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Adult T-cell leukemia (ATL) is a unique malignancy of mature CD4+ T cells caused by human T-cell leukemia virus type 1 (HTLV-1).1–3 Clinically, ATL is subclassified into 4 subtypes: acute, lymphoma, chronic and smoldering. In the relatively indolent smoldering and chronic types, the median survival time is ≥2 years. However, at present, there is no accepted curative therapy for ATL and the condition often progresses to death with a median survival time of 13 months in aggressive ATL.4 Death is usually due to severe infection or hypercalcemia, often associated with resistance to intensive, combined chemotherapy. Therefore, the establishment of new therapeutic strategies for ATL is very important.
Carotenoids are a family of natural pigments with at least 600 members. They have several biological functions, including provitamin A activity, radical scavenging, singlet oxygen-quenching activity, immunomodulation and chemopreventive effects on carcinogenesis.5 Among the carotenoids, β-carotene and lycopene, which are found in terrestrial plants such as vegetables and fruits, have been extensively studied with regard to physiological functions.5 Marine organisms also contain carotenoids with unique structures. Astaxanthin is a nonprovitamin A carotenoid widely distributed in marine animals and algae, and is commonly described as an antioxidant, immune modulator and scavenger of reactive oxygen species. Fucoxanthin is a major marine carotenoid, found in brown seaweed. Its structure, which includes an allenic bond and a 5,6-monoepoxide, differs from that of common carotenoids. Fucoxanthin has been reported to demonstrate anticarcinogenic6 and antiinflammatory effects7 as well as apoptotic effects in cancer cells8, 9 and radical scavenging activity.10 Orally administered fucoxanthin is known to be metabolized to fucoxanthinol and amarouciaxanthin A.11 Because fucoxanthin is a potent inducer of apoptosis in human cancer cells, the comparison of anticancer effects of fucoxanthin and its metabolite is very interesting in biochemical studies of carotenoids.
With the objective of finding newer agents for the treatment of ATL, the present study was designed to investigate the antitumor potential of carotenoids. We first assayed the antiproliferative effects of some carotenoids. We found that both fucoxanthin and fucoxanthinol have remarkable antiproliferative effects on HTLV-1-infected T-cell lines and primary ATL cells in vitro, although the effect of fucoxanthin was less than that of fucoxanthinol. We also examined the tissue distribution of these carotenoids and the underlying mechanisms involved in their antitumor activities. The results showed that orally administered fucoxanthinol induced apoptosis in tumors inoculated subcutaneously into severe combined immunodeficiency (SCID) mice.
AP-1, activator protein-1; ATL, adult T-cell leukemia; EMSA, electrophoretic mobility shift assay; HTLV-1, human T-cell leukemia virus type 1; IL-2Rα, interleukin-2 receptor α chain; NF-κB, nuclear factor-κB; PARP, poly(ADP-ribose) polymerase; PBMCs, peripheral blood mononuclear cells; ppRb, hyperphosphorylated form of the retinoblastoma protein; SCID, severe combined immunodeficiency; sIL-2Rα, soluble IL-2Rα; TUNEL, terminal deoxynucleotidyl transferase mediated nick labeling; WST, water-soluble tetrazolium.
Material and methods
HTLV-1-infected T-cell lines, MT-2,12 MT-4,13 HUT-1021 and ED-40515(-),14 HTLV-1-uninfected T-cell line, Jurkat, and chronic myelogenous leukemia cell line, K562, were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum (JRH Biosciences, Lenexa, KS), 50 U/ml penicillin and 50 μg/ml streptomycin. MT-2 and MT-4 are HTLV-1-transformed T-cell lines and constitutively express viral genes including Tax. ED-40515(-) is a T-cell line of leukemic cell origin that was established from a patient with ATL and does not express viral genes. HUT-102 was also established from a patient with ATL and constitutively expresses viral genes, but its clonal origin is unclear.15 HeLa cervical cancer cells were grown in DMEM supplemented with 10% heat-inactivated fetal bovine serum, 50 U/ml penicillin and 50 μg/ml streptomycin.
The diagnosis of ATL was based on clinical features, hematological findings and the presence of anti-HTLV-1 antibodies in the sera. Monoclonal HTLV-1 provirus integration into the DNA of leukemic cells was confirmed by Southern blot hybridization in all patients (data not shown). Peripheral blood mononuclear cells (PBMCs) from 3 healthy volunteers, 8 patients with acute type ATL and 4 patients with chronic type ATL were analyzed. Mononuclear cells were isolated by Ficoll-Paque density gradient centrifugation (GE Healthcare Biosciences, Uppsala, Sweden) and washed with PBS. All samples were obtained after informed consent.
β-carotene and astaxanthin were purchased from Wako Pure Chemical Industries (Osaka, Japan). Fucoxanthin was extracted from brown algae Undaria pinnatifida using acetone as solvent, and purified by column chromatography, liquid–liquid partition and recrystallization up to ≥95% purity. Further purification was performed by RP-HPLC up to ≥98% purity, for in vitro assay. Fucoxanthinol was prepared by enzymatic hydrolysis of purified fucoxanthin using porcine pancreatic lipase. For this purpose, 195 mg of fucoxanthin, 2 g of sodium taurocholate and 2 g of porcine pancreatic lipase (Type II; Sigma Chemical, St. Louis, MO) were dissolved in 30 ml of 0.1 M sodium phosphate buffer (pH 7.0). The reaction buffer was incubated at 37°C for 3 hr. Fucoxanthinol was purified by ODS column chromatography, liquid–liquid partition and recrystallization. In the experiment, we prepared 142 mg of purified fucoxanthinol (≥95% purity, 72% yield). Further purification was performed by RP-HPLC up to ≥98% purity, for in vitro assay.
Rabbit polyclonal antibodies to cyclin D2, cIAP2, survivin, IκBα, JunD, nuclear factor-κB (NF-κB) subunits p65, p50, c-Rel and p52, and activator protein-1 (AP-1) subunits c-Fos, FosB, Fra-1, Fra-2, c-Jun, JunB and JunD and mouse monoclonal antibody to GADD45α were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Rabbit polyclonal antibody to Bcl-xL was purchased from BD Transduction Laboratories (San Jose, CA). Mouse monoclonal antibodies to Bcl-2, CDK4, CDK6, p53, actin and hyperphosphorylated form of the retinoblastoma protein (ppRb) (Ser780) were purchased from NeoMarkers (Fremont, CA). Mouse monoclonal antibodies to XIAP and cyclin D1 were purchased from Medical & Biological Laboratories (MBL; Nagoya, Japan). Mouse monoclonal antibody to phospho-IκBα (Ser32/36), caspase-8 and -9, rabbit monoclonal antibody to cleaved caspase-3 and rabbit polyclonal antibody to cleaved poly(ADP-ribose) polymerase (PARP) were purchased from Cell Signaling Technology (Beverly, MA).
Cell viability and apoptosis assays
The effect of carotenoids on cell viability was examined by the cell proliferation reagent, water-soluble tetrazolium (WST)-8 (Wako Chemicals). Briefly, 1 × 105 cells/ml (cell lines) or 1 × 106 cells/ml (PBMCs) were incubated in a 96-well microculture plate in the absence or presence of various concentrations of carotenoids. After 24 hr of culture, WST-8 (5 μl) was added for the last 4 hr of incubation and absorbance at 450 nm was measured using an automated microplate reader. Measurement of mitochondrial dehydrogenase cleavage of WST-8 to formazan dye provides an indication of the level of cell viability. Apoptotic events in cells were detected by staining with phycoerythrin-conjugated APO2.7 monoclonal antibody (Beckman Coulter, Marseille, France)16 and analyzed by flow cytometry (Epics XL, Beckman Coulter, Fullerton, CA). For analysis of morphologic changes of nuclei, cells were stained by 10 μg/ml Hoechst 33342 (Wako Pure Chemical Industries) and photographed through an ultraviolet filter using an Olympus IX70 microscopy (Olympus, Tokyo, Japan).
Cell cycle analysis
Cell cycle analysis was performed with the CycleTEST PLUS DNA reagent kit (Becton Dickinson Immunocytometry Systems, San Jose, CA). In brief, 1 × 106 cells were washed with a buffer solution containing sodium citrate, sucrose and dimethyl sulfoxide, suspended in a solution containing RNase A and stained with 125 μg/ml propidium iodide for 10 min. After passing the cells through a nylon mesh, cell suspensions were analyzed on an Epics XL. The population of cells in each cell cycle phase was determined.
In vitro measurement of caspase activity
Cell extracts were recovered with the use of the cell lysis buffer and assessed for caspase-3, -8 and -9 activities using colorimetric probes (MBL). The colorimetric caspase assay kits are based on detection of the chromophore p-nitroanilide after cleavage from caspase-specific-labeled substrates. Colorimetric readings were performed in an automated microplate reader at an optical density of 400 nm.
Western blot analysis
Cells were lysed in a buffer containing 62.5 mM Tris-HCl (pH 6.8), 2% SDS, 10% glycerol, 6% 2-mercaptoethanol and 0.01% bromophenol blue. Samples were subjected to electrophoresis on SDS-polyacrylamide gels followed by transfer to a polyvinylidene difluoride membrane and probing with the specific antibodies. The bands were visualized with the enhanced chemiluminescence kit (GE Healthcare Unlimited, Buckinghamshire, UK).
Preparation of nuclear extracts and electrophoretic mobility shift assay
Cells were placed in culture and examined for inhibition of NF-κB and AP-1 after exposure to carotenoids for 12 hr. Nuclear proteins were extracted, and NF-κB and AP-1 binding activities to NF-κB and AP-1 elements were examined by electrophoretic mobility shift assay (EMSA) as described previously.17 In brief, 5 μg of nuclear extracts were preincubated in a binding buffer containing 1 μg poly-deoxy-inosinic-deoxy-cytidylic acid (GE Healthcare Biosciences), followed by the addition of [α-32P]-labeled oligonucleotide probe containing NF-κB element (∼50,000 cpm). These mixtures were incubated for 15 min at room temperature. The DNA protein complexes were separated on 4% polyacrylamide gels and visualized by autoradiography. To examine the specificity of the NF-κB element probe, unlabeled competitor oligonucleotides were preincubated with nuclear extracts for 15 min before incubation with probes. The probes or competitors used were prepared by annealing the sense and antisense synthetic oligonucleotides; a typical NF-κB element from the interleukin-2 receptor α chain (IL-2Rα) gene (5′-gatcCGGCAGGGGAATCTCCCT CTC-3′) and an AP-1 element of the IL-8 gene (5′-gatcGTGAT GACTCAGGTT-3′). The oligonucleotide 5′-gatcTGTCGAATG CAAATCACTAGAA-3′, containing the consensus sequence of the octamer binding motif, was used to identify specific binding of the transcription factor Oct-1. This transcription factor regulates transcription of a number of so-called housekeeping genes. Underlined sequences represent the NF-κB, AP-1 or Oct-1 binding site. To identify NF-κB proteins in the DNA protein complex detected by EMSA, we used antibodies specific for various NF-κB family proteins, including p65, p50, c-Rel and p52, and various AP-1 family proteins, such as c-Fos, FosB, Fra-1, Fra-2, c-Jun, JunB and JunD (Santa Cruz Biotechnology), to elicit a supershift DNA-protein complex formation. These antibodies were incubated with the nuclear extracts for 45 min at room temperature before incubation with the radiolabeled probes.
