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It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future.
In this study, CUR-loaded methoxy polyethylene glycol–polylactide (CUR/mPEG–PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently.
The average size of CUR/mPEG–PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067–0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG–PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG–PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG–PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG–PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax.
The mPEG–PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG–PLA micelles have promising clinical potential in treating NSCLC.
Lung cancer is one of the malignant tumors with the highest morbidity and mortality in the world, among which non-small-cell lung cancer (NSCLC) accounts for 85% of cases.1 Chemotherapy is the main strategy for those with advanced lung cancer or unsuitable for surgery with metastasis.2 Unfortunately, the use of traditional chemotherapy drug is limited by its unsatisfactory efficacy, poor selectivity, high drug resistance and toxicity to normal tissue.3 Therefore, it is necessary to develop novel drug formulations with high efficacy but low toxicity.
Curcumin (CUR), a natural polyphenolic compound isolated from the rhizome of Curcuma longa, has the potential to inhibit cell survival, proliferation, invasion, migration and angiogenesis.4–6 A variety of signaling pathways, including Cyclin D1, COX-2, nuclear factor-kappa B (NF-κB) and matrix metal-loproteinases (MMPs), have been shown to be involved in the multi-therapeutic activities of CUR.7,8 More importantly, no sign of toxicity was observed in animals or humans treated with CUR, indicating its in vivo safety.9 However, its clinical application is still restricted by poor solubility in aqueous solution, poor oral bioavailability and extensive first-pass metabolism.10
Nanotechnology has been widely used in the field of drug delivery and cancer therapy due to its advantages in developing aqueous-based formulations for hydrophobic drugs.11–13 For example, liposomes, nanotubes and polymer nanoparticles have been successfully used as drug delivery systems (DDSs) to develop aqueous formulations and improve antitumor efficacy.14–16 Recently, scientists have shown interest in amphiphilic polymer micelles owing to their core–shell geometry17,18 and excellent characteristics, such as low toxicity, good biocompatibility and high biodegradability.19 As a perfect example, methoxy polyethylene glycol–polylactide (mPEG–PLA) polymeric micelles are composed of hydrophilic mPEG and hydrophobic PLA. On one hand, mPEG can act as a hydrophilic shell to reduce the nonspecific uptake by the reticuloendothelial system (RES), thus prolonging the circulation time in blood.20 PLA, on the other hand, mainly acts as hydrophobic core for drug loading (DL). More recently, mPEG–PLA polymeric micelles have been proven as excellent DDSs for CUR.21 However, the effect of CUR-loaded mPEG–PLA polymeric micelles (CUR/mPEG–PLA micelles) for treating NSCLC remains unknown.
Hence, CUR/mPEG–PLA micelles were prepared in this study. Subsequently, their efficiency was examined at the cellular level by investigating the drug uptake, apoptosis and cytotoxicity to A549 cells in vitro. More importantly, the anti-angiogenesis effect on human umbilical vein endothelial cells (HUVECs) was evaluated.
3-(4,5-Dimethylthiazol-2-yl)-2,5-di-phenyltetrazolium bromide (MTT) and Hoechst 33258 were purchased from Sigma (St Louis, MO, USA). CUR was obtained from Aladdin (Shanghai, China) and Matrigel from BD Biosciences (San Jose, CA, USA). Anti-Bcl-2, anti-Bax, anti-MMP-2 and anti-MMP-9 were provided by Abcam (Cambridge, UK), while anti-vascular endothelial growth factor (VEGF) was obtained from Boster (Wuhan, China). The secondary antibody goat anti-rabbit-IgG horseradish peroxidase (HRP) was from Jackson ImmunoResearch Laboratories Inc (West Grove, PA, USA).
mPEG (molecular weight =5000 Da) and stannous 2-ethylhexanoate were obtained from Aladdin. d,l-Lactide was obtained from Dibo (Shanghai, China). The mPEG–PLA diblock copolymers were synthesized by ring-opening polymerization reaction following a previously reported procedure.22 Briefly, 2.5 g of pure d,l-lactide and 5 g of mPEG were placed in a dried round-bottomed flask. The reactants were gently heated with stirring till they turned into liquid. Stannous octoate was added as a catalyst into the reaction mixture. The flask was sealed under nitrogen, and the copolymerization was carried out at 130°C for 24 hours. The crude product was dissolved in dichloromethane and then purified by precipitation in ice cold diethyl ether followed by filtration. The obtained mPEG–PLA copolymer was characterized by Fourier transform infrared spectroscopy (FTIR, Nicolet 6700; Thermo Fisher, Grand Island, NY, USA) and 1H nuclear magnetic resonance (1H-NMR) spectroscopy (AVANCE III 400 MHz; Bruker, Bern, Switzerland). The number average molecular weight of mPEG–PLA copolymer was 7,402 Da, calculated by 1H NMR (data not shown).
The human lung cancer A549 cells and HUVECs were purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China). They were cultured in Roswell Park Memorial Institute (RPMI)-1640 (Gibco, Grand Island, NY, USA) supplemented with fetal bovine serum (FBS; Gibco). HUVECs were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 10% FBS. All the abovementioned cells were maintained at 37°C in a humidified incubator containing 5% CO2. Permission for this study was obtained from the Ethics Committee of Southern Medical University.
CUR/mPEG–PLA micelles were prepared by thin-film hydration method. Briefly, 10 mg of CUR and 90 mg of mPEG–PLA copolymer were co-dissolved in 10 mL of methanol under mild stirring. Then, the solution was evaporated in rotary evaporator at 60°C. During this process, homogenous co-evaporation was obtained, and CUR was distributed in mPEG–PLA copolymer as an amorphous substance. Subsequently, the co-evaporation was dissolved in water at 60°C to self-assemble into micelles with CUR encapsulated inside. The CUR/mPEG–PLA micelles solution was filtered through a 0.22 μm syringe filter (Jinteng, Tianjin, China), lyophilized and stored at 4°C prior to use.
The prepared blank mPEG–PLA micelles and CUR/mPEG–PLA micelles were assessed by Malvern-3000Hs particle size analyzer at 25°C for parameters such as particle size distribution, polydispersity index (PDI) and zeta potential. For each sample, such assessment was taken three times, and the average results were obtained.
The morphological characteristics of CUR/mPEG–PLA micelles were examined by transmission electron microscope (TEM; H-7650; Hitachi, Tokyo, Japan). The CUR/mPEG–PLA micelles were diluted with distilled water and placed on a copper grid covered with nitrocellulose. Samples were negatively stained with 2% phosphotungstic acid and dried at room temperature.
Crystallographic assays were performed on CUR powder, a physical mixture of CUR and mPEG–PLA, lyophilized blank mPEG–PLA micelles and lyophilized CUR/mPEG–PLA micelles powder using an X-ray diffractometer (D8 ADVANCE; Bruker, Ettlingen, Germany). The samples were scanned from 5° to 50° at a scanning speed of 1/min and a step size of 0.02°. The X-ray tube was operated at a potential of 40 kV and a current of 40 mA.
The physical status of CUR powder, lyophilized blank mPEG–PLA micelles and lyophilized CUR/mPEG–PLA micelles powder was studied by Simultaneous Thermal Analyzer (STA449 F3; NETZSCH, Ahlden, Germany) under nitrogen atmosphere at a flow rate of 20 mL/min. The temperature gradually increased from 20°C to 250°C with a changing rate of 10°C/min.
The concentration of CUR was determined by high- performance liquid chromatography (HPLC; LC-20A; Shimadzu, Tokyo, Japan) with sample being diluted before measurement. Detection was taken on a Shimadzu SPD-M20A detector. Chromatographic separations were performed on a Diamonsil ODS C18 column (250×4.6 mm, pore size 5 μm; Dikma, Beijing, China). The column temperature was kept at 28°C. Acetonitrile/2.5% acetic acid (58/42, v/v) was used as eluent at a flow rate of 1 mL/min. EE and DL of CUR/mPEG–PLA micelles were determined as follows. Briefly, 10 mg of lyophilized CUR/mPEG–PLA micelles were dissolved in 0.1 mL of methanol to disrupt and release CUR, and then, the solution was centrifuged at 12,000 rpm for 5 min. The supernatant was determined by HPLC. The EE and DL were expressed by the equation:
In vitro drug release behaviors of CUR/mPEG–PLA micelles and free CUR were evaluated by the dialysis membrane method. Briefly, 1 mL solution (either CUR/mPEG–PLA micelles or free CUR solution) was placed in dialysis bags (molecular mass cutoff is 3.5 kDa). The dialysis bags were incubated in 40 mL of phosphate-buffered saline (PBS) (pH =7.4) containing Tween80 (0.5 wt%) at 37°C with gentle shaking. At predetermined time point, release medium samples were withdrawn and replaced with fresh release medium. The samples were centrifuged, and then, the supernatant was collected and stored at −20°C till analysis. The released CUR samples were quantified by HPLC.
Cellular uptake of free CUR and CUR/mPEG–PLA micelles was measured by confocal microscopy (FV10i-w; Olympus, Tokyo, Japan) and flow cytometry (FCM; BD Biosciences) analysis, respectively. A549 cells were grown on a confocal dish in complete medium. After 24 hours, the medium were removed, and cells were treated with serum-free medium containing either free CUR (20 μg/mL), CUR/mPEG–PLA micelles (20 μg/mL) or blank mPEG–PLA micelles. After incubation for 0, 1 and 4 hours, the medium were removed and washed with PBS. Subsequently, cells were stained with Hoechst 33258 for 5 minutes, subsequently washed with PBS and fixed with cold 4% paraformaldehyde for 10 minutes. Thereafter, they were washed again with PBS and examined using a confocal microscopy.
