac development and hypertrophy. However, the role of ERK1/2 in the development of atherosclerosis, particularly in macrophage cholesterol homeostasis, is unknown. In this study, we investigated the effects of ERK1/2 activity on macrophage ABCA1 expression and cholesterol efflux. Compared with a minor effect by inhibition of other kinases, inhibition of ERK1/2 significantly increased macrophage cholesterol efflux to apoAI and HDL. In contrast, activation of ERK1/2 reduced macrophage cholesterol efflux and ABCA1 expression. The increased cholesterol efflux by ERK1/2 inhibitors was associated with the increased ABCA1 levels and the binding of apoAI to cells. The increased ABCA1 by ERK1/2 inhibitors was due to increased ABCA1 mRNA and protein stability. The induction of ABCA1 expression and cholesterol efflux by ERK1/2 inhibitors was concentration-dependent. The mechanism study indicated that activation of liver X receptor (LXR) had little effect on ERK1/2 expression and activation. ERK1/2 inhibitors had no effect on macrophage LXRalpha/beta expression, whereas they did not influence the activation or the inhibition of the ABCA1 promoter by LXR or sterol regulatory element-binding protein (SREBP). However, inhibition of ERK1/2 and activation of LXR synergistically induced macrophage cholesterol efflux and ABCA1 expression. Our data suggest that ERK1/2 activity can play an important role in macrophage cholesterol trafficking.

Genetic deletion of low density lipoprotein receptor impairs sterol-induced mouse macrophage ABCA1 expression. A new SREBP1-dependent mechanism.

Low density lipoprotein receptor (LDLR) mutations cause familial hypercholesterolemia and early atherosclerosis. ABCA1 facilitates free cholesterol efflux from peripheral tissues. We investigated the effects of LDLR deletion (LDLR(-/-)) on ABCA1 expression. LDLR(-/-) macrophages had reduced basal levels of ABCA1, ABCG1, and cholesterol efflux. A high fat diet increased cholesterol in LDLR(-/-) macrophages but not wild type cells. A liver X receptor (LXR) agonist induced expression of ABCA1, ABCG1, and cholesterol efflux in both LDLR(-/-) and wild type macrophages, whereas expression of LXRalpha or LXRbeta was similar. Interestingly, oxidized LDL induced more ABCA1 in wild type macrophages than LDLR(-/-) cells. LDL induced ABCA1 expression in wild type cells but inhibited it in LDLR(-/-) macrophages in a concentration-dependent manner. However, lipoproteins regulated ABCG1 expression similarly in LDLR(-/-) and wild type macrophages. Cholesterol or oxysterols induced ABCA1 expression in wild type macrophages but had little or inhibitory effects on ABCA1 expression in LDLR(-/-) macrophages. Active sterol regulatory element-binding protein 1a (SREBP1a) inhibited ABCA1 promoter activity in an LXRE-dependent manner and decreased both macrophage ABCA1 expression and cholesterol efflux. Expression of ABCA1 in animal tissues was inversely correlated to active SREBP1. Oxysterols inactivated SREBP1 in wild type macrophages but not in LDLR(-/-) cells. Oxysterol synergized with nonsteroid LXR ligand induced ABCA1 expression in wild type macrophages but blocked induction in LDLR(-/-) cells. Taken together, our studies suggest that LDLR is critical in the regulation of cholesterol efflux and ABCA1 expression in macrophage. Lack of the LDLR impairs sterol-induced macrophage ABCA1 expression by a sterol regulatory element-binding protein 1-dependent mechanism that can result in reduced cholesterol efflux and lipid accumulation in macrophages under hypercholesterolemic conditions.

Functional interplay between the macrophage scavenger receptor class B type I and pitavastatin (NK-104).