In vivo administration of fucoxanthinol
Five-week-old female C.B-17/Icr-SCID mice obtained from Ryukyu Biotec (Urasoe, Japan) were maintained in containment level 2 cabinets and provided with autoclaved food and water ad libitum. Mice were engrafted with 1 × 107 HUT-102 cells by subcutaneous injection in the postauricular region and were randomly placed into 2 cohorts of 6 mice each that received vehicle and fucoxanthinol, respectively. Treatment was initiated on the day after cell injection. Fucoxanthinol was dissolved in soybean oil at a concentration of 13.3 mg/ml, and 200 mg/kg body weight of fucoxanthinol was administered by oral gavage every day for 28 days. Control mice received the same volume of the vehicle (soybean oil) only. Body weight and tumor numbers and size were monitored once a week. All mice were sacrificed on day 28, and then the tumors were dissected out and their weight was physically measured. Thereafter, tumors were fixed for paraffin embedding and tissue sectioning. Analysis of DNA fragmentation by fluorescent terminal deoxynucleotidyl transferase mediated nick labeling (TUNEL) was performed using a commercial kit (Takara Bio, Otsu, Japan) as described in the instructions provided by the manufacturer. The efficacy of the treatment was determined by measuring the serum levels of soluble IL-2Rα (sIL-2Rα) by ELISA (BioSource, Camarillo, CA) at 28 days after injection. This experiment was performed according to the Guidelines for the Animal Experimentation of the University of the Ryukyus and was approved by the Animal Care and Use Committee of the University of the Ryukyus.
Serum extraction and analysis
A mixture of serum (50 μl) and ethanol (200 μl) was vortex mixed and centrifuged at 2,000g. The precipitate was reextracted with ethanol (200 μl) and the mixture was centrifuged. The supernatants were combined and made up to 500 μl with ethanol and the solution was used for HPLC analysis. HPLC analysis was carried out on an Agilent 1100 series HPLC system equipped with a photodiode array detector under the following conditions: injected sample volume, 10 μl; column, Hypersil ODS-5 column (4.0 mm × 125 mm); mobile phase, 70% methanol (0 min)-100% methanol (25 min) linear gradient at a flow rate of 0.4 ml/min. Fucoxanthinol was detected at 440 nm wavelength and quantified from the peak area by using the standard curve prepared using pure fucoxanthin.
Tissue extraction and analysis
Respective tissues (hearts, lungs, livers, spleens, kidneys, thymus glands and transplanted tumors) from 6 mice were combined, immersed in ethanol (5 ml for thymus, 20 ml for transplanted tumors and 10 ml for other organs) and preserved at −30°C until used for analysis (about 17 days). Ethanol solutions were separated from tissues by filtration and made up with ethanol to 10 ml (thymus) or to 25 ml (other organs). The second extraction was made by cutting the tissues into small pieces and immersing them in ethanol, in a manner similar to the first extraction. The tissues were preserved in ethanol at −80°C until analysis (about 11 days). The first and second extracts were analyzed separately under the HPLC conditions described for the serum sample.
Data were expressed as mean ± SD. Volume and weight of tumors and serum levels of sIL-2Rα in fucoxanthinol-treated mice were compared with those in the vehicle-treated controls by the Mann-Whitney U-test. A p value less than 0.05 denoted the presence of a statistically significant difference.
Fucoxanthin and fucoxanthinol inhibit cell viability of HTLV-1-infected T-cell lines and primary ATL cells
We first examined the effects of carotenoids on the cell viability of HTLV-1-infected T-cell lines. Tax protein was detected by immunoblot analysis in the 3 HTLV-1-infected T-cell lines (MT-2, HUT-102 and MT-4) but not in the ATL-derived T-cell line [ED-40515(-)]. Culture of cells with various concentrations of carotenoids for 24 hr resulted in the suppression of cell viability in a dose-dependent manner in all 4 lines tested as assessed by the WST-8 assay (Fig. 1a). Inhibition of cell viability was significantly more severe in the cells treated with fucoxanthin and fucoxanthinol than those treated with β-carotene and astaxanthin. The effect of fucoxanthin was not significant on control uninfected cell lines K562 and HeLa. Cell viability of an uninfected T-cell line, Jurkat, was also inhibited, but Jurkat was less susceptible to fucoxanthin than HTLV-1-infected T-cell lines. The cell viability inhibition activity of fucoxanthinol was more pronounced than that of fucoxanthin with IC50 values of 0.86–1.83 μM (1.24 ± 0.43 μM) and 1.20–4.46 μM (3.31 ± 1.44 μM), respectively.
We also evaluated the effects of the 2 carotenoids on the cell viability of fresh ATL cells obtained from 12 independent ATL patients. As shown in Figure 1b, fucoxanthin and fucoxanthinol inhibited the cell viability of fresh ATL cells. All patients were negative for Tax protein by immunoblot analysis (data not shown). Fresh ATL leukemic cells were more susceptible to fucoxanthin and fucoxanthinol-induced cell viability inhibition than control PBMCs from healthy individuals. Like the data in Figure 1a with T-cell lines, fucoxanthinol-induced cell viability inhibition was more pronounced than that of fucoxanthin with IC50 values of 0.46–3.84 μM (1.72 ± 0.97 μM) and 1.29–3.75 μM (2.74 ± 0.83 μM), respectively.
Fucoxanthin and fucoxanthinol induce apoptosis of HTLV-1-infected T-cell lines
To examine whether induction of apoptosis accounts for the cell viability inhibition observed in HTLV-1-infected T-cell lines, cells were treated with fucoxanthin and fucoxanthinol then probed with the APO2.7 monoclonal antibody. Both carotenoids increased the proportion of apoptotic cells in all HTLV-1-infected T-cell lines, but not in HeLa (Fig. 2a). They increased the proportion of apoptotic cells in Jurkat, but Jurkat was less susceptible to them than HTLV-1-infected T-cell lines. Furthermore, Hoechst 33342 staining of nuclei showed apoptotic changes (Fig. 2b). Taken together, these results indicate that fucoxanthin and fucoxanthinol inhibit cell viability of HTLV-1-infected T-cell lines through cell apoptosis.
Fucoxanthin- and fucoxanthinol-induced apoptosis is caspase-dependent
We next examined whether caspase activation is involved in fucoxanthin- and fucoxanthinol-induced apoptosis. We measured the levels of caspase-3, -8, -9 and PARP in HUT-102 cells after exposure to fucoxanthinol. Fucoxanthinol cleaved caspase-3, -8, -9 and PARP, indicating activation of these cystein proteases (Fig. 2c). Furthermore, both carotenoids activated caspases-3, -8 and -9 in HUT-102 and ED-40515(-) cells (Fig. 2d). These results demonstrate the involvement of caspase activation in fucoxanthin- and fucoxanthinol-induced apoptosis in HTLV-1-infected T-cell lines.
Fucoxanthin and fucoxanthinol induce cell cycle arrest
We also investigated the effect of both carotenoids on the cell cycle progression in cell lines. HUT-102 cells were incubated with fucoxanthinol (5 μM) for various time intervals (0 to 24 hr) and analyzed for cell cycle distribution by flow cytometry (Fig. 3a). Cultivation with fucoxanthinol for 12 hr increased the population of cells in the G1 phase, with a marked reduction of cells in the S phase. At 24 hr after treatment, the percentage of apoptotic cells markedly increased, suggesting that cell cycle arrest is the cause of apoptosis. Therefore, cells were incubated with fucoxanthin (10 μM) and fucoxanthinol (5 μM) for 12 hr and analyzed for cell cycle distribution by flow cytometry (Fig. 3b). Both carotenoids inhibited cell cycle progression, as evidenced by the increased proportion of cells in G1 phase and reduction of cells in the S phase, indicating G1 arrest in all cell lines. These results clearly show that both carotenoids induce G1 arrest of the cells.
Effects of fucoxanthin and fucoxanthinol on the expression of cell cycle- and apoptosis-related proteins
To clarify the molecular mechanisms of fucoxanthin and fucoxanthinol-induced inhibition of cell viability and apoptosis in HTLV-1-infected T-cell lines, we examined the expression of several intracellular regulators of cell cycle and apoptosis, including cyclin D1, cyclin D2, CDK4, CDK6, p53, GADD45α, Bax, Bcl-2, Bcl-xL, XIAP, cIAP2 and survivin by Western blot analysis. As shown in Figure 4a, fucoxanthin and fucoxanthinol did not alter p53, Bax and Bcl-xL levels. In contrast, they significantly decreased the expression of survivin, XIAP, cyclin D1, cyclin D2 and CDK4, and induced the expression of GADD45α in HUT-102 and MT-2 cells in a time-dependent manner. Both carotenoids also decreased the expression of Bcl-2 in MT-2 cells but not in HUT-102 cells. Furthermore, cIAP2 levels were decreased in fucoxanthinol-treated HUT-102 and MT-2 cells and in fucoxanthin-treated MT-2 cells. Fucoxanthinol but not fucoxanthin decreased the expression of CDK6. Comparable loading of protein was confirmed with a specific antibody for the housekeeping gene product actin. Finally, fucoxanthin and fucoxanthinol decreased the expression of XIAP and cyclin D2 in freshly isolated ATL cells (Fig. 4b).
Fucoxanthin and fucoxanthinol modulate activated NF-κB
NF-κB is a transcription factor involved in the control of apoptosis, cell cycle progression and cell differentiation.18 NF-κB is constitutively activated in Tax-expressing and HTLV-1-infected T-cell lines as well as primary ATL cells,17 and such activation correlates with leukemogenesis.19 Because NF-κB regulates the expression of survivin, XIAP, cIAP2, Bcl-2, cyclin D1, cyclin D2, CDK4 and CDK6,20–26 we examined whether fucoxanthin and fucoxanthinol inhibit the NF-κB pathway. To study the DNA-binding activity of NF-κB, we performed EMSA with radiolabeled double-stranded NF-κB oligonucleotides and nuclear extracts from untreated or fucoxanthin- or fucoxanthinol-treated HTLV-1-infected T-cell lines. NF-κB oligonucleotide probe with nuclear extracts from untreated HTLV-1-infected T-cell lines generated DNA-protein gel shift complexes (Fig. 5a, top panel). These complexes were due to specific binding of nuclear proteins to the NF-κB sequence, because these binding activities were reduced by the addition of cold probe but not by an irrespective sequence (Fig. 5a, top panel, lanes 2 and 3). Furthermore, NF-κB complexes contained p50, p65 and c-Rel (Fig. 5a, top panel, lanes 4–7). Nuclear extracts prepared from HTLV-1-infected T-cell lines treated with fucoxanthin and fucoxanthinol for 12 hr exhibited a decrease in the intensity of the NF-κB-containing gel shift complexes (Fig. 5b). This finding suggests that both carotenoids downregulate the DNA-binding activities of NF-κB. Inhibition appeared specific to NF-κB and not due to cell death, because no significant change in binding activity of Oct-1 was observed after treatment of cells with fucoxanthin and fucoxanthinol.
Degradation of IκBα and subsequent release of NF-κB requires prior phosphorylation at Ser32 and Ser36 residues.27 To investigate whether the inhibitory effects of the carotenoids were mediated through alteration of phosphorylation of IκBα, HUT-102 and MT-2 cells were treated with fucoxanthin and their protein extracts were checked for phospho-IκBα expression. Untreated HUT-102 and MT-2 cells constitutively expressed Ser32/36-phosphorylated IκBα, while fucoxanthin treatment decreased the phosphorylated IκBα in a time-dependent manner (Fig. 5c), with a concomitant rise in IκBα level, suggesting that fucoxanthin inhibits phosphorylation of IκBα followed by accumulation of this protein.