For FCM analysis, cells were collected and washed with PBS. Then, intracellular CUR fluorescence was analyzed by FCM after excitation with a 488 nm argon laser. Fluorescence emission at 520–530 nm from 10,000 cells was collected, amplified and scaled to generate single parameter histogram.
The cytotoxicity assay of free CUR or CUR/mPEG–PLA micelles was evaluated by MTT method. Cells were plated at a density of 1×104 cells per well in 96-well plates and grown for 24 hours. Then, cells were exposed to a series of free CUR, CUR/mPEG–PLA micelles or blank mPEG–PLA micelles at different concentrations for 48 hours, respectively. After the incubation period, the cells were treated with 5 mg/mL of MTT solution for 4 hours, then the solution was removed and 150 μL of dimethyl sulfoxide (DMSO) was added into each well. Absorbance intensity was measured by using a microplate reader (iMark; Bio-Rad, Hercules, CA, USA) at 570 nm.
About 1×103 cells were added into each well of a six-well culture plate (three wells for each group). After incubation at 37°C for 14 days, the cells were washed twice with PBS and stained with 0.1% crystal violet solution. The number of colonies containing ≥20 cells was counted under a microscope.
FCM assay was performed to investigate the cell cycle arrest and apoptotic effect of CUR/mPEG–PLA micelles. A549 cells cultured in six-well plates were treated with blank mPEG–PLA micelles, free CUR (20 μg/mL) and CUR/mPEG–PLA micelles (20 μg/mL) for 24 hours, and medium without treatment was considered as control. For the cell cycle analysis, they were washed with PBS, fixed with 70% ethanol overnight, pretreated with 100 μL RNase A and stained with 400 μL propidium iodide (PI) for 30 minutes. Cell apoptosis was determined using the Annexin V-fluorescein isothiocyanate (FITC)/PI detection kit (KeyGEN BioTECH, Nanjing, China). The cells were collected and then washed twice with PBS, gently resuspended in 500 μL of binding buffer and stained with 5 μL of Annexin V-FITC and 5 μL of PI solution according to the manufacturer’s instructions.
The activity of caspase 3 was measured using caspase 3 activity assay kits (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) according to the manufacturer’s protocol. The assay is based on spectrophotometric detection of the chromatophore ρ-nitroaniline (ρNA) after cleavage from the labeled substrate Ac-DEVD-ρNA by caspase 3 protease. The level of caspase 3 activity was tested at 405 nm in a microplate reader. Fold increase in caspase 3 activity was determined by comparing the absorbance from an apoptotic sample with an untreated control after subtracting the background value reading from cell lysates and buffers.
The tube formation assay was performed as described previously.23 A 24-well plate was coated with 100 μL Matrigel per well and allowed to polymerize for 2 hours. Then, HUVECs suspended in DMEM medium were seeded on to the Matrigel, and the cells were treated with either blank mPEG–PLA micelles, free CUR or CUR/mPEG–PLA micelles. After 6 hours, images were taken by a digital camera (IX83; Olympus, Toyko, Japan) attached to an inverted microscope.
For migration assay, wound-healing assay was done. HUVECs and A549 cells were seeded in a six-well dish and incubated for 24 hours; monolayer was then scratched with pipette tips and washed with PBS. Subsequently, fresh medium containing either blank mPEG–PLA micelles, free CUR or CUR/mPEG–PLA micelles was added to the scratched HUVECs and A549 cells. Medium without treatment was considered as control. Photographs were taken at 0 and 24 hours in an inverted microscope. The migrated cells were quantified by image-pro-plus (IPP) software, and the percentage of inhibition was calculated on the basis of untreated cells as 100.
For invasion assays, 5×104 cells in serum-free medium were placed in the upper chamber of the transwell plate (24-well insert, pore size: 8 μm) coated with Matrigel, and the lower chambers were filled with 10% FBS medium. The blank mPEG–PLA micelles, free CUR and CUR/mPEG–PLA micelles were added to the upper chamber, respectively. After 24 hours of incubation at 37°C, noninvasive cells were scraped, and migrated cells were fixed with 4% paraformaldehyde and stained with 0.05% crystal violet. The invasive cells were quantified by IPP software, and the percentage of invasive cells inhibited by CUR/mPEG–PLA micelles was calculated using untreated cells as 100.
The total cell proteins were extracted using Radio Immunoprecipitation Assay (RIPA) lysis buffer containing 1% phenylmethylsulfonyl fluoride (PMSF) and 1% protease inhibitors and then separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The proteins were transferred on to nitrocellulose filter membranes. The membranes were blocked in 5% fat-free dry milk for 2 hours and incubated with specific primary antibody in an appropriate dilution ratio including Bax (1:2,500), BcL-2 (1:1,000), VEGF (1:200), MMP-2 (1:2,500), MMP-9 (1:5,500) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 1:1,000) overnight at 4°C and incubated with the corresponding secondary antibodies. Specific protein bands were visualized using an enhanced chemiluminescence (ECL) advanced Western blot detection kit (Merck Millipore, Billerica, MA,USA).
The results were expressed as the mean ± standard deviation (SD). Statistical analysis was performed with one-way analysis of variance (ANOVA) using the SPSS 13.0 software. P<0.05 denoted significance in all cases.
Figure 1A illustrates CUR and mPEG–PLA self-assembled into CUR/mPEG–PLA micelles, which encapsulated CUR in the core part, with a hydrophilic shell. As shown in Figure 1B, the average particle size, PDI and zeta potential of obtained CUR/mPEG–PLA micelles were 34.9±2.1 nm, 0.1±0.04 and 0.90±0.35 mV, respectively. Furthermore, TEM imaging revealed that CUR/mPEG–PLA micelles were spherical in aqueous solution and monodisperse with a mean diameter of ~24 nm (Figure 1C). HPLC assay was used to determine CUR concentrations in the micelles. The EE and DL of these CUR/mPEG–PLA micelles were 90.2%±0.78% and 9.1%±0.07%, respectively.
The in vitro release of CUR from micelles was investigated by dialysis under sink conditions with a 0.5% Tween 80 solution in PBS (pH 7.4) as the release medium. As shown in Figure 1D, 90.6%±2.2% of free CUR was released into the medium in the first 48 hours, whereas only 34.9%±1.9% of CUR from the CUR/mPEG–PLA micelles. The cumulative release rate from CUR/mPEG-PLA micelles was 52.4%±2.8% over 5 days, compared with 94.6%±1.6% from free CUR.
The physical form of the drug encapsulated in the polymeric matrix was evaluated by XRD and DSC analysis. The XRD spectra are presented in Figure 2A, in comparison with the XRD diagrams of CUR, blank mPEG–PLA micelles and the physical mixture of CUR and the mPEG–PLA copolymer; the absence of specific diffraction peaks in the XRD spectra of CUR/mPEG–PLA micelles indicated that there are no CUR crystals in the CUR/mPEG–PLA micelles. The thermograms of CUR and CUR/mPEG–PLA micelles shown in Figure 2B also confirmed that CUR exhibited an endothermic melting peak at 171.3°C; upon encapsulation inside the micelles, the melting peak of CUR disappeared. Thus, Figure 2 suggested that CUR was completely and amorphously encapsulated within the core–shell structure of particles.
The MTT assay was applied to investigate the cytotoxicity of A549 cells. As shown in Figure 3A, CUR/mPEG–PLA micelles had higher cytotoxicity against A549 cells compared with free CUR. Half maximal inhibitory concentration (IC50) of CUR/mPEG–PLA micelles at 48 hours (30.18 μg/mL) was lower than that of free CUR (36.69 μg/mL). Meanwhile, cytotoxicity of mPEG–PLA copolymer was investigated on A549 cells (data not shown), suggesting that mPEG–PLA copolymer had low cytotoxicity and could serve as a safe carrier.
To understand why CUR/mPEG–PLA micelles may enhance cytotoxicity, cellular uptake ability was compared between CUR/mPEG–PLA micelles and free CUR on A549 cells. While there was no fluorescence in cells treated with blank mPEG–PLA micelles (data not shown), only a slight increase in fluorescence intensity was observed in cells treated with free CUR (20 μg/mL) for either 1 or 4 hours. On the contrary, bright green fluorescence was observed for CUR/mPEG–PLA micelles (20 μg/mL) for 1 hour and even brighter for 4 hours (Figure 3B), clearly indicating that CUR/mPEG–PLA micelles exhibited a much higher cellular uptake.
The enhanced cellular uptake of CUR/mPEG–PLA micelles was also confirmed by FCM analysis. Figure 3C–E shows that fluorescence intensity of cells treated with CUR/mPEG–PLA micelles is much higher than that in free CUR group after incubation for either 1 or 4 hours (P<0.01).
To evaluate whether CUR/mPEG–PLA micelles modulate cycle kinetics in A549 cells, cell cycle analysis was performed on A549 cells using FCM analysis after 24 hours of drug exposure. As shown in Figure 4A and C, the blank mPEG–PLA micelles treatment showed no obvious effects on cell cycle distribution. However, at 20 μg/mL, free CUR induced G2/M cell cycle arrest, resulting in a considerable increase in the G2/M phase from 6.59%±0.75% to 12.76%±1.03% (P<0.01). Furthermore, CUR/mPEG–PLA micelles gave rise to an even more obvious cell proliferation inhibition, where cell cycle was apparently retarded at the G2/M transition point from 6.59%±0.75% to 18.52%±1.21% (P<0.01).
