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High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that high-fructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor-γ coactivator-1β and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor-α (PPARα). PPARα physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPARα constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.
- hypertriglyceridemia
- forkhead box O1
- peroxisome proliferator-activated receptor-α
- apolipoprotein C-III
- very-low-density lipoprotein-triglyceride
- microsomal triglyceride transfer protein
hypertriglyceridemia is characterized by increased production of very-low-density lipoprotein (VLDL) and/or decreased clearance of triglyceride (TG)-rich particles (4). Due to its proatherogenic profile, hypertriglyceridemia is a major contributing factor for the pathogenesis of atherosclerosis and coronary artery disease in obesity and type 2 diabetes. While the pathophysiology of hypertriglyceridemia is poorly understood, its close association with visceral adiposity and type 2 diabetes implicates insulin resistance as a causative factor in the development of hypertriglyceridemia (5, 12, 22, 29, 42). However, the molecular events that link insulin resistance to the pathogenesis of hypertriglyceridemia remain elusive.
An important player in plasma VLDL-TG metabolism is apolipoprotein C-III (apoC-III). It functions as an inhibitor of lipoprotein lipase and hepatic lipase, playing a pivotal role in the hydrolysis and clearance of TG-rich particles such as VLDL-TG and chylomicrons (27, 36, 51, 53). Elevated plasma apoC-III levels are associated with impaired clearance of TG-rich particles, leading to the accumulation of TG-rich lipoprotein remnants in plasma and the development of hypertriglyceridemia.
Our recent data indicate that forkhead box O1 (FoxO1), a nuclear transcription factor known to be a mediator of insulin signaling, plays an important role in hepatic regulation of apoC-III. FoxO1 stimulates hepatic apoC-III expression, which is counteracted by insulin (2). Elevated FoxO1 production in liver augments hepatic apoC-III expression, resulting in increased plasma TG levels and impaired postprandial fat clearance in mice (2). Transgenic mice expressing a FoxO1 constitutively active allele develop hypertriglyceridemia, as manifested by significantly elevated plasma VLDL-TG levels and retarded postprandial fat clearance (2). In insulin-resistant states, hepatic FoxO1 activity becomes deregulated, culminating in elevated hepatic production along with skewed nuclear redistribution and accounting for its increased trans-activation activity in liver (2, 3). Furthermore, anti-sense oligonucleotide-mediated inhibition of FoxO1 activity improves hepatic and peripheral insulin action in high-fat-diet-induced obese mice (47). These data implicate FoxO1 at the interface between impaired insulin action and aberrant apoC-III expression, contributing to the pathogenesis of hypertriglyceridemia in insulin-resistant subjects.
Fibrates are commonly used as hypolipidemic agents for treating hypertriglyceridemia (13, 23, 33). An important function of fibrates is to suppress apoC-III production, contributing to increased VLDL-TG catabolism and decreased plasma TG levels (15, 16, 45, 52). Fibrates bind and activate peroxisome proliferator-activated receptor-α (PPARα), a transcription factor that is abundantly expressed in liver (8, 21, 32, 37, 38). However, it is conceptually difficult to reconcile fibrate-mediated activation of PPARα activity with reduced apoC-III production and improved TG metabolism (24, 25, 28, 44). Based on the findings that FoxO1 mediates the inhibitory effect of insulin on hepatic apoC-III expression and excessive FoxO1 activity may contribute to unrestrained apoC-III production and metabolic aberrations in diabetes (2), we hypothesized that fibrates would suppress FoxO1 expression and reduce apoC-III production, contributing to improved VLDL-TG metabolism.
We tested this hypothesis in high-fructose-fed hamsters. Syrian golden hamsters develop hypertriglyceridemia, accompanied by insulin resistance, in response to high-fructose feeding (10, 14, 30). But the underlying pathogenesis of high-fructose-induced insulin resistance and hypertriglyceridemia remains elusive. To address the function of FoxO1 in hypertriglyceridemia and define the mechanism of fibrate action in TG metabolism, we studied hepatic FoxO1 expression in hamsters fed a high-fructose diet vs. regular chow, with and without fibrate treatment. We show that high-fructose feeding augmented hepatic FoxO1 production and promoted its nuclear localization. This effect, along with impaired insulin action, contributes to apoC-III overproduction and the development of hypertriglyceridemia. High-fructose feeding also resulted in marked induction of hepatic expression of PPARγ coactivator-1β (PGC-1β) (31), a coactivator of sterol regulatory element-binding protein-1c (SREBP-1c), accounting for increased fat infiltration in liver. Fibrates upregulated hepatic production of PPARα, which antagonized FoxO1 activity and corrected FoxO1 deregulation in liver, contributing to enhanced insulin sensitivity and the amelioration of hypertriglyceridemia in high-fructose-fed hamsters. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia and illustrate a novel mechanism by which fibrates act to improve plasma VLDL-TG metabolism.
Animal studies.