Fucoxanthin and fucoxanthinol modulate activated AP-1
Transcription factor AP-1 is also identified as a crucial mediator of both cell cycle enhancing and cell death inhibiting pathways in HTLV-1-infected T-cells.28 Therefore, we focused on AP-1 inactivation after exposure to fucoxanthin and fucoxanthinol. HUT-102 and MT-2 cells exhibited elevated constitutive AP-1 DNA-binding activity (Fig. 5a, bottom panel). Supershift analysis with antibodies indicated that the AP-1 complex in both cell lines contained JunD. Fucoxanthin and fucoxanthinol reduced AP-1 DNA-binding activity (Fig. 5b) and also decreased time-dependently the expression of JunD, which composes the increased DNA-binding AP-1 protein (Fig. 5c). These findings suggest that the 2 carotenoids deplete JunD, resulting in inactivation of AP-1.
Antitumor effects of fucoxanthinol on subcutaneous HUT-102 tumors
Finally, we examined the effects of fucoxanthinol against ATL in vivo. SCID mice (n = 12) were inoculated with HUT-102 and then divided into 2 groups: untreated mice (n = 6) and fucoxanthinol-treated mice (n = 6). Treatment commenced on the day after inoculation and the effects of treatment on tumorigenicity were assessed over 4 weeks. During treatment, all mice displayed no adverse events with respect to general appearance, body weight (Fig. 6a) and food intake. Fucoxanthinol did not affect tumor incidence but significantly slowed the growth of the transplanted tumors. After 14-day treatment, fucoxanthinol significantly decreased tumor volume compared with vehicle-treated mice (p < 0.01). Statistically similar differences were found in tumor weights at necropsy (p < 0.05) (Fig. 6a). The efficacy of treatment was reflected by a decrease in serum levels of the surrogate marker sIL-2Rα (p < 0.05). On the other hand, TUNEL assay showed few apoptotic cells in tumors from untreated mice, while abundant apoptotic cells were noted in tumors from fucoxanthinol-treated mice (Fig. 6c). At necropsy, gross and histopathological examinations showed no apparent pathological findings, neoplastic lesions or metastatic tumors in the lungs, liver, pancreas, kidneys, spleen or large bowel in all mice.
We examined the tissue distribution of fucoxanthinol in mice treated orally for 28 days. Fucoxanthinol showed extensive distribution into all sampled tissues (serum, 0.51 μg/ml; heart, 10.48 μg/g; lung, 18.48 μg/g; thymus, 24.70 μg/g; liver, 15.32 μg/g; spleen, 33.02 μg/g), with highest concentrations in the kidney (33.37 μg/g). Tumor fucoxanthinol levels were 3.51 μg/g. This concentration is equivalent to 5.70 μM, suggesting that therapeutically effective concentrations of fucoxanthinol may be easy to achieve in vivo. These results suggest that fucoxanthinol is therapeutically beneficial in mice with ATL.
ATL follows an invariably fatal clinical course in spite of the introduction of various chemotherapeutic agents. Although many ATL patients initially respond to chemotherapy, drug-resistance eventually develops, which prevents curative treatment. Although allogenic hematopoietic stem cell transplantation produces better results, it often causes serious side effects and entails the risk of graft versus host-disease.29 In addition, its application is limited because of the advanced age of patients with ATL. Therefore, a novel therapeutic approach based on new insights into the pathogenesis of ATL is strongly desired. Advances in molecular biology have provided many new insights into the biology and treatment options for ATL. Recently, the strategy of targeting the molecules critical for maintenance and growth of the tumor cells was considered important for the development of more effective treatment with less undesirable effects.30 This strategy intensifies the specificity of treatment to tumor cells and minimizes undesirable effects to normal cells.
In our study, we examined the inhibitory effects of 4 carotenoids on the cell viability of HTLV-1-infected T-cell lines. The inhibitory activities of fucoxanthin and its deacetylated derivative, fucoxanthinol, were stronger than those of β-carotene and astaxanthin. Because dietary fucoxanthin is hydrolyzed into fucoxanthinol in the gastrointestinal tract before absorption in the intestine and the inhibitory effect of fucoxanthinol was higher than that of fucoxanthin, fucoxanthinol may be more effective than fucoxanthin in vivo. Furthermore, we showed that HTLV-1-infected T-cell lines and primary ATL cells are more susceptible to cell viability inhibition induced by treatment with fucoxanthin and fucoxanthinol than normal PBMCs and uninfected cell lines. These data therefore demonstrate that both carotenoids are cytotoxic to HTLV-1-infected cells but not to normal cells.
Our results showed that the cell viability-inhibitory potential of fucoxanthin and fucoxanthinol on HTLV-1-infected T-cell lines was mainly due to the induction of G1 cell cycle arrest and apoptosis. Such cell cycle arrest in G1 phase was associated with downregulation of expression of proteins in G1/S transition such as cyclin D1, cyclin D2, CDK4 and CDK6, and upregulation of expression of GADD45α, which inhibits entry of cells into S phase. In agreement with our findings, Satomi and Nishino showed that fucoxanthin induced G1 cell cycle arrest and GADD45 gene expression in human cancer cells.31 GADD45α is a known transcriptional downstream target of p53; however, this cannot solely explain fucoxanthin-induced GADD45α. Fucoxanthin and fucoxanthinol did not increase p53 levels, suggesting that upregulation of GADD45α is independent of p53.
Both carotenoids induced apoptosis of HTLV-1-infected T-cell lines, which was associated with activation of caspase-3, -8 and -9, as well as downregulation of expression of antiapoptotic proteins, XIAP, cIAP2, Bcl-2 and survivin. Bcl-2 is the principal regulator of the mitochondrial-dependent pathway for apoptosis,32 and its downregulation is involved in caspase-9-dependent apoptosis. Because XIAP and cIAP2 inhibit caspase-3 and -9 activities,33 it appears that the 2 carotenoids stimulate caspase-3- and -9-dependent apoptosis by downregulating XIAP and cIAP2 expression. In our study, the expression of survivin, another member of the IAP family, was also downregulated by fucoxanthin and fucoxanthinol. Because caspase-3 can be inhibited by survivin,34 it is possible that downregulation of survivin by the 2 carotenoids could lead to activation of caspase-3. Caspase-8 is activated by death receptors, such as CD95, tumor necrosis factor receptor and tumor necrosis factor-related apoptosis-inducing ligand receptor, which are expressed on HTLV-1-infected T cells. These death receptors may trigger signaling pathways in cells treated with fucoxanthin and its metabolite.
Detailed mapping of intracellular molecules and signaling pathways might provide more efficient and less toxic treatment opportunities in which cellular components, critical for survival of the tumor, can be selectively targeted. We found that both carotenoids possessed anti-NF-κB activity. They inhibited IκBα phosphorylation and NF-κB DNA-binding activity. Activation of NF-κB plays an important role in cell proliferation and prevention of apoptosis due to upregulation of several NF-κB-inducible molecules. We found that suppression of NF-κB by fucoxanthin and fucoxanthinol correlated with downregulation of the expression of several gene products regulated by NF-κB.20–26 Thus, both carotenoids reduced the expression levels of XIAP, cIAP2, survivin, Bcl-2, cyclin D1, cyclin D2, CDK4 and CDK6. Interestingly, various target genes showed different susceptibility to the inhibitory effects of fucoxanthin and fucoxanthinol. NF-κB participates in the transcription of over 150 target genes, but not all are activated when NF-κB is induced. It is possible that several different mechanisms confer selectivity on the NF-κB inhibitory response to fucoxanthin and fucoxanthinol. A decrease in NF-κB activity may be at least in part responsible for induction of cell cycle arrest and apoptosis by both carotenoids in HTLV-1-infected T-cell lines.
The AP-1 is known to regulate cell proliferation, differentiation and apoptosis in various cell lines.35 In HTLV-1-infected T-cell lines, fucoxanthin and fucoxanthinol inhibited JunD expression, resulting in the suppression of AP-1 DNA-binding. AP-1 is required for proliferation of HTLV-1-infected T cells.28 Although cyclin D1 expression is regulated by NF-κB,24 AP-1 proteins also bind directly to the cyclin D1 promoter and activate it.36 Furthermore, the cyclin D2 promoter contains NF-κB and AP-1 sites.37 It is therefore likely that NF-κB and AP-1, in concert, support proliferation of HTLV-1-infected T cells by activating cyclin D1 and cyclin D2. We speculate that fucoxanthin and fucoxanthinol inhibit cyclin D1 and cyclin D2 expression through the suppression of both NF-κB and AP-1, resulting in the induction of cell cycle arrest at the G1 phase. Based on these findings, it is likely that the 2 carotenoids exert their anti-ATL effects through the suppression of HTLV-1-induced activation of NF-κB and AP-1.
In HTLV-1-expressing cells, Tax, the virus-encoded regulatory protein, plays a critical role in the growth and survival of infected T cells by perturbing normal regulatory mechanisms, including transcription, signal transduction and cell cycle progression, resulting in uncontrolled cell growth.38 Tax activates NF-κB by stimulating the activity of the IκB kinase, which in turn leads to phosphorylation and degradation of IκBα.19 Tax also activates AP-1.28, 39 However, primary ATL cells are known to have very low or no expression of Tax and therefore, growth of ATL cells in vivo is believed to be Tax-independent.40 Fucoxanthin and fucoxanthinol induced cell death of Tax-negative HTLV-1-infected T-cell line, ED-40515(-), and primary ATL cells. In addition, both carotenoids did not inhibit the level of Tax expression in HTLV-1-infected T-cell lines (data not shown). Therefore, the effects of fucoxanthin and fucoxanthinol on HTLV-1-infected T-cell lines and primary ATL cells appear to be mediated through a Tax-independent pathway.
The potent and selective apoptotic effects of fucoxanthin and fucoxanthinol against HTLV-1-infected T-cell lines and primary ATL cells in vitro prompted us to evaluate their in vivo anti-ATL effects in SCID mice bearing an HTLV-1-infected T-cell line, HUT-102. We used fucoxanthinol, a metabolite of fucoxanthin, and found that it also inhibited tumor formation in vivo. During the period from day 0 to 28, the control mice showed signs of severe disease, including piloerection. In contrast, mice treated with fucoxanthinol showed no significant adverse effects and tolerated the dose well. We conclude that fucoxanthinol could be potentially beneficial as a chemotherapeutic or chemopreventive agent in ATL. Further clinical studies are necessary to assess its effects on fresh primary ATL cells.
We are indebted to the patients with ATL and the control subjects who provided blood samples for these studies. We also thank Dr. M. Maeda for providing ED-40515(-) and the Fujisaki Cell Center, Hayashibara Biomedical Laboratories (Okayama, Japan) for providing HUT-102.