Cell colony formation unit assay was also carried out. As shown in Figure 4B and D, when A549 cells were treated with free CUR or CUR/mPEG–PLA micelles, the ability to form colonies was obviously changed compared to the untreated group. In addition, CUR/mPEG–PLA micelles exhibited less A549 cell numbers than free CUR groups (P<0.01), indicating that CUR/mPEG–PLA micelles could inhibit the proliferation and clone formation ability of A549 cells.
Cell apoptotic rate was analyzed via FCM analysis. As shown in Figure 5A, no apparent sign of cell apoptosis was observed in untreated cells or blank mPEG–PLA micelle-treated cells. However, treatment of CUR increased the apoptotic cell proportion from 5.96%±0.18% to 16.33%±0.68% (P<0.01). Furthermore, CUR/mPEG–PLA micelles treatment increased the cell apoptotic rate from 5.96%±0.18% to 24.93%±0.51%, especially at early stage (Figure 5B) (P<0.01). These results displayed that CUR/mPEG–PLA micelles induced intense apoptosis in A549 cells.
Apoptosis is a course of a series of gene activation and regulation. The protein level of Bax/Bcl-2 was increased in CUR/mPEG–PLA micelles group compared with free CUR group (Figure 5C), suggesting an increased apoptosis by CUR/mPEG–PLA micelles in comparison with free CUR. In addition, the caspase 3 kit analysis showed that CUR/mPEG–PLA micelles induced more caspase 3 activation than free CUR (Figure 5D) (P<0.01), further supporting the enhanced proapoptotic effect of CUR/mPEG–PLA micelles.
Treatment with free CUR and CUR/mPEG–PLA micelles significantly reduced A549 cell migration compared to untreated cells (P<0.01) (Figure 6A and C). Moreover, the inhibitory migration effect of CUR/mPEG–PLA micelles was significantly higher than that of free CUR (P<0.01). CUR/mPEG–PLA micelles also showed a stronger inhibitory effect than free CUR in the transwell invasion assay (P<0.01) (Figure 6B and D). These findings clearly revealed that CUR inhibited the migration and invasion on lung cancer cells. Moreover, this activity was related to the decreased expression of VEGF, MMP-2 and MMP-9 in human lung cancer A549 cells (Figure 6E).
Angiogenesis is a very complex process. HUVECs are usually used to evaluate the anti-angiogenesis activity in vitro.24 As shown in Figure 7A and E, HUVECs formed capillary-like structures on the surface of Matrigel within 6 h in untreated and blank mPEG–PLA micelles group. In contrast, the tube formation of HUVECs was inhibited by treating with free CUR or CUR/mPEG–PLA micelles, and CUR/mPEG–PLA micelles induced a stronger inhibitory effect than free CUR (P<0.01). The effects of the CUR/mPEG–PLA micelles on the migration and invasion capacity of HUVECs were evaluated by wound-healing assay and transwell invasion assay, respectively. It was shown that the migration ability of HUVECs was inhibited in both CUR/mPEG–PLA micelles and free CUR groups (Figure 7B and F) and that CUR/mPEG–PLA micelles group exhibited a stronger inhibitory effect than free CUR group (P<0.01). Tran-swell invasion assays were performed to evaluate the ability of HUVECs passing through the Matrigel in the presence of blank mPEG–PLA micelles, free CUR or CUR/mPEG–PLA micelles. As shown in Figure 7C and G, in comparison with free CUR group, the inhibitory effect was improved in the CUR/mPEG–PLA micelles group (P<0.01). The MTT assay was performed to evaluate the cytotoxicity effects of CUR/mPEG–PLA micelles on HUVECs. Figure 7D showed that the growth ability of HUVECs was dramatically inhibited in a dose-dependent manner in both free CUR and CUR/mPEG–PLA micelles groups and that CUR/mPEG–PLA micelles had a lower IC50 (31.39 μg/mL) than free CUR (43.02 μg/mL).
As a popular natural medicine, CUR has been widely used for treating patients with a variety of tumors.25 However, its clinical application was restricted by its hydrophobicity. As such, increasing solubility of CUR is an urgent strategy to facilitate its clinical application.26,27 In this study, CUR/mPEG–PLA micelles were successfully developed, and their antitumor and anti-angiogenesis activity suggested their clinical potential for treating NSCLC.
Nanometer material has been reported to successfully enhance solubility and biological availability of hydrophobic drugs.28–30 Previously, mPEG–PLA has been employed as nanometer material to deliver doxorubicin,31 paclitaxel32 and 7-ethyl-10-hydroxy camptothecin33 for cancer therapy, leading to a considerable improvement in their anticancer effects. As an amphiphilic block copolymer composed of hydrophilic and hydrophobic segments, mPEG–PLA has a tendency to self-assemble into micelles in a specific solvent. In this study, a thin-film hydration method was applied to obtain CUR/mPEG–PLA micelles. Such CUR/mPEG–PLA micelles were monodispersed with PDI of 0.1±0.04 in aqueous phase. Meanwhile, the CUR/mPEG–PLA micelles were characterized with stable DL, high EE and slow release behavior, which may be attributed to the core–shell structure of polymeric micelles.34 It has been confirmed that drug-loaded micelles with small size (10–100 nm) could increase the accumulation in tumor tissue by enhancing permeability and retention (EPR) effect,35 therefore improving antitumor effects. The CUR/mPEG–PLA micelles prepared in this study have an average diameter of 34.9±2.1 nm, which, together with its considerably enhanced cellular uptake, should contribute to its good antitumor potentials. A series of experiments was performed in this study to evaluate the antitumor effect of CUR/mPEG–PLA micelles in A549 cells. Our results showed that CUR/mPEG–PLA micelles enhanced cytotoxicity and decreased IC50 cell viability, whereas mPEG–PLA exhibited low cytotoxicity to A549 cells. It was previously reported that both free CUR and CUR nanomaterials were nontoxic to human bronchus epithelial cell line BEAS-2B (normal cell).36,37 As such, CUR/mPEG–PLA micelles are considered to be safe to normal cells, but to be lethal to tumor cells. The CUR/mPEG–PLA micelles decreased the colony formation unit number as compared with free CUR group. It was also found that the proportion of cells in the G2/M was increased in CUR/mPEG–PLA micelles group. These findings indicated that CUR/mPEG–PLA micelle-induced cell growth inhibition was involved with cell cycle arrest. Apoptosis plays an important role in the initiation and progression of tumor, and Bax and Bcl-2 family pathway is involved in regulating cell propagation and cell apoptosis.38 Our results showed that CUR/mPEG–PLA micelles may enhance A549 cells apoptosis and significantly increased the expression of Bax and reduced the expression of Bcl-2. Moreover, CUR/mPEG–PLA micelles increased caspase 3 activity, which is the final stage of apoptosis initiation shared by both pathways.39
Metastasis is a complex multistep process that requires detachment from the primary tumor mass, migration through the extracellular matrix (ECM) and the colonization of surrounding sites.40 The migration assay and invasion assay demonstrated that CUR/mPEG–PLA micelles significantly inhibited A549 cells migration and invasion than free CUR. One of the key factors associated with the invasion and metastasis of cancer cells is MMPs, which led cancer cells to invade and migrate by degrading the ECM. Among MMPs, MMP-2 and MMP-9 expression is correlated with lung cancer metastasis.41,42 Additionally, VEGF, the key mediator of angiogenesis, also plays a crucial role in the process of metastasis.43 Therefore, the protein levels of MMP-2, MMP-9 and VEGF in A549 cells were evaluated. Our results that much lower expression of the abovementioned proteins in CUR/mPEG–PLA micelles group than in the free CUR group clearly indicated that CUR/mPEG–PLA micelles may induce apoptosis and inhibit cell growth, migration and invasion.
Angiogenesis plays a vital role in tumor growth and metastasis via supplying oxygen and nutrient.44,45 Anti-angiogenesis has been proposed as a promising therapeutic strategy for clinical therapy of tumors,46,47 mainly by slowing down tumor dissemination and increasing tumor responses to chemotherapeutics and radiotherapy.48 Clinical trial data show that several drugs, including bevacizumab, play an important role in the treatment of advanced NSCLC by targeting VEGF pathway.49 Therefore, the effect of CUR micelles was further investigated on angiogenesis in HUVECs in vitro. Our results showed that CUR/mPEG–PLA micelles induced cytotoxicity to HUVECs and inhibited the migration, invasion and tube formation of HUVECs, which was consistent with their effect on colon cancer.50 It is therefore believed that CUR/mPEG–PLA micelles can effectively inhibit the angiogenesis.
CUR/mPEG–PLA micelles were successfully prepared by a thin-film hydration method, with a high EE, and sustained release behavior in vitro. It was suggested that CUR/mPEG–PLA micelles are capable of enhancing the cellular uptake, cytotoxicity and apoptosis, while inhibiting the proliferation, migration and metastasis of A549 cells. Their angiogenesis ability was also confirmed in HUVECs. Our findings suggested that this novel formulation has potential clinical application for treating NSCLC. However, further in vivo investigations are warranted using A549 cell-bearing tumor model to better understand their antitumor potential.
This study was supported by the National Natural Science Foundations of China (Nos 81373365 and 81572219) and Guangdong Science and Technology Project (No 2015A010105014).
The authors report no conflicts of interest in this work.