BACKGROUND: Scavenger receptor class B type I (SR-BI), a receptor for high-density lipoprotein (HDL), plays an important role in the bidirectional cholesterol exchange between cells and HDL particles and the atherosclerotic lesion development. Enhancement of SR-BI expression significantly reduces, whereas lack of SR-BI expression accelerates, the atherosclerotic lesion development in proatherogenic mice. Statins, a class of inhibitors for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, significantly suppress de novo cholesterol synthesis and reduce the incidence of coronary heart disease. Statins also display multiple pleiotropic effects independently of cholesterol synthesis in the vascular cells. Here, we investigated the effects of pitavastatin (NK-104), a newly synthesized statin, on macrophage SR-BI expression. METHODS AND RESULTS: We found that pitavastatin significantly increased SR-BI mRNA and protein expression in a macrophage cell line in a concentration- and time-dependent manner. It also increased SR-BI expression in both mouse peritoneal and human monocyte-derived macrophages. Associated with increased SR-BI expression, pitavastatin enhanced macrophage HDL binding, uptake of [14C]cholesteryl oleate/HDL, and efflux of [3H]cholesterol to HDL. Pitavastatin abolished the inhibition of macrophage SR-BI expression by cholesterol biosynthetic intermediates. It also restored SR-BI expression inhibited by lipopolysaccharide and tumor necrosis factor-alpha through its inactivation of the transcription factor nuclear factor-kappaB. CONCLUSIONS: Our data demonstrate that pitavastatin can stimulate macrophage SR-BI expression by reduction of cholesterol biosynthetic intermediates and antiinflammatory action and suggest additional pleiotropic effects of statins by which they may reduce the incidence of coronary heart disease.

Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36.

BACKGROUND: Pitavastatin (NK-104) is a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol biosynthesis. In clinical trials, pitavastatin has been shown to significantly decrease serum LDL cholesterol and triglyceride levels and increase HDL cholesterol. Scavenger receptor-mediated accumulation of oxidized LDL (OxLDL)-derived cholesteryl ester is considered to be a critical step in the development of atherosclerotic foam cell formation. We studied the effect of pitavastatin on CD36 (a class B scavenger receptor) expression by murine macrophages. METHODS AND RESULTS: Treatment of J774 cells and murine peritoneal macrophages with pitavastatin decreased CD36 mRNA expression in a dose-dependent manner. Decreased CD36 mRNA was associated with decreased CD36 cell surface protein expression in human THP-1 cells and human monocyte-derived macrophages. Pitavastatin also reduced the increase in CD36 mRNA, cell surface protein, and binding/uptake of OxLDL induced by peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and/or OxLDL. Pitavastatin did not alter the half-life of CD36 mRNA, which suggests pitavastatin downregulates CD36 expression by reducing CD36 transcription. In addition, pitavastatin significantly decreased PPARgamma mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPARgamma phosphorylation and increased the ratio of phosphorylated PPARgamma to nonphosphorylated PPARgamma. CONCLUSIONS: The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPARgamma-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.

Regulation of peroxisome proliferator-activated receptor-gamma-mediated gene expression. A new mechanism of action for high density lipoprotein.

Cellular cholesterol content reflects a balance of lipid influx by lipoprotein receptors and endogenous synthesis and efflux to cholesterol acceptor particles. The beneficial effect of high density lipoprotein (HDL) in protecting against the development of cardiovascular disease is thought to be mediated predominately through its induction of cellular cholesterol efflux and "reverse cholesterol transport" from peripheral tissues to the liver. We tested the hypothesis that HDL could inhibit cellular lipid accumulation by modulating expression of peroxisome proliferator-activated receptor-gamma (PPARgamma)-responsive genes. To this end, we evaluated expression of two PPARgamma-responsive genes, CD36, a receptor for oxidized low density lipoprotein, and aP2, a fatty acid-binding protein. HDL decreased expression of macrophage CD36 and aP2 in a dose-dependent manner. HDL also decreased aP2 expression in fibroblasts, reduced accumulation of lipid, and slowed differentiation of fibroblasts into adipocytes. HDL stimulated mitogen-activated protein (MAP) kinase activity, and inhibition of CD36 expression was blocked by co-incubation with a MAP kinase inhibitor. HDL increased expression of PPARgamma mRNA and protein, induced translocation of PPARgamma from the cytoplasm to the nucleus, and increased PPARgamma phosphorylation. Our data demonstrate that despite induction and translocation of PPARgamma in response to HDL, MAP kinase-mediated phosphorylation of PPARgamma inhibited expression of PPARgamma-responsive genes and suggest mechanisms by which HDL may inhibit cellular lipid accumulation.