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Last night’s 2017 Screen Actors Guild Awards was a celebration of talent in the Hollywood industry, honoring the most deserving actors of our time. And – as always – A-listers like Emma Stone, Kirsten Dunst, and Kerry Washington were their best-dressed selves, wearing truly winning looks on the red carpet. Scroll through Savoir Flair’s gallery below to see our picks of the most beautiful red-carpet looks from the star-studded event.
Kirsten Dunst in Dior
Emma Stone in Alexander McQueen
Emily Blunt in Roberto Cavalli Couture
Amy Adams in Brandon Maxwell
Nicole Kidman in Gucci
Michelle Williams in Louis Vuitton

domain: celebrity


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The archive’s collection consists of over 4,400 testimonies that record the experiences of over 4,000 survivors, witnesses, bystanders and liberators of the Holocaust. Our testimonies are available for research and can be watched at over forty partner locations worldwide, including at the Fortunoff Archive’s office at Yale University.
Researchers can visit either the Fortunoff Archive or our partner locations to view testimonies from our collection. You do not need to be part of the Yale community or affiliated with an academic institution to use our testimonies. The Fortunoff Archive is open by appointment to researchers outside the Yale community. To schedule an appointment or to otherwise learn more about viewing testimonies at the archive, please contact us. If you are a Yale affiliate, you can learn how to view testimonies throughout campus here. Our testimonies are not just available for research–we also release excerpts of them for use in publications, documentaries, films, podcasts, and other media. Licensing is required and limits on testimony usage may apply. We encourage you to contact us to learn more.

domain: library


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So as we continue in the stress management month and talk about mind issues, what happens when it seems you have lost your mind? You know that feeling where the very fiber of your being has fallen and you are at your wit’s end. You have taken the time to meditate and pray and you still seem lost. What does one do when you are in this state? You reach out for help. We all have feelings of being helpless at times but if you truly can’t shake this feeling and you feel overwhelmed then help is your next move.
Talk to your doctor. Yes your doctor the man or woman in charge of your health. Talk to them about what you have been feeling, how long you have been feeling this and what are the attributes of how you feel. The attributes of how you feel could be more tired, sick with no explained reason for being sick, worried feelings that take up a majority of your day, helplessness, stomach and headache pain that doesn’t go away, etc. These will be vital to see how your mind is taken on your situation and you may need some assistance. This could come in the form of getting involved in a support group for whatever is troubling you. It could come in a form of meeting with a therapist or even medication if its determined you need it.
Let me take the time to crush some misguided information:
- Seeking help doesn’t make you a failure or weak
- Contrary to popular belief especially with minorities, seeking help doesn’t mean you are letting folks in on your business to harm you.
- If you take medication it doesn’t mean it has to be ongoing or something you take for a lifetime. Some people use it temporary and are weaned off it and go to live productive lives.
- Therapists are just like pastors without sometimes the spiritual apathy. You can still pray and see your therapist. We need to knock this one out of the park. You don’t need to listen to someone tell you that therapy is against God’s will. This is simply not true and watch your leadership that tells you that.
I have said many times and will continue to push the importance of mental health. It isn’t something that is geared toward “weak-minded” folks. If you are one who think this way please change your own way of thinking. People from all walks of life can have a moment when they can lose their way. I believe in encouraging people to do what is best for them. I would rather have someone get the help that they need than to harm themselves or someone else just to save face in their community. Having good mental health can be the catalyst for having a better life.
If you are suffering from mental health and you need help please and are having suicidal thoughts please call and reach out:
There are resources that can aid you regardless of your ability or inability to pay
Here are some ways that people can encourage those around them to get help:
- Never minimize how someone feels-phrases like “get over it,” “it ain’t that deep,” or “suck it up” never works. You are not helping you are only perpetuating that their issue is not a real concern which discourages others to get help
- Encourage someone to get help and let them know you care.
- Smile more-some people are really in a bad place dealing with some sad things so a smile can be one of the most encouraging forms of medication someone may need
- Don’t tell someone to call you anytime or talk to you when you really don’t mean it. People don’t always have a sounding board so if you are really not equipped to handle someone in their lowest moment don’t offer and then not support them. This can be worst than not having someone to support you in the first place.

domain: psychology


Summer season has already arrived in country. Like previously passed summers, severe heat wave is also expected this year. With day by day increasing temperature will also increase use of air conditioners. It is better to prepare air conditioners with a proper service or maintenance so they can give best results in peak season. Gree has been number one in educating consumers about their product. Following are few mandatory steps which should be taken to ensure air conditioner’s performance.


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Lower Doses of Rituxan Equally Effective at Controlling AAV, Study Suggests
Lower doses of Rituxan (rituximab) appear to be as safe and effective as the standard Rituxan regimen for inducing remission in ANCA-associated vasculitis (AAV) patients, a retrospective Japanese study suggests.
The study, “Low-dose rituximab as induction therapy for ANCA-associated vasculitis,” was published in Clinical Rheumatology.
AAV consists of a group of autoimmune inflammatory disorders that can be deadly. Treatment is done with immunosuppressive therapy that decreases the activity of the immune system. Often, this therapy includes glucocorticoids in combination with Rituxan.
Rituxan is an antibody that targets a receptor on B cells — cells that make self-targeting antibodies that drive inflammation in AAV. Its optimal dosage is based on studies in lymphoma patients, yet recent evidence from other areas, including rheumatoid arthritis and kidney transplantation, suggests that lower dosages might be equally effective for AAV.
To test this, researchers retrospectively analyzed 28 AAV patients who had been treated with a standard Rituxan regimen, or with low-dose Rituxan. The standard regimen consisted of a 375 mg/m2 dose, given once a week for four weeks; the low-dose was given once a week for only two weeks.
Although the groups were similar in many clinical respects, there were some notable differences; for example, significantly more elderly patients were in the low-dose group.
The researchers compared complete response rates between the two groups and found that there was no significant difference one year after treatment — 88.2% for standard Rituxan and 90.2% for low-dose.
There was also no significant difference in relapse rates after a year — 13.3% versus 20%. The incidences of disease-specific phenotypes that were assessed were also comparable between the groups.
There was no difference in the rate of serious adverse reactions between the two groups, although some side effects, including infection and anemia, were common in both, and there were serious infections that required hospitalization in both groups.
The researchers concluded that the low dosage of Rituxan seemed just as effective at controlling disease progression as the previously standard higher dosage. “This [low-dose Rituxan] regimen may improve the cost/benefit profile of RTX therapy for AAV,” the investigators said.
Because this study is limited by its retrospective nature and relatively small sample size, further studies and trials will be needed to validate the results.

domain: medical


The list of essential Aretha Franklin tracks Jimmy Johnson played guitar on is staggering. "Respect." "Chain of Fools." "Baby I Love You." "Think." " I Never Loved A Man (The Way I Love You)." "Do Right Woman, Do Right Man."
That's just for starters.
Johnson is a member of the Muscle Shoals Rhythm Section, immortalized by their nickname "The Swampers" in Lynyrd Skynyrd's Southern-rock anthem "Sweet Home Alabama."
Johnson, drummer Roger Hawkins and keyboardist Spooner Oldham first began working with Franklin at Muscle Shoals' FAME Studios. (Swampers bassist David Hood contributed on trombone and would play bass on later Franklin projects.)
The sessions were for Franklin's 1967 breakthrough album " I Never Loved a Man the Way I Love You," her 11th record, but first for Atlantic Records.
The singer was in her mid-20s at the time.
With Atlantic's Jerry Wexler producing, the resulting LP, which opens with R&B scorcher "Respect," were transcendent.
Johnson and company would go on to appear on a string of Franklin albums including "Lady Soul," "Aretha Arrives," "Aretha Now" and "This Girl's In Love With You."
Muscle Shoals, FAME and The Swampers had previously scored hit records, with acts like Etta James and Wilson Pickett. Franklin's recordings heightened that buzz and cred.
On Aug. 16, the day Franklin died from pancreatic cancer at age 76, Johnson called in for an interview to talk about the Queen of Soul and the unforgettable music they made together.
Edited excerpts are below - along with YouTube clips of some key Aretha cuts Johnson played on.