domain: chemistry


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domain: artistic


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An Egyptian university student and social media influencer has been arrested on charges of inciting immorality and debauchery.
In the video in question Haneen Hussam, an archaeology student at Cairo University who has over one million followers on TikTok, asked women to post a video of themselves with the aim of recruiting them to join an agency she created on the video sharing platform Likee.
The women would then promote the platform in exchange for between $36 and $2-3,000.
Haneen said that the women must be above 18, wear formal clothes and dress and behave in a decent manner. She said she wanted the women to be fully clothed, would not accept abusive behaviour, and only those with a good reputation need apply.
Her critics are now calling for an investigation into her video on the grounds that she “legalised prostitution”.
TV presenter Nashaat Al-Dihy accused her of “inciting debauchery” and called on authorities to “preserve the identity of the Egyptian family” and asked them to take punitive measures against social media apps including TikTok.
Cairo University has said Haneen is now under investigation for “behaviours inconsistent with public morals and the university’s values and traditions” after people complained she was asking women to shoot inappropriate videos in exchange for money.
In her defence, Haneen has said that she made a three-minute video clip in which she asked women to apply but that the media reduced it to ten seconds taking her comments completely out of context, adding that her parents agreed to the videos before she published them.
Her father has said in press statements that his daughter is innocent and has not incited debauchery and that her videos are in line with what other women of her age publish online.
Several women in Egypt have been accused of “inciting debauchery”, including actress Rania Youssef, after critics took against her choice of dress for the Cairo Film Festival in 2018.
A number of singers and belly dancers have also had the charge levelled at them as the government has cracked down on all forms of free expression, including the arts.
In 2018 Egypt’s parliament passed a law stipulating that social media accounts and blogs with more than 5,000 followers will be treated as media outlets and those commanding them can be prosecuted for publishing false news.
The Sisi government maintains tight control over the state media in the country but has struggled to control the narrative on social media where it is easier to be critical of the regime.
Egypt’s National Telecom Regulatory Authority says the use of TikTok in Egypt has increased by 194 per cent since the curfew was put in place in March.

domain: sociology


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|Title:||Tetrahydrocurcumin inhibits HT1080 cell migration and invasion via downregulation of MMPs and uPA|
Pharmacology, Toxicology and Pharmaceutics
|Abstract:||Aim:Tetrahydrocurcumin (THC) is an active metabolite of curcumin. It has been reported to have similar pharmacological activity to curcumin. The proteases that participate in extracellular matrix (ECM) degradation are involved in cancer cell metastasis. The present study investigates the effect of an ultimate metabolite of curcumin, THC, on the invasion and motility of highly-metastatic HT1080 human fibrosarcoma cells.Methods:The effect of THC on HT1080 cell invasion and migration was determined using Boyden chamber assay. Cell-adhesion assay was used for examining the binding of cells to ECM molecules. Zymography assay was used to analyze the effect of THC on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion from HT1080 cells. Tissue inhibitor of metalloproteinase (TIMP)-2 and membrane-type 1 matrix metalloproteinase (MT1-MMP) proteins levels were analyzed by Western blotting.Results:Treatment with THC reduced HT1080 cell invasion and migration in a dose-dependent manner. THC also decreased the cell adhesion to Matrigel and laminin-coated plates. Analysis by zymography demonstrated that treatment with THC reduced the levels of MMP-2, MMP-9, and uPA. THC also inhibited the levels of MT1-MMP and TIMP-2 proteins detected by Western blot analysis.Conclusion:Our findings revealed that THC reduced HT1080 cell invasion and migration. The inhibition of cancer cell invasion is associated with the downregulation of ECM degradation enzymes and the inhibition of cell adhesion to ECM proteins. © 2008 CPS and SIMM.|
|Appears in Collections:||CMUL: Journal Articles|
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domain: medical


text:
- Nigeria's highest law-making legislature, Senate, has voted to increase CBN's borrowing to the Nigerian government
- The Senate amended the 2022 Appropriation Supplementary Budget to accommodate the new borrowing limit
- The upper legislative body also stated that the amendment also allows MDaAs to utilize all funds released to them
In an emergency session on Saturday, May 27, 2023, the Nigerian Senate amended the Central Bank of Nigeria (CBN) Act to boost the total CBN advances known as Ways and Means to the Nigerian government from 5% to a maximum of 15%.
Nairametrics said there were reports earlier that the emergency session was explicitly held to Amend the CBN act for more borrowing.
The bill allows the Nigerian government to meet financial obligations
The Senate Session reportedly began at about 11 am on Saturday, May 27, 2023, which is a deviation from the usual practice, which has its sittings day on Tuesdays and Wednesdays.
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Senate Leader Abdullahi Gobir read the debate on the bill and said the proposed amendment allows the Federal Government to meet its current and future obligations in approving the Ways and Means by the legislature and advances to the federal government by the CBN.
During the committee's sitting, the Senate amended the 2022 Supplementary Appropriation Act to extend the implementation year from June 30 to December 31, 2023.
The move allows the full implementation of the budget, particularly regarding the 2022 supplementary budget approved in December 2022. It will enable Ministries, Departments, and government agencies to use a large part of their allocated funds.
Gobir stated that many funds remain with MDAs and will need a further extension to be fully utilized.
Government agencies compelled to use full allocated funds
The Senate Leader said considering the essential importance of some critical projects almost completed, requesting a further extension of the expiration clause in the 2022 Supplementary Appropriation Bill, it is reasonable to avoid the problem of abandoned projects as some needed to be captured in the 2023 budget.
Gobir stated that the Senate is amending the 2022 appropriation act to permit full implementation of the capital releases to help reflate the economy.
The Senate is therefore amending the 2022 appropriation act to allow full utilization of the capital releases to help reflate the economy.
CBN Says it will beg the Dangote refinery to sell dollars, other currencies to banks at a reasonable rate
Legit.ng reported that following the Dangote Refinery commissioning and its plan to deliver its first products in July, the Governor of the Central Bank of Nigeria (CBN), Godwin Emefiele, has said that the bank will ask the refinery to sell foreign exchange to banks at a reasonable rate.
Emefiele stated his team would engage Aliko Dangote, Chairman of Dangote Group, to ensure that Nigerians benefit from the refinery, saying that the country helped him set it up.
The apex bank boss expressed hope that the 650,000bpd capacity refinery would reduce forex scarcity in Nigeria, stating that about 20% of the total cost of importing petroleum products into the country would be saved, leading to price reduction.

domain: finance


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This is the final part of Chapter 1 of “The Dog” by William Youatt.. While this book was published in the mid-1800s, there is still much that remains unchanged today, including the Dogs devotion to its master and family, and sometimes to its fellow dogs.
We continue discussing “The Dog” with this discussion of the faithful dog.
In Part IV we discussed dogs used in the chase of prey, or the hunting dog. We continue Chapter 1 of the book with some stories about the faithful dog, being true to their master, even when separated by time or death.
The hunting dog shows up late in the history of the dog.
In Part III, we discussed how the dog was treated and referenced in both ancient mythology and in the Bible. While revered in Egyptian mythology, the Bible appeared to be less kind, even lumping the dog in with other unclean beasts. This really was not as bad as it sounded, though, since unclean really referred to not eating them.

domain: literature


The presidential decree described the tree, the peak of a four-storey constructing, as a “beacon of Kenya’s cultural and ecological heritage.”
The fig tree is taken into account sacred amongst Kenya’s most populous ethnic group, the Kikuyu.
Environmentalists had been campaigning in opposition to the deliberate destruction of the tree, which stands on Waiyaki Way within the west of town, the place engineers are constructing the expressway above the present highway on pillars.
“It is now a presidential declaration that this tree will be conserved,” Mohammed Badi, director normal of Nairobi Metropolitan Services (NMS), informed a information convention subsequent to the tree.
The East African nation’s roads company had mentioned in October it deliberate to uproot and transplant it with a purpose to erect a pillar to help the expressway.
The tree can be adopted by the NMS on behalf of town’s residents and each the China Road and Bridge Corporation (CRBC) and the Kenya National Highways Authority have agreed to reroute the highway.
The tree will now stand as an indication of town’s aspirations, mentioned Elizabeth Wathuti, a outstanding Kenyan environmental activist.
“This particular fig tree is just a symbol of the bigger picture of what we are asking for. We want a green and clean city, and clean Kenya.”


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Four goals in third period secures victory for Elora Rocks
ELORA – The Elora Rocks struck for four goals in the third period to secure an 8-4 victory over the Stratford Fighting Irish Friday night at the Elora and District Community Centre to complete their regular-season schedule in the inaugural Western Ontario Super Hockey League season.
The Rocks, who’ll finish atop the standings, outscored Stratford 2-1 in each of the first two periods.
Elora Rocks 8 Stratford 4
Spencer Maccormack and Brad Krysko hit for two goals apiece for the Rocks while single goals were netted by Klayton Hoelscher, Matteo Condotta, Alex Utley and Tye Campbell. Krysko, Campbell and Spencer Gourlay each had two assists while Trevor Lord, Andrew Whalen, Michael Giacometti, Jeremey Goodwin, Mark Hamilton and Craig Byford each had one.
Matt Martin tallied twice for Stratford while the other goals were scored by Hayden Broomhead and Andrew Bogdon. Colin Martin and Cameron Stokes each had two assists and Ray Robbins, Broomhead and Tanner Johnson each had one.
The Rocks outshot the Irish 34-33 and Stratford didn’t score on the game’s only power play.
Craig Byford turned aside 29 shots to get the win in net for the Rocks while Marc Nother had 26 saves for Stratford.
The Rocks complete the regular season with a 17-3-2-0 record and are eight points ahead of the Strathroy Jets who have one game left to play. Stratford’s fourth at 8-9-0-1 and is a point behind the third-place Tillsonburg Thunder and the teams are to meet Saturday night at Tillsonburg.
Playoffs are expected to begin next week.
- Guelph Sports Journal

domain: news


One of Cumbernauld and Kilsyth’s best-loved charities has been handed a £700,000 lottery grant to boost its Hospice @ Home service.
The cash will cover nearly 70 per cent of the cost of the service for the next five years, with additional help from the Robertson Trust and NHS Forth Valley Endowments.
Irene McKie, Strathcarron’s chief executive, said: “It will make a huge difference to patients and their carers.
“The Hospice @ Home team will provide compassionate and practical support for them at what can be a very difficult and challenging time.”
She added: “It will give patients and carers the confidence they need to stay at home where possible.
“It will complement services provided by the NHS, social work, and Strathcarron’s Clinical Nurse Specialist Team.”
The National Survey of Bereaved People, published recently by The Office for National Statistics, revealed that only one third of people who express a preference to die at home actually do.
The lottery grant will mean many more local people are offered the choice.
Strathcarron’s director of nursing, Mrs Marjory Mackay, said that under Hospice @ Home, experienced hospice health-care assistants will work with people and their carers in their own homes.
She added: “They will provide emotional and practical support, as well as personal care, to allow patients to stay at home in the last days of their life, if that is their wish.”
Jenny Stevenson, who will manage the new service, said: “Like Strathcarron, we will strive to improve the lives of people who have advanced illness, helping them to live well until they die.
“The Hospice@Home team are committed to working with people and their carers in a way that makes this happen.”


AUSTIN, Texas (AP) The fight over bathroom rights for transgender students escalated in Texas on Tuesday as the state’s lieutenant governor urged schools to defy the Obama administration while parents of transgender children accused Republican leaders of stoking intolerance and making their kids targets for bullying.
Few states are as publicly and persistently pushing back on transgender rights as Texas. Republican Lt. Gov. Dan Patrick pledged at a press conference to support for schools that refuse to let transgender students use the bathrooms of their choice. Texas is leading an 11-state lawsuit that accuses the federal government of turning schools into “laboratories for a massive social experiment.”
“Transgender students deserve the rights of anyone else. It does not mean they get to use the girls’ room if they’re a boy,” Patrick said.
Parents of transgender students warned outside the Texas Capitol on Tuesday that the constant repudiation is taking a dangerous toll. They included the mother of a 5-year-old transgender girl who held a picture of her child smiling in a pink patterned dress and shoulder-length hair. She cried while asking why the state wants to force her daughter into the boys’ room at school.
She and other parents said Patrick’s comments are provoking hostilities in school hallways. Like many other Republicans across the country, Patrick says the privacy and safety of students are put at risk by letting transgender people use the bathroom that matches their gender identity.
“You, specifically you, are endangering my child’s life,” said Ann Elder, mother of a 10-year-old transgender child near Houston. “You have now told everyone in the state of Texas it is OK to harass my child.”
Transgender-rights advocates say claims of bathroom rights posing a public safety risk are malicious and false. They say that 18 states and scores of cities have experienced no significant public safety problems linked to their existing laws allowing transgender people to use the bathrooms of their choice.
Republican Texas Attorney General Ken Paxton said there wasn’t much research on whether children have been threatened in bathrooms while announcing the 11-state lawsuit against the Obama administration filed last week. The lawsuit asks a federal judge to declare the directive over bathroom rights unlawful and was filed in a North Texas federal court.
Two small school districts that joined the lawsuit, one in Texas and another in Arizona, have fewer than 600 students combined and no transgender students. Other states bringing the challenge are Oklahoma, Alabama, Wisconsin, West Virginia, Tennessee, Maine, Arizona, Louisiana, Utah and Georgia.
Patrick, a former conservative talk radio host, suggested that the Texas Legislature will take up school bathroom access in 2017. He has also asked Paxton to determine whether the Fort Worth school district the sixth-largest in Texas is breaking state education law with privacy rules that opponents say keeps conversations between transgender students and school officials from their parents.
Follow Paul J. Weber on Twitter: www.twitter.com/pauljweber


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Tuesday, May 12, 2009
Return to the Abacos
After dropping Beth off we high-tailed it back to First Edition for a 50 mile trip to Ship Channel Cay to reunite with Celebrian. Although we had good winds we motor-sailed to make time, arriving 8 ½ hours after departing Staniel.
The following morning we had another 8 hour trip to Royal Island, with both boats failing to catch dinner although we did hook 3 barracuda (we got even Beth!), releasing all 3 back to Neptune. We had great company along the way with several dolphin visits.
Just so remind ourselves what work used to be like, we continued the long trek on the third day, leaving Royal at 7 am, motoring for 10 hours to reach the Abacos, entering the cut at Little Harbor. The whole trip I kept thinking it was going to be an interesting entry, as we had a constant six foot swell on the trip there, and I was not wrong. Although it was really no big deal, in this picture you can see the waves breaking at the entrance, with the anchorage behind the breakers.
We now start the complicated re-entry to the States, trying to calculate when to leave, how long it will take, how many nights to be at sea (1-5)setting variables for weather. Once this is guess-timated we need to figure out how to get phone service to set up appointments for boat work (mostly improvements as opposed to repairs, thankfully), doctor visits (annuals with the trillions of docs we see), and quick visits with family and friends. Then, hopefully to Maine…
This boating life can be complicated.

domain: geography


Shakira has confirmed her split with her footballer partner Gerard Piqué after more than a decade together.
The Columbian singer, 45, has two children with Piqué, 35, who has played for FC since 2008 and made over 600 appearances for the club.
In a joint statement released via her publicist, the pair said: ‘We regret to confirm that we are parting ways.
‘For the well-being of our children, who are our highest priority, we ask that you respect their privacy. Thank you for your understanding.’
The pair met back in 2010 while she filmed the video for her World Cup song Waka Waka for the competition in South Africa.
While they never married, they were together for 11 years and share children Milan, nine, and Sasha, seven.
Talking about how their relationship began, Piqué said at the time: ‘It all started when we were in South Africa and I wrote to her.’
He was recently quizzed by Gary Neville on why he’d never tied the knot with the Hips Don’t Lie singer.
During an appearance on The Overlap podcast, he said: ‘No, I’m not married. It’s her mentality.
‘I like it how we are right now. We have two kids, nine and seven right now. We work good as a couple.’
It comes just hours after Shakira spoke out after worried fans spotted she had been seen in an ambulance recently.
Alongside a picture with her father, William Mebarak Chadid, she wrote on Twitter: ‘Guys, I’m getting a lot of messages of concern that I was seen in an ambulance in Barcelona recently.
‘I just wanted to let you know that those photos are from last weekend, when my dad unfortunately had a bad fall and I accompanied him in an ambulance, where he is recovering now.
She went on to thank fans for their supportive messages, concluding: ‘Please do send all your best wishes his way and thank you, as always, all of you for the love and support.’


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A powerful storm is slamming Western Alaska, with reports of major flooding in coastal communities including Golovin, Chevak, Hooper Bay, Kotlik and Shaktoolik.
The storm is the remnants of what was Typhoon Merbok, and forecasters have predicted it could be one of the worst storms to hit Alaska’s western coast in recent history.
Posts on social media Friday night and Saturday morning documented high waters flooding communities and high winds.
In a video recorded Friday in Hooper Bay, 63-year-old Judy Bunyon describes it as the worst storm she’s seen since childhood. The video showed water flooding homes and wind tearing off roofs.
In Golovin, the National Weather Service reported around 7:30 a.m. that everyone is safe, but major flooding continues.
“The highest water levels are not expected until early this afternoon, so flooding will likely get worse,” the weather service said in a Facebook post. “Water is entirely surrounding the school, homes and structures are flooded, at least a couple homes floating off the foundation, some older fuel tanks are tilted over, waves are starting to push into the community driven by 60 mph winds.”
In Chevak, one person wrote: “Practically all boats and sheds sunk/floated away.”
The weather service is also reporting high water and flooding in Kotlik Saturday morning, and significant waves in Shaktoolik.
Alaska’s western coast remains under a flood warning.
This is a developing story. Check back for updates.
Editor’s note: If you live in a community impacted by the historic storm, we’d like to hear from you. If you’re interested in speaking with a reporter, please reach out: email@example.com or 907-550-8444. Thank you.
AKPM & KYUK staff report
Alaska Public Media
alaskapublic.org , https%3A%2F%2Falaskapublic.org%2F2022%2F09%2F17%2Fpowerful-storm-slams-western-alaska%2F , News,Statewide News,Top Stories,Instagram, #Powerful #storm #slams #Western #Alaska