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Much like the ska movement that preceded it, it seems swing merely went back underground--where it originated--and the die-hards kept the torch burning. Which brings us to pianist Brenden Kearney, bassist Steve Grams and drummer Kyle Bronsdon, collectively known as local swing jazz trio Kearney, Grams and Bronsdon. Veterans of Tucson swingsters Kings of Pleasure, the threesome left that unit a year ago to form their trio, which recently issued its self-released debut CD, Nine Waters, No Tip. It's a somewhat bare-bones but winning combination of originals and canonized classics like Louis Jordan's "Is You Is Or Is You Ain't" and Duke Ellington's "I've Got To Be A Rug Cutter."
In a somewhat refreshing bucking of trends, the KGB trio is celebrating its mere paper anniversary (read: one year) this week with a performance on Thursday, August 3, at Boondocks, 3306 N. First Ave. The evening begins with a potluck dinner at 7:30 p.m., and $4 will get you through the door. Call 690-0991 with questions.
HOMECOMING KINGS: Local desert noir duo Calexico is back in town for a brief between-tours stint. It's fresh off a European tour playing those giant outdoor festivals the British are so fond of, followed by a string of West Coast U.S. dates, which included a San Francisco show with Al Perry sitting in. Between promoting its newest release, Hot Rail, and touring as two-thirds of Giant Sand (which played its best local show in years opening for Grandaddy last month--if you missed it, you really missed out), Tucson shows, at least for a while, have become somewhat rare.
For the first time, the duo took the four-piece Mariachi Luz de Luna on tour to fill out the sound and more closely replicate the mariachi-fueled numbers on its records. The experiment seems to have been a success ("Those guys are a real kick in the pants," says Calexico singer/guitarist Joey Burns), enough so that they're invited to participate in the duo's homecoming gig this weekend.
See Calexico team up with Mariachi Luz de Luna, along with DJ Manuelito, at 9 p.m. on Saturday, August 5, at Solar Culture, 31 E. Toole Ave. Admission to this all-ages show is $7, and I'd advise you to get there early. Call 884-0874 with those itching, burning questions.
INDEPENDENT WOMEN: Common sense would tell you that a band called The Rondelles would be some now-forgotten '60s girl group, and common sense would be on the right track, but in the end, wrong. The Rondelles are instead a very '90s female punk-pop band that merely refers to '60s girl groups for inspiration. Mixing infectious girly-pop hooks with garage punk guitars and peppy organ (think "96 Tears"), the group has recorded platters for esteemed indies K Records and Teenbeat. If you're fans of either of those labels' output, don't miss The Rondelles when they appear at 9 p.m. on Monday, August 7, along with Estrus recording artists The Mooney Suzuki, at Solar Culture, 31 E. Toole Ave. Cover is five bucks, and that number again is 884-0874.
HARD TO GET: A quick heads-up: one of reggae's living legends, Jimmy Cliff, has rescheduled last year's Tucson cancellation for next Thursday, August 10. The word comes along with a good news/bad news caveat. The good news is that the show will take place at Bob's, 6350 E. Tanque Verde Road, about as intimate a setting as you'll ever get to catch the artist known for classics like "You Can Get It If You Really Want," "The Harder They Come" and "Many Rivers To Cross." The bad news is that the show will take place at Bob's, a venue so intimate that the show will, no doubt, sell out in a heartbeat. If you plan on attending, I'd highly recommend getting your tickets as soon as possible to avoid being shut out of the festivities.
Jimmy Cliff appears on Thursday, August 10, at Bob's. Doors open at 8:30 p.m. and Papa Ranger will occupy the opening slot. Advance tickets are available for $20 at CD Depot; Hear's Music; Guitars, Etc.; Zip's University; and Bob's. You can also purchase tickets on the Web at www.ticketweb.com or by phone at 1-800-965-4827. They'll be $25 at the door. For more information call 733-6262.

domain: entertainment


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I-Octane, Tifa Ignite Dancehall Night at Reggae Sumfest
Dancehall star I-Octane and certified diva Tifa sizzled the opening night of Reggae Sumfest last Thursday. Treating an entertainment-drenched crowd to hit iconic lyrics – the Digicel-endorsed duo lead by example in delivering positive lyrics at the show.
Tifa – who was chicly dressed in a red and white bedazzling ensemble – fed the crowd with sugar-sweet lyrics such as ‘Spell It Out’, ‘Nah Stop Shine’ and ‘Future Fambo’. The songstress erupted loud cheers of approval from the excited Catherine Hall when she delivered grand finale on stage with recent hit ‘I am swagging’. The swag queen was among the top performing female dancehall artistes to grace the Reggae Sumfest Stage on Dancehall Night.
Catching up with the Digicel ‘Inspired By Legends’ ambassador after her performance, Tifa expressed that she is pleased with the performance she gave and even more so with the amazing support and forwards she received from fans at the Reggae Sumfest grounds.
Then came the big moment – with a haze of glowing lights of orange and red heralding his appearance on stage at the darkened grounds of Catherine Hall amidst exciting cheers and whistles of support from a crowd of close to 25,000 patrons – Reggae singjay I-Octane lead by example in inspiring positivity in the clean lyrics he delivered at Reggae Sumfest.
Seamlessly transitioning between hard-hitting and conscious lyrics that set the crowd in frenzy – I-Octane commanded a magnificent air of confidence. Rocking the stage with hits such as ‘puff it’, ‘Mama You Alone’ and ‘lose a friend’ – I-Octane a received a flurry of forwards from males and females alike.
In the meantime, Digicel’s Senior Sponsorship and Activations Manager, Shelly-Ann Curran sung high praises for the company’s brand ambassadors performances at Reggae Sumfest. Commented Curran;
“We are absolutely delighted at the rocking performances that our brand ambassadors gave at Reggae Sumfest – the energy, swag and enthusiasm become the talent and determination that many young Jamaicans aspire to and that is something that Digicel fully embraces.”
Check out Digicel Photo Highlights Below:

domain: news


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Mom’s Sweet Potato Bake
Total TimePrep: 10 min. Bake: 45 min.
My family have loved this recipe for years! It is "dessert" sweet, so I cut the sugar to 1/2 cup, and it is still pretty sweet... but we like it that way. The topping is tasty and the crunch and flavor or the pecans is so nice. This is a tradition at our holiday table.
We love this recipe! It was a great change from our marshmallow sweet potato casserole. I cooked my sweet potatoes in a slow cooker for four hours on high, then was able to scoop the flesh out easily to make this dish. I wouldn’t change a thing, it’s perfect as is! I will definitely be making this over the holidays again next year!
This is the sweet potato casserole I’ve made for 43 years. The only difference, I do the mixture in a large blender. It gives it a soufflé texture that is very unexpected! Occasionally, I will substitute orange juice for the milk at Christmas.
This is almost exactly how I’ve made my famous sweet potato casserole for years. I devoure the leftovers (even for breakfast). It’s one of the few foods my mother-in-law would actually say something nice about. She can’t stand her yankee DIL is a better cook.
Once baked do you eat it hot or cold?
Made this yesterday with just a couple of slight adjustments; used double the amount of sweet potatoes, 1 cup of brown sugar but kept the rest of the ingredients the same. Everyone LOVED it and this looks like it will be my new go to sweet potato recipe! Thx! Oh, and can be prepped in advance, refrigerated and then baked which is always a good thing to be able to do when hosting 10 for dinner!
Excellent and so easy to put together. We will make this recipe throughout the year not just for Thanksgiving. The only addition that I will make in the future is to add some cinnamon and nutmeg.
these were excellent. Made them just as is. company loved them too. Will definitely make again.
No comment left
I made this for Thanksgiving, but used two 49 oz cans of sweet potatoes (drained). Because the potatoes were already sweet from the syrup I left out the sugar called for in the recipe, and only used a tablespoon of milk. It still turned out well, although next time I won't use the canned potatoes. The topping really makes this dish extra special. As others have said, don't add the pecans until the butter, flour and brown sugar are crumbly. Thanks for the great recipe!

domain: food


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Lebanon and Syria have long been a refuge for political and religious groups. This hospitality has attracted many foreigners and has resulted in the wearing of a wide variety of costumes within this small area. Christians, Moslems and Druzes have kept their own styles of dress while living regionally apart.
The Maronite Christians have lived mainly in North Lebanon from Tripoli to The Cedars, spreading south to Dog River. The Metoualis (the Shiite Moslems) inhabited the east side of the Lebanon mountains. The Druzes held the territory in the center of the country and fanned out over the area bound by Mount Hermon, the B'kaa Valley, Damascus and the Jebel Druze.
Minority groups such as the Armenians and the Kurds came fairly recently into this area. The former wear European dress but the Kurds stand out vividly among the local population in their colorful everyday costumes.
Outside influence has modified Lebanese and Syrian costumes. Strongest single influence was exercised by the Turks who ruled the area for many years. The governing Turkish Pasha, representing the Sultan, effected local dress by his own costume and that of this retinue, and by the rich garments of Turkish design which he bestowed as gifts upon the local emirs. After 1850 when feudalism ended in Leba non and when commerce with Europe took on an increasing importance, Turkish and European styles exerted an even stronger effect on local dress.
Today traditional costumes are mixed with European dress. In some cases western styles have entirely supplanted local dress.
With the one exception of the costume of the Lebanese princess, all of the clothes illustrated in this collection may be seen being worn today.

domain: geography


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1915. Thirteen-year-old Finbar Kennedy suffers from prophetic nightmares. His latest is of an explosion on a big ship, and he’s…
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Over the last 20 years The Historical Novels Review (the society’s print magazine for our members) has published reviews of some 15,000 historical fiction books.


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The Department of Work and Pensions has announced an extensive list of evidence it is free to gather on anyone trying to claim Personal Independence Payment (PIP).
PIP is a vital, tax-free benefit that around 2.7 million people around the UK currently make use of.
It provides additional financial assistance if you have a long term physical or mental healthy condition or disability, depending on how it affects your life.
Now, the DWP has updated their guide on how a claimant is assessed for PIP.
Below is the list of evidence that the DWP is entitled to collect.
What evidence can the DWP gather on me?
When a person tries to claim PIP, once their basic eligibility has been established, they are then usually asked to complete a questionnaire. Then, an assessment provider will look at individual’s ability to carry out a series of everyday activities, before reporting their findings back to the DWP.
This is done in a number of different ways. Sometimes, it's based on the paperwork they already have regarding the claimant, or from a consultation with the applicant.
It could be that a health professional needs additional evidence on a person and the DWP has detailed that this can mean gathering:
a report from other health professionals involved in the claimant’s care such as a community psychiatric nurse (CPN)
a report from an NHS hospital
a factual report from a GP
a report from a local authority-funded clinic
current repeat prescription lists
care or treatment plans
evidence from any other professional involved in supporting the claimant, such as social workers, key workers or care co-ordinators
telephone conversations with any such professionals
information from a disabled young person’s school or special educational needs co-ordinator (SENCO)
an occupational therapist’s report
a report from an ophthalmologist
an audiologist’s report
contacting the claimant by telephone for further information.
The DWP points out that it can withhold any information it discovers that is deemed seriously harmful to the claimant if they were aware of it.
This can include a poor prognosis that is unknown to the claimant, or a diagnosis of a psychotic illness in a claimant who lacks insight into their condition.
Claimants are told that if they tell their assessor something but claim it is confidential, it won't be taken into account for their claim because it cannot be disclosed to the DWP case manager.
The activities explored during the PIP assessment are:
Daily living (10 activities):
preparing and cooking a simple meal
managing therapy or monitoring a health condition
washing and bathing
managing toilet needs or incontinence
dressing and undressing
reading and understanding signs, symbols and words
engaging with other people face-to-face
making budgeting decisions
Mobility (2 activities):
planning and following journeys
During the pandemic, face-to-face consultations were suspended and all appointments were carried out by telephone instead. Face-to-face appointments started again in May 2021, but they aren't carried out if the initial information given by a claimant is "consistent and medically reasonable" or if such a meeting is likely to cause stress (such as for claimants with autism, cognitive impairment or learning disability).
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domain: law