McAninch Corporation is at work on the largest grading project in Missouri Department of Transportation history, reshaping more than seven miles of rocky and rugged Ozarks terrain for a realignment of Route 5 from the Niangua Bridge south to near Route 7 at Camdenton.
Combining the power and brute force of some of the largest equipment in the industry with the accuracy and finesse of Global Positioning System (GPS) technology, the West Des Moines, Iowa-based contractor will move more than 7.5 million cubic yards of soil and rock for the new realignment. The $44-million project also includes extensive drainage work and the construction of two interchanges and four bridges. McAninch began its work a year ago with completion scheduled for August of 2008.
"Aside from just the sheer magnitude of the project, the topography and the materials have proven to be a challenge," said Don Taylor, vice president of McAninch's Heavy-Highway Division. "It's really rugged terrain and that creates challenges even in terms of simple access to the site. One of our partners on the job is Cretex and they supplied concrete pipe for the job. We couldn't start the mass excavation until the pipe was installed and we had to work out how to get the pipe delivered. Some of those places were so steep that we had to blaze roads to them with D-11s just to get the trucks in and out. And the material is very tough. We knew that going in and that's why we have the big excavators there."
The big excavators Taylor alluded to are two Caterpillar 5110Bs, one with a 13-yard bucket, the other a 10-yard bucket.
Considering that the company and its Chairman/CEO Dwayne McAninch pioneered the use of GPS in earthmoving — with Trimble systems on their dozers, scrapers, excavators and foremen's trucks — it's no surprise that they have even equipped one of the 5110Bs with GPS.
"We have GPS on the 5110 with the 10-yard bucket and it is a tremendous time and labor saver," said McAninch Project Superintendent Bill Botkin. "By having GPS on the 5110, we don't have to be there constantly setting stakes and checking grade. That frees up my foreman and grade checkers to be other places they need to be. The operator watches the screen as he's digging and the monitor tells him exactly where he is relative to grade. It's an amazing tool and though it may be unusual to see GPS on an excavator of that size, using the technology helps us to be successful on projects of this magnitude."
Other major equipment on the project, all Caterpillar, includes nine 740 articulated dump trucks, a D-11 dozer with ripper, and several dozer/scraper spreads from D-11s with 651s and D-10s with 641s to D-9s with 631s. Because of the volume of material being moved on the project, where the deepest cut is 70 feet and the highest fill is 60 feet, crews are using D-9Ls as their fill dozer tractors.
McAninch also has GPS-equipped D-7s and D-6s for the fill and finish work as well as a 385 excavator with GPS for pipe and miscellaneous work. Foremen have Trimble systems in their trucks and grade checkers use the hand held Trimble 5800s.
In addition to the machine power and technology McAninch is bringing to bear on the project, the company's experience helped to avoid potential problems with water availability before the fact. Though surrounded by water in "lake country," McAninch hired the installation of a well and pump on the project that is paying dividends.
"We realized when we got started on the project that water was going to be very important," said Botkin. "Like Doug said (company President and COO Doug McAninch), particularly during the height of the season, if we didn't have the water we needed, we wouldn't be able to keep our dust under control on the haul roads and we wouldn't be able to keep our fills up to optimum moisture."
To ensure an adequate and convenient supply of water, McAninch hired a local well driller, Lloyd Moreland, to drill a well about 800 feet deep. The well is equipped with a pump that can supply up to 300 gallons per minute and keeps a 12,000-gallon water stand full on the project. Water truck operators can fill their trucks with 4,000 gallons in about two minutes.
"The initial investment was a consideration, of course, but it's paying off for us," Botkin said.
Though moving 7.5 million cubic yards of rock and soil in 15 months is a challenge, Botkin said the work is progressing well.
"Actually, we're a little ahead of schedule. We are a little over 50-percent done on the material," he said in late April. "Our completion date is August of 2008 but I'm fairly confident that we can get it done in late spring or early summer next year if we don't encounter any major weather problems.
The Route 5 realignment will relieve congestion and enhance safety in the busy tourist area where the traffic count averages about 4,400 vehicles per hour. The project, strongly supported by area development and transportation groups, was accelerated with Amendment 3 monies.


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EastEnders' star Danny Dyer has said one of his testicles is the size of a jacket potato.
The Cockney hard-man admitted in a new interview that his inflated testicle is his party trick, and he likes to get it out and show it to people for a joke.
Speaking to Heat magazine, the 42-year-old actor said: "I've got a big b*****k – just one. It's the size of a jacket potato and, er, sometimes I get it out, pad it in glitter and we have a little pipe at it."
The phrase "pipe" is Cockney rhyming slang for taking a look at something.
Danny was one of a number of celebrities to take part in the party trick segment in Heat.
However, he was the only star to talk about his genitalia.
EastEnders fans have long commented on the actor's bulge, with it being spotted several times on the show.
If you search Danny Dyer bulge on Twitter, you are met with a number of comments.
One social networker commented: "When your goggling s***e on the internet and come across 'Danny Dyer bulge' how did I stumble across this and more worryingly how did i miss it??'"
While another continued: "Danny Dyer huge bulge."
A third added: "Can we all please take a moment to appreciate Danny Dyer's massive bulge and chunky thighs..."
In 2017, he mentioned his package on Celebrity Juice.
One of his co-star's Tom Rosenthal has also previously commented on what Danny's packing.
Tom remarked: "I don't want to be crass, but in the competition between our genitalia, I finish third, do you know what I mean? Huge. Monster of a thing."


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Over the past three years, I've been in various places: the south suburbs of Illinois; northern Illinois just by Iowa; Denver, Colorado; Bemidji, Minnesota; and more recently, Barcelona, Spain.
In the last week of October, I had no idea where I would be living: would I go more to Ohio with my parents? Try to stay in the south suburbs of Chicago or move to the city? Or would I try to live in Denver with my sister? The answer: none of the above.
I got hired on the fly and was asked to move to the Twin Cities. I'm living in St. Paul, learning, exploring it, and coming to really like it here. I imagine I'll go to other parts of the world sooner or later. Imagine me on a plane, on a bus, or a hippie van if you will. This is one rooted writer waiting in transition for the next part of her life.
+++These last few days have been trying. A few weeks ago I was bright, idealistic, and had no idea what I was signing up for when I enrolled in the Oxford Seminar TEFL course. I knew it would an intensive three weeks, but I trusted that I would get through whatever the course hurled my way. What I had not imagined:
1- There was no way I was going to be able to get all the reading done, especially…
Wazir Khan Masjid, Lahore’s old Walled City, Photographs by ||| Tammie
Book on Navigation, Late 17th century-early 18th century
Ink and pigments on laid European paper bound between boards covered with red leather with gold.
Old Walled City — Lahore, Pakistan, 2012


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Regular price: $6.95
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What would you do if your family wanted you to marry a good-standing gentleman, purely for social status? Would you marry the next appropriate suitor that your family chose for you, or would you follow your curiosity and be with someone who unlocks your most intense desires you never knew you had?
Meet Miss Regina Lily. She is a proper lady who is thoughtful, well-spoken, and kind. After beginning charity work at a rehab house, to save her reputation after her mother's indiscretions, she meets Mr. Geoffrey Woodsworth. Geoffrey is a devilishly handsome and sinfully sexy man who makes Regina's heart beat fast.
After their first meeting, Regina is infatuated and continues to visit Geoffrey, no matter how unladylike it may be. Her desire to be in his company is just too hard to fight. But little does she know, Geoffrey has a secret; he is a werewolf.
Will Regina ever know the truth about Geoffrey and why he has shackles in his room, or will he keep her in the dark from fear of losing her forever?
Customer ReviewsMost Helpful
By KGLP host/producer & traveling therapist. on 08-16-16
Brief period pc anglo girl shifter boy conflict.
Very very short story. Period piece Victorian time. Young anglo female who's parents were involved with a scandel. The girl tries to do good works by reading to the sick & afflicted. One of the patients is a male anglo rich drug user. He catches her eye. He uses drugs to cover pain from shifting. The rest is predictable. Mild sex scene at end. Worth a credit?? flip a coin.


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Here's some advice for you: don't attempt to touch Reeve Carney's face – his cheekbones are so sharp your fingers might bleed. The man who is currently in Dublin filming Showtime's Penny Dreadful (portraying Oscar Wilde's Dorian Gray) is also lined up to play Jeff Buckley in the officially sanctioned biopic Mystery White Boy . To say that you need a good-looking guy for these projects is an understatement, but 30-year-old Carney definitely doesn't allow his face to get in the way of good work.
The truth is, he's something of an entertainment brat, with showbiz blood flowing through his veins. His great-uncle was Irish-American actor Art Carney: he may be best known for his recurring role in the US comedy show The Honeymooners , but he also nabbed an Academy Award (best actor in 1974 for Harry and Tonto , beating the likes of Dustin Hoffman, Jack Nicholson and Al Pacino), was nominated for a Tony Award (in 1969, for his Broadway performance in Brian Friel's Lovers ), and won six Emmy Awards (for The Honeymooners ). He is surely the only actor – alive or dead, garlanded or not – who was once granted an Honorary Life Membership of the Florida Water and Sewage Works Operators Association in recognition for his regular amusing reminders throughout The Honeymooners that sewage systems not only exist but work. His great-nephew is suitably impressed.
“It was a bit like growing up in a family of carpenters or electricians,” says Reeve. “It just kind of made sense, and I never really thought about doing anything else, even though my parents were occasionally whispering into my ears when I was asleep, ‘Doctor, lawyer, doctor, lawyer’.
"Art passed away when I was 20 so we saw him quite a bit when we were kids. He lived in Connecticut, and we lived there when I was younger. The main thing was watching The Honeymooners – I grew up watching that, but I wasn't aware of his theatre background at all until I started on Broadway myself."
On the road with mom
This brings the topic of conversation around to Reeve's own achievements. His early love of graphic art morphed into a headstrong, precociously talented love of blues music. At the age of 12 he was dabbling on piano but deeper into guitar. An unusually understanding and clever mother managed to bridge the gap between youthful obsession and diligent schooling. So Reeve was playing music venues at the age of 14, but there, right at the side of the stage, was his mother.
“Yes, I know, 14 is really young to be in these clubs – and I was really short, so I looked even younger. At that time, though, I didn’t have too much self-consciousness, either, so I wasn’t really nervous. The reason why my mother took me to these venues was twofold: firstly, my parents got divorced and so it was around the time when she was struggling to raise three kids; secondly, there wasn’t a lot of money for guitar lessons, and because she knew it was what I really wanted to do, she’d take me to these blues clubs, where I learned and played for free.”
Reeve and his chaperone would arrive at the clubs around 9pm and leave after midnight. “Then I’d go home, sleep for several hours and get up for school at around 6am. And before anyone says anything, I’d be made to do my homework before we went out to the venues.”
Caught in a web
After music and a stint in a semi-successful band (Carney, now on ice, once opened for U2 on the latter's 360-Degrees Tour), Reeve then heard of a Broadway musical that was auditioning for roles. Before he could say something along the speech-bubbled lines of "whaam", "splaatt" or "kapowww", he had landed the much coveted role of Peter Parker in Spider-Man : Turn Off the Dark .
As we now know, that show, featuring music and lyrics by The Edge and Bono, clocked up records that no Broadway production wants or needs: it is, to date, the most expensive production in Broadway history (€55 million), and it ended up having the longest preview period in Broadway history (182 performances). The show was a nightmare – its investors, lost in the region of €44 million.
Reeve, who left the show last year in order to work on Penny Dreadful , other screen projects and his debut solo album, isn't too fussed about the past. The show was, he says, "a wonderful opportunity". That noted, he emphasises that he had never before appeared on a Broadway stage, and therefore he had no reference points.
“To me all the things happening didn’t seem that strange. I thought being on Broadway was always like a nightmare. It was tough, but then anything of any value is generally hard work. I don’t think I had any prima donna moments during it, and I’m fairly sure that if I had previous experience of Broadway then I would have known that something was going on.”
His friends, apparently, kept him clued in. “All I kept hearing from them was along the lines of, ‘just so you know, this is a very unique experience you’re having right now’.”
Reeve Carney plays Dublin's Workman's Club on Saturday. Penny Dreadful is scheduled to run on Sky Atlantic/Showtime from May

domain: entertainment


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2 edition of Environmental policy of Japan found in the catalog.
Environmental policy of Japan
Organisation for Economic Co-operation and Development. Environment Committee.
|Statement||prepared by Japan for the Analysis Meeting.|
|The Physical Object|
|Number of Pages||347|
OECD Environmental Performance Reviews: Japan This review of Japan's environmental conditions and policies evaluates progress in reducing the pollution burden, improving natural resource management, integrating environmental and economic policies, and strengthening international co . Book Description. From a nuclear North Korea and territorial disputes in the East China Sea, to global climate change and Asia-Pacific free trade agreements, Japan is at the center of some of the most challenging issues that the world faces today. and networks influencing Japanese foreign policy, the Routledge Handbook of Japanese Foreign.
Junko Edahiro is one of Japan’s top environmental journalists and a major proponent of the country’s slow-living movement. She has translated books by Lester Brown, Al Gore, Dennis Meadows, Donella Meadows, David Suzuki and many others into Japanese, and written dozens of her own books on climate change, energy, happiness, systems thinking and many other sustainability topics. collected samples. Japanese environmental policies are outlined in Section 3, and in Section 4 the relationship between environmental management and environmental performance are reviewed in the light of the survey results. Section 5 covers incentives and factors which affect motivation to introduce.
This book examines the development and current state of environmental policy, and in particular of environmental impact assessment, (EIA) in Japan. The first part reviews interest group participation in environmental policy making, the history and current state of environmental problems in Japan, the land use and economic planning framework. As the official journal of the Society for Environmental Economics and Policy Studies and the official journal of the Asian Association of Environmental and Resource Economics, it provides an international forum for debates among diverse disciplines such as environmental economics, environmental policy studies, and related fields.
LISP 1.5 primer.
The 2000 Import and Export Market for Coal, Lignite, and Peat in Argentina (World Trade Report)
Internal and international dynamics of ethnic conflict
Report by Departments Inspectors on Ballymoney High School, inspected May 1993.
Proteas in Hawaii
System of nomenclature for terpene hydrocarbons
The British Army
Selwyn Lloyd report
Sir William Walton
The sacred festival-drama of Parsifal
A sermon preachd at the consecration of the Chappel of St. Catherine
Feeding and Managing Growing and Finishing Pigs.
The book introduces Japan s environmental history, its key environmental regulations and the forces that have driven Japan to introduce these environmental Environmental policy of Japan book and programs.
It also examines the various formal and informal institutional mechanisms and policy instruments that have been introduced over the past several decades to implement pollution control and energy conservation.
First published in Japanese attitudes to pollution and environmental protection were distinctly equivocal. The Japanese are a nature-loving people, yet they are responsible for widespread environmental destruction; Japan has some of the world’s strictest environmental quality standards, but the country also has some of the world’s most environmentally damaged by: By examining the issues of environmental policy formation and implementation linked to economic development, and reviewing the Japanese experiences and the examples of other Asian countries, this book reveals factors of dynamism between environmental policy and social change in a domestic, regional and global context.
About this book By examining the issues of environmental policy formation and implementation linked to economic development, and reviewing the Japanese experiences and the examples of other Asian countries, this book reveals factors of dynamism between environmental policy and social change in a domestic, regional and global : Palgrave Macmillan UK.
A booklet titled "Water Environmental Management in Japan" includes the details of such history (Note 2), together with overall policies and data related to the water environment in Japan. The outbreak of the Minamata Disease, which occurred as a result of methylmercury poisoning, was first reported in Environmental Protection Policy in Japan - Introduction.
During the 20 years after the establishment of the Environment Agency inthe environmental situation at the national and global levels has undergone substantial changes.
At the national level, notable achievements have been made in combating severe pollution during the period of high economic growth. Environmental Protection Policy in Japan - Introduction; Environment Agency’s Policy Focus for FY ; Environment & Economy.
Practical guide for Scenario Analysis in line with TCFD recommendations -2nd edition-[PDF 28MB] Practical guide for Scenario Analysis in line with TCFD recommendations[PDF MB] Environmental Reporting Guidelines. Environmental Issues Facing Japan.
Even though Japan is one of the countries that have taken a bold step regarding responsiveness to environmental issues and overall cleanliness, industrial activities and agriculture still pose some environmental challenges. Waste management is the biggest environmental problem in Japan. A booklet named "Water Environmental Management in Japan" includes details of such history, *2 together with overall policies and data related to the water environment in Japan.
The outbreak of Minamata Disease, which occurred as a result of methylmercury poisoning, was first reported in With post-Fukushima energy policy remaining controversial, Japan falls into the upper-middle ranks (rank 14) with regard to environmental policy.
Its score on this measure has improved by points relative to Nuclear power plants have restarted following the Fukushima disaster, but concerns continue to keep this process slow.
Demonstrating that bridging policy gaps between local action, national policy and global strategies is potentially a way of reinventing environmental policy, this book will be of interest to students and scholars of Environmental Studies, Environmental Politics and Japanese Politics.
"Providing a detailed analysis of environmental policies and policy instruments in Japan by leading experts in the field, this book will be of great interest to students of environmental policy and politics and policymakers concerned with environmental protection in Asia."--Jacket.
Compared to other policy areas such as economics and finance, environmental policy is relatively new. Wide-ranging, the field of environmental policy spans from local garbage disposal to environmental protection on a global level.
Part III: Three Pillars of Japan's Defense (Means to Achieve the Objectives of Defense) Chapter 1 Japan's Own Architecture for National Defense.
Section 1 Truly Effective Defense Capability; Section 2 Role that Japan's Defense Forces Have to Fulfill; Chapter 2 Japan-U.S. Alliance. Section 1 Outline of the Japan-U.S. Security Arrangements. Environmental Policy and Impact Assessment in Japan How we measure 'reads' A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors).
In Novemberthe Experts' Study Committee on A Recycle-Oriented Society for Environmental Protection of the Japan Environment Agency (JEA), published a report that formed the basis for Japan's recycling law (Japanese Environment Agency, ).
Industry also appears to have made big changes in its environmental policy since In the s and s, Japan was known as the leading innovator in environmental policy. Other OECD countries found much to emulate. Two decades later, Japan appears to have lost its innovative edge to other OECD countries.
Why has Japan fallen from its position as the global leader. How should Japan regain its reputation. Possible causes of the rise and fall of Japanese environmental policy. Development of Environmental Policy in Japan and Asian Countries This book examines the issues of environmental policy formation and implementation linked to economic development, by reviewing the Japanese experiences and the examples of other Asian countries.
Genre/Form: Aufsatzsammlung: Additional Physical Format: Online version: Environmental policy in Japan. Berlin: Edition Sigma, © (OCoLC) Environmental Policy and Impact Assessment in Japan.
DOI link for Environmental Policy and Impact Assessment in Japan. Environmental Policy and Impact Assessment in Japan book. and thus the area’s environmental quality. The establishment of an environmental management system, of which EIA would be one component, is restricted in Japan by Author: Brendan F.
Barrett, Riki Therivel. This book examines the issues of environmental policy formation and implementation linked to economic development, by reviewing the Japanese experiences and the examples of other Asian countries.
This reveals factors, which could mutually influence effectiveness in environmental policy, of dynamism between environmental policy and social change in a domestic, regional and global context. The catalyst for drastic change in Japan’s energy and environmental policies is the Fukushima No.
1 nuclear power plant disaster that started in A gold mine of information, this book gives a balanced, comprehensive, and authoritative analysis of Japan's environmental policy and candidly covers [End Page ] both its considerable achievements and persistent limitations.
Although this volume focuses on issues of policy implementation, it impressively addresses most aspects of environmental issues in Japan.

domain: library


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Excitatory amino acids play a key role in stress-induced remodeling of dendrites in the hippocampus as well as in suppression of neurogenesis in the dentate gyrus. The regulation of extracellular glutamate levels has been suggested as a potential mechanism through which repeated stress causes dendritic remodeling of CA3 pyramidal neurons. Accordingly, the current study examined the distribution and regulation of the glia glutamate transporter GLT-1 and the recently identified GLT isoform, GLT-1b, in the hippocampus of rats subjected to chronic restraint stress (CRS). We also examined the ability of the antidepressant tianeptine, which blocks CRS-induced dendritic remodeling, to modulate CRS-mediated changes in GLT-1 and GLT-1b expression. CRS increased GLT-1 mRNA expression in the dentate gyrus and CA3 region of Ammon's horn, increases that were inhibited by tianeptine. CRS more selectively increased GLT-1 protein levels in the subregion where dendritic remodeling is most prominent, namely the CA3 region, increases that were also inhibited by tianeptine administration. In contrast, GLT-1b mRNA expression was not modulated in the hippocampus in any of these groups, but CRS increased GLT-1b protein levels in all hippocampal subfields examined, increases that were unaffected by tianeptine treatment. These results point to the importance of understanding the mechanism for the differential and subregional regulation of GLT-1 isoforms in neuronal and glial compartments in the hippocampus as a basis for understanding the effects of chronic stress on structural plasticity as well as the neuroprotective properties of agents such as tianeptine.
|Number of pages
|Proceedings of the National Academy of Sciences of the United States of America
|Published - Feb 17 2004
ASJC Scopus subject areas