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Lab-Developed Tests: FDA Gives Extra Time For Input On Oversight Plan
This article was originally published in The Gray Sheet
FDA plans to accept feedback through Sept. 15 on its ongoing efforts to develop a regulatory framework for tests developed and offered as services by clinical laboratories
You may also be interested in...
FDA says it will tailor its future oversight of laboratory tests and services based on risk, but experts warn that "high risk" will be hard to define for these diagnostics
FDA could have a final framework in place for overseeing a greatly expanded range of laboratory test services within months of a public meeting scheduled for July, according to agency officials
Abbott is launching a second test to detect COVID-19. The diagnostics giant announced on 27 March the release of a rapid, point-of-care test that can deliver results within five minutes.

domain: health


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The Van Cleef & Arpels piece is inspired by an exuberant German bridal crown.
One senses that the establishment of Van Cleef & Arpels was preordained. The husband and wife Alfred Van Cleef and Estelle Arpels — the son of a diamond cutter and the daughter of a gemstone dealer — opened the French maison in 1906 in Paris’s First Arrondissement, where they began making wristwatches and jewelry adorned with wood and gems inspired by good luck charms. During the following decades, the brand continued to innovate — inventing the minaudière and creating necklaces that could be worn as bracelets — and in 1933 it introduced the Mystery Setting, in which
→ Continue reading at The New York Times

domain: artistic


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In the Credit Usage window the following information is displayed:
This page gives a breakdown of credit usage by year and month. Selecting a month will provide a list of credits spent by date. Clicking the View Details button will show a detailed breakdown of the credit usage for the time selected.
Updated about 5 years ago

domain: economics


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ABOUT THE MANALAGI PROJECT
Manalagi: Aotearoa Pacific Rainbow LGBTQIA+ MVPFAFF+ Health and Wellbeing Project
Enhancing the Mana of Pacific Peoples through Research
The Manalagi: Aotearoa Pacific Rainbow Health and Wellbeing Project is funded by the Health Research Council of New Zealand, hosted at the University of Auckland and in collaboration with F'INE Pasifika Aotearoa. It aims to create a safe cultural research space for Pacific Rainbow+ communities to communicate their unique health and wellbeing needs.
As both Pacific and Rainbow individuals face stigma as a barrier to their health and wellbeing in New Zealand, the Manalagi project takes the ethos of co-community driven, embedded and owned, to empower Pacific Rainbow communities to help co-design health policy and services through research.
The project will document self-reported health information for those who self-identify as part of the Pacific Rainbow community through a three-year period. This consists of
extensive community consultation; delivery of a Pacific Rainbow Health Survey aimed at collecting 500-1000 respondents, and a culturally-appropriate collection and documentation of 50-60 Pacific Rainbow individual narratives detailing their experiences with health service delivery through the blending of talanoa, Pacific concepts of space like the vā, and relationality with qualitative interviews.

domain: sociology


Pacific Chorale is internationally recognized for exceptional artistic expression, stimulating American-focused programming, and influential education programs. Under the inspired guidance of Artistic Director John Alexander, Pacific Chorale has infused an Old World art form with California’s hallmark innovation and cultural independence.
Who We Are and What We Do
• Founded in 1968 as a community choir in Irvine, Pacific Chorale has since evolved to become one of America’s most highly acclaimed choirs.
• We offer two unique musical experiences: the 140-voice Pacific Chorale, boasting 140 of Southern California's finest professional and volunteer singers, and the 24-voice John Alexander Singers, a professional vocal ensemble recognized as one of the country's most accomplished and versatile.
• Our music programming ranges throughout history, from the great classical masters of the past to today’s leading American composers.
• Our Artistic Director, John Alexander, is one of America’s most respected choral conductors, having conducted hundreds of choral and orchestral performances around the world.
• All of our singers have passed a rigorous audition test to become a member of Pacific Chorale and/or the John Alexander Singers.
• Pacific Chorale is the resident choir of Segerstrom Center for the Arts.
• Pacific Chorale boasts a long-standing partnership with Pacific Symphony, and numerous guest performances with symphonies around the world.
• A major emphasis of the organization is to provide educational programs for both school-aged children and adults.
• We are committed to bringing the Orange County community together through song.
• We tour and perform in other countries, bringing international awareness and acclaim to Pacific Chorale and Orange County.
Interested in singing with us? Visit our Auditions page for details about our audition process and registration info!


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UP TO one in three stroke victims are refusing to take life-saving statins due to fears of side-effects, a study shows.
The cholesterol-busting pills are prescribed to patients to slash their chances of a second deadly attack.
More than 100,000 Britons suffer a stroke each year. But many of those at high-risk are ignoring doctors’ warnings and ditching the 6p-a-day medication.
Cambridge University experts found concerns over side-effects – such as muscle pain – or negative experiences of the drug were often to blame.
Around 30 per cent of victims refuse statins.
Lead researcher Dr Anna De Simoni said: “Doctors need to listen to these concerns, discuss the benefits and drawbacks of taking the medication, and be willing to support a patient’s informed decision to refuse medications.”
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More than seven million UK adults take the pills to cut their heart attack and stroke risk. One in five complain of muscle pain.
Dr Mike Knapton of the British Heart Foundation called the findings “deeply concerning”.


Here comes an exciting piece of news for all the fans of Shaheer Sheikh who were disappointed with the news of his ongoing show Yeh Rishtey Hain Pyaar Ke going off-air. The actor is all set for his next appearance already. You heard it right, Shaheer who is playing Abir on the TV screen right now is marking his digital debut with the web series 'Paurashpur'. The fiction series is a period drama and the shoot for the web series has already begun.
Along with Shaheer many other popular faces like Shilpa Shinde, Milind Soman, Annu Kapoor, Sahil Salathia, Poulomi Das, Anant Joshi, Flora Saini, Kashish Rai and others are part of the series. Official Instagram of ALT Balaji shared this exciting news on their page by posting the mahurat clip of the series tagging the cast, "Shoot begins of a magnum opus #Paurashpur, a period drama! A story of kingdoms, gender power struggles and politics. Stay tuned to #ALTBalaji to know more!". ALSO READ: Shaheer Sheikh: I Don't Mind Playing A Negative Role'- EXCLUSIVE
Although not many details about the series have come out yet the announcement of the star cast has already raised our excitement level.ALSO READ: Shaheer Sheikh On Turning Down Bollywood Offers: 'If I Am Committed To A TV Show, I Will Not Leave It For A Film'- EXCLUSIVE
Shaheer who has been the main lead of TV shows like Navya, Mahabharat, Kuch Rang Pyar Ke Aise Bhi and Dastaan-E-Mohabbat Salim Anarkali recently opened up on the characters he would like to play in future in our exclusive interview. Talking to SpotboyE.com exclusively, Shaheer said, "I like to play one character at a time and that's why I haven't done anything on the digital platform yet. Now, I have not signed or given a commitment to any TV show, so, I will take up any exciting work which comes my way, which can be on a digital platform or it can be a film". And it seems the actor has already signed one.
Image source: Instagram/shaheernsheikh
They say the best things in life are free! India’s favourite music channels 9XM, 9X Jalwa, 9X Jhakaas & 9X Tashan are available Free-To-Air. Make a request for these channels from your Cable, DTH or HITS operator.


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Listen free for 30 days
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A suspenseful, racy, and achingly honest story of the entangled lives of six young women and men as they take Silicon Valley’s hottest dating app public.
Tara Taylor runs six miles every morning, never eats after 09:00 p.m., is the first to arrive and last to leave the office, but is starting to wonder why she bothers. When her old Stanford flame, Todd Kent, asks her to join his four-person team handling Hook’s IPO, the deal of the decade, she sees her opportunity to break through the glass ceiling and justify six boyfriendless years of sacrifices for her career. And the $14 billion dating app might have more in store for her than a bigger bonus. But that kind of money changes people. When the deal is thrown into a tailspin, Tara and five others will each find out just what they’re willing to give up - love, family, integrity - to get to the top.
What the critics say
**A Huffington Post, New York Post and Metro Summer Reading Pick**
"Michelle Miller is a master at pacing - this tour de force gathers speed as it heats up. Adrenaline junkies, take note: You’re in for a wild ride." (Glamour)
“A digital-age Edith Wharton...hilarious, exhilarating, and so, so clever.” (Kevin Kwan, author of Crazy Rich Asians)
"You’d think it would be hard to write a rip-roaring novel that actually elicited our sympathy towards investment bankers - but Michelle Miller has managed it. Miller not only gets the reader to care about [their] anxieties and secret desires...she also spins an exciting piece of intrigue." (The Guardian, US)
What listeners say about The UnderwritingAverage Customer Ratings
Reviews - Please select the tabs below to change the source of reviews.
Kept me "Hooked"
I was engaged from the very beginning, the story flows as we tag along on a journey to take the popular app Hook public. The characters are fleshed out and quite despicable, and there's a few twists I won't reveal. My only issue with the Audible version is it actually had a moment of censorship, there were beeps during a particularly racy scene and any mention of the correct version of the female anatomy. Seriously??? While this didn't take away from my enjoyment of the book, I was a bit perturbed by the juvenile beeps and non-disclosure from Audible, although they may have rectified it by now. Still, by this book! It's just fun!
6 people found this helpful
I was expecting a lot more from the story and how it ended left me at ends. who did it? what becomes of Tars? What does Juan decide to do? does the RA get charged? what happened to Hook? why didn't you finish the story?
3 people found this helpful
Good story. Primed for a sequel
Like another reviewer said, power through the various points of view. Its an intriguing story that doesn't disappoint! The ending leaves many questions hanging in the air. Wonder if there will be a sequel?
- Sarah Guz
Try to power through the many points of views!
Would you try another book from Michelle Miller and/or the narrators?
Who was your favorite character and why?
I like Tara because of her emotional arc. She's wise for 29.
How could the performance have been better?
Different narrators actually helps guide the reader through the landmine of many, many different perspectives.
Did The Underwriting inspire you to do anything?
Not work on Wall Street
Any additional comments?
The story is written is multiple points of view (There's Todd, Tara, Juan, Nick, Christopher, Amanda, and the girl who is murdered). It's maddening at first, but try to power through. If you do, you won't be disappointed.

domain: literature


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July 18, 2017, 5:45 PM - 7:45 PM @ W T Bland Public Library
Would you like free help in preparing for citizenship? Please join our Citizenship Class for friendly help and advice.
Class students will work with our volunteer instructor to prepare for the Citizenship process. Students will go through the application form to prepare for the verbal interview and written test. This includes speaking, reading, and writing in English and learning Civics (History and Government). Enrolled students receive free preparation materials.
This is a five-week series class, taught by an instructor who became a U.S. citizen in 2005. Please register at the Circulation Desk to confirm your participation (no paperwork is required).
July 18, 2017, 10:30 AM - 11:30 AM @ W.T. Bland Public Library
Bring your preschoolers for a story time with Miss Lynn. After story time stay and play with an assortment of educational toys and activities. Suggested age 2 1/2 and up. Cannot accommodate large groups such as daycares.
July 18, 2017, 6:30 PM - 7:30 PM @ W.T. Bland Public Library
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View all calendars is the default. Choose Select a Calendar to view a specific calendar.