Scheffer to Launch New Offline Finishing System at drupa
Press release from the issuing company
(May 15, 2008) Scheffer Web Finishing - the world's leading supplier of inline and offline web finishing equipment - will debut its all new QCC (Quick Change Cassette) offline finishing system on its stand 13 B91 at drupa 2008.
The newly released QCC line allows printers to quickly and cost efficiently finish pre-printed rolls from multiple press lines with different web and cut-off sizes.
The system can be custom equipped to meet each printer's specific needs. From simple systems with entry level components to sophisticated multi-web systems that can perforate, apply remoistenable pattern glue, spot and flood coat, die cut, stack multiple ribbons, plow fold, apply wetflap pattern gluer, personalize, insert, and full bleed trim.
A QCC (Quick Change Cassette) Variable Rotary Cutter will be exhibited on the Scheffer stand, together with a high speed inline inserter, designed specifically for producing closed end mailers.
Scheffer will also announce the upcoming debut of its ICF cross folder. Based on proven press folder technology, the system allows inline and offline web finishers to cross fold products after they pass through a finishing system's variable rotary cutter. Unlike the fixed assemblies used with traditional press folders, Scheffer's ICF cross folder can be adjusted to accommodate a variety of product lengths and trim sizes.
WhatTheyThink is the global printing industry's leading independent media organization with both print and digital offerings, including WhatTheyThink.com, PrintingNews.com and WhatTheyThink magazine versioned with a Printing News and Wide-Format & Signage edition. Our mission is to provide cogent news and analysis about trends, technologies, operations, and events in all the markets that comprise today’s printing and sign industries including commercial, in-plant, mailing, finishing, sign, display, textile, industrial, finishing, labels, packaging, marketing technology, software and workflow.


text: The West Residence had many items that involved decorative concrete. An exotic front patio laden with Mexican Pebble and acid stain, a rear patio designed with colorful bands and a water feature in the center, and perfect seat walls around the patio perimeter. The West Floors were a special blend of acid stains and tile and the design was a collaboration with Lincoln West, Tom Ralston and Bill Goff. TRC used 3-different acid stains and incorporated a diagonal saw cut pattern while carefully inserting various pieces of Mexican Tile. The results were stunning and everyone who has visited the West Home have had high praises for the acid stained floors.


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Combine half-and-half, milk, sugar, and salt in a 4-quart saucepan; cook over medium heat 10 minutes or until thickened, stirring constantly.
Combine eggs and egg yolks. Stir one-fourth of half-and-half mixture into egg mixture. Add to remaining half-and-half mixture, stirring constantly. Cook 1 minute; remove from heat, and let mixture cool.
Beat whipping cream until stiff. Fold cream, coconut, vanilla, and coconut extract into half-and-half mixture. Pour into freezer can of a 1-gallon hand-turned or electric freezer. Freeze according to manufacturer's instructions. Let ripen 1 hour before serving.
Oxmoor House Homestyle Recipes

domain: food


LUTER Arm Sleeves, Arm Cooling Sleeve Covers With UV Sun Protection, Anti Mosquito Bites Special Material and Compression Design for Cycling/Golf/Running/Basketbal/Driving/Climbing For Men and Women
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Jane eyre heroine. Jane Eyre: Heroine of Heroines 2022-10-28
Jane eyre heroine Rating:
Jane Eyre is the titular protagonist of Charlotte Bronte's 1847 novel of the same name. She is a complex and deeply nuanced character, and her story is one of growth, self-discovery, and independence.
At the beginning of the novel, we meet Jane as a young orphan living with her abusive aunt and cousins. Despite the harsh treatment she receives, Jane is a fiercely intelligent and independent-minded individual, and she refuses to let her circumstances define her. She is determined to make a better life for herself, and she refuses to be cowed by the unfairness of the world.
As the novel progresses, we see Jane's character continue to evolve and grow. She attends a boarding school, where she makes friends and begins to assert her own identity. Despite facing numerous challenges and setbacks, Jane remains determined and resilient, and she never gives up on her dreams.
One of the most striking aspects of Jane's character is her sense of morality and her strong sense of right and wrong. She is deeply empathetic and compassionate, and she is always willing to stand up for what she believes in. This is evident in her relationships with others, as she is always willing to offer her help and support to those in need.
Ultimately, it is this sense of morality and independence that helps Jane to achieve her ultimate goal: finding true love and happiness. Despite the many obstacles she faces, Jane never gives up on her dreams, and she ultimately finds the love and acceptance she has always sought.
In conclusion, Jane Eyre is a complex and deeply nuanced character, and her story is one of growth, self-discovery, and independence. Her strength, determination, and sense of morality make her a true hero, and her story continues to inspire readers around the world.
Jane Eyre: Heroine of Heroines
Could I really forego the performative exuberance that I saw in others, merely state my mind, and be loved for it? Eventually, of course, she is united with him, and finds perfect bliss in her conjugal life with him. When she receives the inheritance from her uncle John, she becomes an independent woman and because of that, Mr. Their conversational duels are witty, poetic and transcendent. This sense of the dignity of her sex shows that she does not regard woman as a commodity whom a man can acquire by his status or wealth. The fact that Bronte chooses Jane to be inspired by female characters reinforces the points that women can be intelligent and independent, and at the same time inspire others to become better people. Men were considered to be very much superior to women and they were to be treated with respect by the latter, whether they agreed with their views or not. This idea is reinforced throughout the novel, especially when it comes to religion.
Jane Eyre is no ordinary heroine — Sophia Tobin author site
Revisiting this topic through your eyes, I realise another reason Jane Eyre offered me such hope was that she is so very well loved for or inspite of traits that I also share. Although they are not of the same social class and gender, the relationship between Mr. She will not hide out. Analyze how two or more texts address similar themes or topics in order to build knowledge or to compare the approaches the authors take. Rather than to bend to the males laws and the society from which she receives opposition, Jane Eyre defies the chauvinist society and pursuit her own vision of a female life.
Jane Eyre: An Unconventional Heroine Essay Example
This lesson also may serve as an appropriate introduction to any number of other Victorian novels, including those by Brontë's siblings. Believing that Jane would accept because it is what a good woman will do. Writing log entries will help students clarify their assessment of Jane's character. But back then, as my first introduction to how autism can affect an adult woman, I was flooded with a sense of belonging and pride. By doing so, Bronte shows that women can be equal to men, not only in intelligence, but in actions as well. For those who love Jane Eyre, I hope that the possibility of her autism may help put autistic people in a new light — as minds worth exploring, and people worth befriending.
Jane Eyre: An Unconventional Heroine Free Essay Example
One of the most remarkable things about Jane is her relationship with Rochester in which gender and social class are not relevant. Jane understands that no matter what, at the end of your own life-story, you must have your dignity. She uses this character to challenge different ideas about religion. One reason is that little girls tend to receive harsher feedback than boys for unusual behavior, and may learn to act against their nature in an effort to comply. Permission was required for almost everything and they were expected to abide by rules set out by their owners. This was a fascinating post.
When Charlotte Brontë penned these lines she created quite a stir. No, she decides to forgo convention and grab the life and the love she wants. Of course she does end up with Mr. Her complexity is revealed through an equally complex storyline. Do you think, because I am poor, obscure, plain, and little, I am soulless and heartless? She will not spend one more minute adhering to strict Victorian morals.
Introducing Jane Eyre: An Unlikely Victorian Heroine
In this situation, the gender roles are swapped in which a woman leaves a man instead of the other way around. Here she aptly says to herself that beauty lies in the eyes of the gazer or the beholder. She felt comfortable interacting with him because she respected his intelligence and was not trying or filled with idle chatter like Miss Gryce who was her roommate and fellow teacher at Lowood. In this quote, Jane refers to John, Eliza, and Georgiana, who are told by Mrs. In chapter twenty-three she talks about how much she loved living at Thornfield and all of the stress and even fear that she felt at the thought of leaving what had become her beloved home.
Charlotte Bront"e was well aware of breaking with tradition in making her heroine clever, but plain. Although Jane Eyre was written during this period, Bronte portrays her character in a very unconventional way, following the trends of the Gothic genre. She returns to Mr Rochester as an equal in every way whereas previously she was aware of their social difference , and she returns for love more than anything else. Rochester to discuss his past with an eighteen-year-old governess like Jane. But that may be exactly what autistic behavior is. She uses this character to challenge different ideas about religion.
Like the autistic blogger I did, indeed — but not before a flurry of self-discovery. Rochester that he has no right to give her orders and commands just because he pays her a salary. During this period, women were expected to remain at home and their time was to be spent taking care of household duties and their children. Even as a child, she is different from her cousins at Gateshead. Edward Rochester an ugly, yet wonderful and passionate and charismatic gentleman nearly twenty years aged than her. Throughout the novel, Jane receives many dreams and visions that can be considered the cause of her actions that break the barriers set for women during the Victorian Era.