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homestyle renovation loan lenders home improvement loan for veterans Eligible and qualified Texas veterans can obtain a below-market interest rate loan of up to $484,350 through the texas veterans home loan program for the purchase of their primary residence.. Land & Home Improvement Loans. We do not offer these loans. Veterans. The VA Guaranteed Loan enables eligible and qualified veterans and active-duty.Fairway Independent Mortgage Corporation to Open New Branch in Flagstaff, AZ – The cornerstone of his practice is consistent and strong communication coupled with creative financing options such as FHA, VA, USDA, HUD-184, Conventional, Jumbo, Down Payment Assistance loans, FHA.
The closing costs associated with a refinance can be substantial, but it’s possible to wrap these expenses into your new loan with a no-closing-cost mortgage. In a typical refinance, a borrower.
. closing costs usually total thousands of dollars. Besides writing a check to pay those fees at the closing table, there’s another way to pay them when you refinance your mortgage: by adding them.
Take, for example, a no-closing-cost refinance. While it may sound too good to be true, there are times when it may be worth considering. Here’s a guide to help you understand: What is a no-cost refinance? In short, it’s a mortgage loan that offers homeowners the option to refinance their mortgage without having to pay initial fees to lenders.
With that good faith estimate in hand you can make an accurate comparison of what other lenders are going to charge you in terms of closing costs. (For more, see: 9 Things to Know Before You Refinance.
Though it may come as a surprise, there is no limitation to how frequently you can. Here are some things to consider before you move to refinance your mortgage. 1. What are the closing costs? Are.
Refinancing Mortgage No Closing Costs – If you need to low your monthly payments it’s time to think of mortgages refinancing options. Visit our site and try our refinancing calculator.
Various loan programs allow you to refinance your home without paying any upfront closing costs in exchange for a higher loan balance or interest rate. The product you choose depends on a variety.
The rate is about 1/4 percent higher than a mortgage program that carries typical closing costs. There are no points, no title insurance costs, no appraisal fees,
Get a no-closing-cost mortgage and a low rate, too.. The downside is that you lose home equity when you include closing costs in your refinance loan. In addition, because the costs are being.
Refinancing your mortgage is a big step. At Chase, we can help you free up money in your budget by lowering your monthly payments or provide you a one-time cash payment during refinancing by tapping into your home’s equity. Discover how you can refinance your current mortgage and calculate refinance rates and payments with our mortgage calculators.

domain: finance


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Previous experience with OLT for hilar CCA has been discouraging, and survival was dismal. This study demonstrates that carefully selected patients with unresectable hilar CCA can achieve long-term survival after OLT. The survival rate obtained with this protocol (5-year actuarial survival of 87%) is comparable with the overall survival rate of liver-transplant recipients at the authors' institution. In comparison, the best survival rate after OLT for hilar CCA reported in the literature is 64.8% at 5 years in a subset of nine patients with negative lymph nodes . In the absence of a control group, it is difficult to assess with certainty the role of a combination of chemotherapy and radiotherapy, but in some patients it seems to prevent or slow progression of the disease while waiting for an available organ. Treatment-related morbidity, although significant, is not prohibitive. Nevertheless, a considerable proportion of treated patients ultimately was found to have advanced disease precluding transplantation. This finding confirms the importance of the staging laparotomy as an essential component of the protocol.
ASJC Scopus subject areas

domain: biology


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Monday AM January 11th, 2009
by: Ed Mayberry, January 11, 2010 4:01:31 am
Americans expecting to have less disposable income in 2010 outnumber those who anticipate an increase almost two-to-one. But about a third expect it will remain about the same. Zogby International's Sam Rogers says the poll didn't ask why people have these perceptions.
"We didn't ask a follow-up about why, but we did ask was a follow-up asking if people planned on making any major purchases over the next year, and we gave them a house, car, major appliance, computer. Fifty per cent of people said they weren't planning on purchasing any of the above. And so what we see is a lack of consumer confidence. If I am in the retail business, it's a little frightening that 50 per cent of Americans don't plan on making a major purchase in the next year."
Expectations for a boost in disposable income vary according to age.
"Expectations for a boost in disposable income were higher among the 18-to-29 group. Thirty per cent said that they expect to have more disposable income next year, compared with 21 per cent in the nation overall. So we do see a little more optimism among younger Americans."
Ed: "Did that optimism vary according to somebody's, you know, economic standing?"
"There was some change in the income level. Those on the lower end of the income scale, less likely to expect to have more disposable income in the future."
About 31 per cent of wealthier Americans are concerned that disposable income will decrease, but Rogers says that may be because their income level has been hit hard, with the highest percentage drop in real estate values and 401(k) accounts.


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Some thoughts on a bad week…
This hasn’t been a great week for Bermuda in terms of domestic violence.
I don’t mean that in the sense of a sudden surge in domestic violence incidents – I have no way to say if that is the case or not.
Rather, I’m referring to the sad – and shocking – news that the islands only safe house, operated by the Centre Against Abuse, has been forced to close due to lack of funds, and the disturbing incident of a prominent divorce lawyer being assaulted in Supreme Court by the ex-husband of one of her clients.
Centre Against Abuse Safe House
This fact alone is a sad condemnation of Bermuda’s misplaced priorities regarding how we spend our money – for an island of our wealth, it is shocking we cannot fund such an important service, and in doing so we are condemning women and children (who make up the majority of domestic violence victims) to abuse and possibly even murder.
An article earlier this year states that the safe house provided shelter for 31 women and children fleeing domestic violence in 2013.
That may not sound like a lot of people, but for those involved it provided a crucial lifeline of support in escaping a nightmarish situation.
The same article makes clear that rates of domestic violence greatly increase over the summer months, and as we’re still in the summer (and the upcoming stresses of the new school year), one can only imagine the demand for the safe house is likely highest right now – and just when it’s needed most it’s no longer available.
Some Stats on Domestic Violence
There’s some interesting stats available on domestic violence as it relates to Bermuda.
A report by the Bermuda Health Council in 2013 [opens as a PDF] found that one in eight adults had experienced domestic violence, with partner violence being particularly directed against women and those in the younger age group (see p.61), with women being three times more likely to be the subject of domestic violence than men (see p.62) – that is, roughly one in five of all women in Bermuda reporting domestic violence.
Another report, the Health Survey of Adults in Bermuda 2011 [opens as a PDF] – I cannot find a more recent report and don’t know if they even exist – found that about a third (30%) of all Bermudians have experienced physical abuse from an intimate partner, compared to about a quarter (23%) in 2006 (see p.96; p.95 also provides additional information).
It’s not clear what the current status of domestic violence in Bermuda is, with the most recent crime statistics, quarter two for 2014 [opens as a PDF], not explicitly referring to domestic violence.
Nonetheless, these stats do indicate that incidents of sexual assault and ‘crimes against children’ have increased, which may reflect increased rates of domestic violence.
It’s also important to note that domestic violence is often under-reported.
There’s stats that women only report domestic violence after 32 incidents of domestic violence (see the header on this link; I believe it originates from a WHO report, but I’m not sure which exactly).
It’s also important to know that domestic violence doesn’t just affect the victims themselves – it also leads to greater healthcare costs for us all, as well long-term consequences – we know, for example, that abused women often have long-term mental and other health issues resulting from the abuse, and children growing up in an environment of domestic violence tend to exhibit a greater risk tendency of substance abuse, as well as engaging in violent acts themselves later.
The safe house run by the Centre Against Abuse isn’t the magic bullet to end domestic violence, but it is a key part in dealing with the problem and helping to break cycles of abuse.
I encourage anyone who can to reach out to the Centre Against Abuse and see what they can do to help them out and get the safe house back up and running as soon as possible.
Almost to underline the issue of domestic violence, one of Bermuda’s most prominent divorce lawyers was assaulted on the grounds of the Supreme Court, leaving the woman lawyer requiring hospital treatment.
The man who attacked the lawyer was involved in a divorce case, the lawyer representing the man’s ex-wife.
I’m not interested in getting into the ins and outs of the personal case of that divorce issue, other than to say that, beyond the need for improved security at the Supreme Court, this would indicate a certain mentality of resorting to violence, especially as a form of abuse.
A Quick Note
Just a quick additional note to say that domestic abuse is not restricted solely to physical violence, but also involves emotional and sexual abuse to.


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‘I want to tell the story of a summer I spent with four American gangsters’. Such is the promising opening of this entertaining new novel, which describes the adventures of its protagonist, Anton, from the point when, dumped by his girlfriend Eleanor, he leaves his home city of Hamburg to spend the summer in Manhattan, living with his ‘uncle’ Jimmy, a Mexican immigrant and former boyfriend of his mother. For the duration of his stay he works in Jimmy’s luncheonette, manning the kitchen alongside his eclectic team, the easy-going 69-year-old Italian Francis (originally Francesco) and the Columbian compulsive gambler Zac, until the luncheonette becomes his second home.
Apart from the luncheonette, Jimmy has one overwhelming passion: Alcatraz, the legendary prison island in San Francisco Bay. Adding wherever possible to his large repertoire of anecdotes and theories, Jimmy has meticulously researched Alcatraz, and keeps all the information he can find in a big white box. He is particularly fascinated by the great escape of 1962, when three inmates succeeded in breaking out, and vehemently defends the opinion that they succeeded in reaching the mainland and began a new life. While drawn in by Jimmy’s stories, Anton is also confronted by phases of his own past, especially those associated with his stay in a mental hospital, which he would rather forget. The summer thus also reflects a process of insight, in which the twenty-four-year-old discovers why it can be vital to believe in the possibility of escaping one’s own circumstances and starting afresh. His stay in New York comes to an abrupt end when Jimmy dies of a heart attack and he himself returns to Hamburg – with good intentions for the future, and Jimmy’s large white box.
The style of this novel is in many ways more akin to spoken than written German. The biographies of the escaped inmates of Alcatraz and details of the prison and the great escape are rendered in italics and the latter part of the text also picks up the story of a small Mexican boy, who turns out to be Jimmy – which explains his obsession. It may also be remarked that Lebert’s first novel Crazy was successfully translated into more than thirty languages, suggesting that this young author holds international appeal. One to welcome back.


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MALAYSIA last played Ireland in the Champions Challenge in Kuantan last year, and the hosts snapped up the bronze medal with a convincing 4-2 score.
But the Irish did deny Malaysia a spot in the London Olympics, when they held us to a 1-1 draw at the Dublin Qualifier on St Patrick's day.
This scribe was there to watch both the matches, one played during a massive parade in chilly Dublin, the other played under sunny conditions and sea breeze in Kuantan.
In Dublin, Ireland went on to play in the final against South Korea, and the Asian giants beat them to the Olympics.
Malaysia play Ireland on the 25th, 8pm, and the only route for coach Tai Beng Hai and his men is a win or it will be bust all the way in the next two matches.
Ireland, ranked 14th, are two rungs below Malaysia: "Rankings do not matter in this tournament as every team is chasing for a spot in the Olympics and playing on a different level than what they are capable of normally," said Malaysian coach Beng Hai.
China were a classic example, as even though ranked 31st and 19 below Malaysia they played gallantly and only lost 2-3.
The matches here have been close, as even Pakistan could only beat Poland 2-1, while India scraped past France 3-2.
Belgium and Britain played to a 2-2 draw, while the only match that went to rankings was when Australia thrashed France 10-0.
On Monday, the Malaysian team were given a free day, and they went around in groups sightseeing and shopping in Antwerp to rest their edge nerves, as their next match was only three days away.
Yesterday, there was some light training and tomorrow will be another rest day for Malaysia before the Ireland do-or-die.

domain: sports


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ARTD 19A Figure Painting
3 Units (Degree Applicable)
(May be taken for option of letter grade or Pass/No Pass)
Lecture: 36 Lab: 71
Prerequisite: ARTD 17A
Painting the draped and nude figure with emphasis on observation and accurate representation. Through poses of various lengths, students will learn to depict the human figure using light logic, color palettes, compositional devices, and painting techniques.


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Dear Home-Ec 101,
I have a dilemma in that I looked up the tiny flies that are strolling around my plant soil. I found that they are called fungus flies and live on the decaying soil matter. I’ve sprayed the soil with Home Defense both bug spray and soapy water (nope), put a dish of apple cider vinegar with a drop of dish washing liquid in it to bait them (nope), and most recently, put coarse sand on top of the soil so the “babies that hatch” can’t crawl up and out and die (yech). Needless to say, they are no longer visible on that plant but the fliers have moved on to my other plants. I will never buy that type of soil again (with small wood chips or something) because I’ve never seen this before.
Is there any other way to rid myself of these without buying enough sand to put on all of my plants? They don’t damage the plants (I’m told), but I can’t stand bugs.
There’s a Party in My Plants and They Won’t Go Home
Fungus gnats, fruit flies, and drain flies are all pretty annoying, but mostly harmless pests. I say mostly because they are aggravating as all get out.
Cider traps don’t work for fungus gnats like they do for fruit flies because fungus gnats don’t eat rotting plant material, they eat what grows on the material. Fungus gnats smell cider and say, “Sorry, I’m just not that into you.” Okay, maybe not literally, but close enough for our purposes.
The solution for getting rid of the fungus gnats has three parts; the most important being perseverance. Due to the life cycle of the flies, it’s going to take weeks to get rid of the little buggers (ha ha) once and for all.
Dry out the fungus the gnats feed on.
First, you’ll need to ensure that the top two inches of soil are as dry as your plants can tolerate. Those two inches will need to stay dry for as long as they will tolerate. If possible, practice what is called bottom watering.
To start bottom watering, you’ll need to set the plant’s pot in a container of water. Ensure that the water level in the container does not rise above the top two inches of soil. Let your plant hang out in the container until you begin to feel moisture along the wall of the container in the top two inches. You’ll want to avoid setting the wet pot on a surface that can be damaged by water until the container itself is dry.
Allowing the top two inches of the soil to dry will reduce the amount of food supply the larva have available.
Capture the breeding adults.
Unlike immature humans, fungus flies can’t breed until they are fully grown. This handy evolutionary trait allows you to implement step two – hopefully before the procreation happens.
Find sticky traps like these Gnat Stix. You should be able to find them in the garden section of most big box stores or your local nursery. You may want to give them a call first to make sure, though. You’ll want to place at least one sticky trap in each of your plant’s container. Replace the traps when the stickiness wears out or you can’t stand looking at the little carcasses any longer.
Keep at it.
Here’s where the perseverance part comes into play. You’ll need to keep using both of these techniques for a few weeks after the fungus gnats first appear to be gone.
The next batch of eggs and larva are hanging out in the soil and are just waiting for you to water your plant from the top and ring the bell signaling dinner is ready at the fungal buffet.
Another option is to get a medium the gnats don’t want to hang out in and cover the soil in each plant, this is similar to the sand technique you mentioned but with a different material. I haven’t tried this technique so I can’t vouch for the effectiveness.
I hope this helps. Thank you for writing in.
Check out these other Pest Related Posts
Submit your questions to email@example.com
2 thoughts on “There’s A[n Unwelcome] Party In My Plants”
You can also try some Nematodes, which are available from Home Depot. I think they’re also marketed as “ladies in red”. They eat the fungus gnat larvae.
While the adult gnats themselves are annoying but essentially harmless, their larvae will feed on the roots of your plants and over time can cause extensive damage. I’m currently in an epic battle against the little hellions and I have seen so many posts toting these pests’ general inefficacy and inability to damage your plants and unless you’re able to wipe them out in their first generation it is simply not true. The only real success I have had in killing the larvae is a diluted (approx 1-6 ratio) mix of 3% hydrogen peroxide and water. I have heard nematodes are quite effective as well but have been unable to find them in any of my local stores.
Good luck, they are a real pain to get rid of, especially once they start jumping plants.

domain: hobby


[Numpy-discussion] The future of Numpy
Barrett at stsci.edu
Fri May 25 15:15:30 EDT 2001
Mark Esplin wrote:
> What is the plan for the future development of Numerical Python? For
> example, will additional special functions be included in numpy, or is
> NumPy to be a building block for other applications? I guess the big
> question is "Will Numerical Python become a complete computing
> environment like Matlab or IDL?"
> There is an interesting series of article on Numerical Python by Eric
> Hagemann on O'Reilly network (www.oreillynet.com) where Eric Hagemann
> is using NumPy with other python modules as a computing environment
> more than as a software development framework.
> I think NumPy could become a lot like the development of linux. Linux
> strictly speaking is only the operating system kernel. However, a
> linux system has come to includes a whole set of packages that work
> together to make up a whole system.
See PEP 209: Multi-dimensional Arrays
Paul Barrett, PhD Space Telescope Science Institute
Phone: 410-338-4475 ESS/Science Software Group
FAX: 410-338-4767 Baltimore, MD 21218
More information about the NumPy-Discussion


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The Weeknd’s Blinding Lights track just created some new records! It completed one full year in the Billboard Top 10 musical chart.
The single came out last year before the launch of the Heartless hitmaker’s full-fledged album.
‘Blinding Lights’ still strong in Billboard charts
Apart from being in the top 10 for more than a year, the fantastic track also created a new record. It spanned around 43 weeks in the top five songs alone, in Billboard’s charts. That’s an outstanding achievement.
While doing so, it surpassed the previous milestone of Post Malone’s Circles. The latter remained in the top five for 39 weeks continuously.
In a recent interaction with Variety, The Weeknd expressed his happiness over Blinding Lights’ immense love.
“I thought maybe it [the album] was too much,” he said.
“But it wasn’t until people liked ‘Blinding Lights’ that I was like, ‘This is so not what now is, and people loved it anyway.'”
The After Hours album was the fourth studio album by the In Your Eyes artist. So far, he’s not revealed details regarding his latest project.
His fans will be looking forward to the next big surprise.
Some early rumors have pointed towards a possible collaboration with Imagine Dragons.
The Grammys and the most prominent snub
Although his album’s love was mostly limitless, The Weeknd somehow failed to make it into the Grammys nominations. Upon its announcement, the list subbed the Starboy singer’s iconic 2020 record.
As expected, music lovers, fans, and even famous artists were antagonistic towards the awards jury.
God’s Plan hitmaker and his friend Drake came forward while criticizing the selection committee. He was shocked after Abel Tesfaye was left out of the final contenders for top honors in various categories.
On the other hand, the artist’s reaction to missing the nod was quite normal despite a successful album. He gave more importance to his listeners and everyone who supported After Hours.
“People told me I was going to get nominated,” he said in his interaction with Billboard.
“The world told me. Like, ‘This is it; this is your year.’ We were all baffled.”
He already has three Grammys for the period between 2015 and 2017.
Blinding Lights is available to stream on major music platforms. And yes, it’s still going strong in the global charts.
Image courtesy of The Weeknd/YouTube Screenshot


This page has a list of qualified piano teachers who teach Other and if that's your preference, you can choose a teacher you like and click on the piano teacher to see more details about it, and on that page , you can contact the teacher directly via a contact form on the public piano teacher profile page, once you do that, your piano teacher will get back to you shortly to answer any question you may have or to start the learning process.
Professional Pianist with 10 years+ of experience and an orchestra background. Doctorate (D.M.A) from Rutgers University, USA. Methods taught, such as RCM and Yamaha. I am classically trained and started my music journey with the piano and flute at the age of 5. I started playing bassoon when I was 11 years old. Between grades 3 and 12, I studied in a music-gifted program. I have attended the following schools earning the following degrees:
• Rutgers University, Mason Gross School of the Arts, New Jersey (Doctor of Musical Arts)
• Mannes School of Music, The New School, New York (Master of Music)
• University of Taipei, Taiwan (Bachelor of Music).
In class, I follow RCM and Yamaha methods and textbooks. I teach piano and music theory in a couple of music schools in Toronto. I encourage students' musical, social, personal, and emotional development by creating dynamic, well-thought-out lesson plans that empower and engage them. I will assist you with preparing for any future music theory test or simply learning music for enjoyment.
I am a self-motivated, creative individual who champions diversity, equality, and inclusion in music education, as well as developing and promoting novel teaching ways to overcome learning hurdles. I am a multilingual communicator (Mandarin Chinese and Taiwanese) who develops great bonds with kids and their parents/guardians from a variety of ethnic, cultural, and socioeconomic backgrounds.
Miss Donna Huang is a dynamic, dedicated, and creative piano teacher whose passion lies in teaching and empowering children. She values children's amazing gifts and hopes to inspire and empower her students to do their best and to be themselves. While imparting musical knowledge and skills to her students is essential, building positive relationships with her students is integral to their well-being and self-confidence - so that they know and feel that she believes in them always!
She has over 18 years of piano teaching experience and have worked with children for more than 23 years. She believes the first piano learning experience is the most special and unique moment in a child's life. She knows how important it is to provide a positive, fun, and encouraging learning environment so that children's natural curiosity, use of imagination, self-expression, and creativity can be explored and nurtured.
Besides her love for teaching, Miss Donna loves to mentor piano teachers, build businesses, and be inspired by other teachers and colleagues. Her experience extends beyond teaching piano...more here: http://www.happykeysmusic.ca/more-about-miss-donna.html