Syrian golden hamsters (male, 5-wk old, body weight of 81–90 g) were purchased from Charles River Laboratory (Wilmington, MA). Animals were fed with standard rodent chow and water ad libitum in sterile cages with a 12:12-h light-dark cycle. To induce hypertriglyceridemia, hamsters were fed a high-fructose diet (60% fructose, 6% fat, DYET no. 161506; Dyets, Bethlehem, PA) for 4 wk. For fibrate treatment, high-fructose-induced hamsters were randomly divided into two groups (n = 9), which were treated with once-daily oral gavage of 250-μl fenofibrate (50 mg/kg; Abbott Laboratories, Chicago, IL) or 250-μl saline as control. All hamsters were maintained on a high-fructose diet during a 4-wk treatment. In addition, one group of hamsters fed regular rodent chow was used as normal control. Blood was collected from the tail vein into capillary tubes precoated with potassium-EDTA (Sarstedt, Nümbrecht, Germany) for the preparation of plasma or the determination of blood glucose levels using Glucometer Elite (Bayer, IN). Plasma levels of TG and cholesterol were determined using Thermo Infinity TG and cholesterol reagents (Thermo Electron, Melbourne, Australia). Plasma free fatty acid (FFA) levels were determined using the Wako FFA assay kit (Wako Chemical USA, Richmond, VA). Plasma insulin levels were determined by anti-human insulin ELISA that cross-reacts with hamster insulin (ALPCO, Windham, NH). At the end of study, animals were killed by CO2 inhalation, and liver tissue was frozen in liquid N2. All procedures were approved by the Institutional Animal Care and Use Committee of the Children's Hospital of Pittsburgh (protocol no. 41-04).
Glucose tolerance test.
Hamsters were fasted for 5 h and injected intraperitoneally with 50% dextrose solution (Abbott Laboratories) at 5 g/kg body wt. Blood glucose levels were determined and plotted as a function of time. Area under the curve was calculated using the KaleidaGraph software (Synergy Software, Reading, PA).
Insulin sensitivity index.
Insulin sensitivity index (ISI) was calculated using the formula ISI = 2/[(INS × GLU) + 1], where INS is fasting plasma insulin levels and GLU is fasting blood glucose levels, with all values being converted to μmol/l as described (7). A similar homeostasis model assessment (HOMA) for calculating ISI has been described by Mattews et al. (35). The principle of this formula is as follows: a reduction in insulin sensitivity results in elevated levels of either blood glucose, plasma insulin, or both. ISI is a function of the compound effect of fasting blood glucose and plasma insulin levels. Preclinical and clinical data indicate that ISI correlates inversely with insulin resistance (6, 7, 35).
Hepatic lipid content.
Forty milligrams of liver tissue were homogenized in 800 μl of HPLC grade acetone. After incubation with agitation at room temperature overnight, aliquots (5 μl) of acetone-extract lipid suspension were used for the determination of TG concentrations using the Thermo Infinity TG reagent (Thermo Electron). Hepatic lipid content was defined as milligrams of TG per gram of liver tissue.
Western blot analysis.
Isolation of nuclear proteins from homogenized liver tissue using the Pierce NE-PER extraction reagents (Pierce, Rockford, IL) has been described (2). Aliquots (40 mg) of liver tissue were homogenized in 400 μl of ice-cold cytosolic extraction reagent-I solution (Pierce), supplemented with 4-μl protease inhibitor cocktail (Pierce). Nuclear fractions were separated from cytoplasm and subjected to immunoblot analysis using antibody against FoxO1, PPARα, SREBP-1c, PGC-1β, and β-actin proteins, as previously described (2). The intensity of protein bands was quantified by densitometry using the National Institutes of Health Image software (NIH, Bethesda, MD), as described (2). Polyclonal rabbit anti-FoxO1 antibody was developed in our laboratory by immunization of rabbits with the glutathione S-transferase-tagged human FoxO1 protein (Genemed Synthesis, San Francisco, CA). Rabbit anti-PGC-1β antibody was provided by Dr. Spiegelman's laboratory (31). Antibodies against PPARα (ABR Affinity BioReagents, Golden, CO), SREBP-1c (catalog no. sc-13551; Santa Cruz Biotechnology, Santa Cruz, CA), and β-actin (sc-1615, Santa Cruz Biotechnology) were commercially available. To determine plasma apoC-III levels, aliquots of plasma at a fixed quantity of protein (20 μg) were blotted to a piece of nitrocellulose membrane by dot blotting. The membrane was probed with goat anti-apoC-III antibody (1:1,000 dilution; Abcam, Cambridge, MA), followed by incubation with rabbit anti-goat IgG conjugated with peroxidase (1:6,000 dilution; Jackson ImmunoResearch Laboratories, West Grove, PA). ApoC-III protein was detected using the enhanced chemiluminescence detection reagents (GE HealthCare), as described (2). In addition, aliquots of plasma at a fixed concentration of 15-μg proteins per lane were applied to 4–20% polyacrylamide gels. The gels were subjected to Western blot assay using goat anti-apoC-III antibody (Abcam). ApoC-III proteins were visualized by enhanced chemiluminescence detection reagents, and the relative intensities of protein bands were quantified by densitometry, as described (2). For the determination of hepatic microsomal TG transfer protein (MTP) levels by the immunoblot assay, we have generated polyclonal anti-MTP antibody derived against a homologous region of MTP protein between rodents and humans (SYSASVKGHTTGLSLN, corresponding to MTP amino acid residues 14–29). After affinity purification by protein-A column chromatography, this MTP antibody (1:1,000 dilution) reacted specifically with both rodent and human MTP proteins on Western blots.
Immunoprecipitation of FoxO1 from liver tissue by protein-A chromatography has been described (3). Aliquots of liver tissue (20 mg) were homogenized in 800 μl of M-PER buffer supplemented with 8-μl protease inhibitor cocktail (Pierce). After centrifugation at 13,000 rpm for 10 min in a microfuge, aliquots of protein lysates (600 μg) were incubated with 5 μg of rabbit anti-FoxO1 antibody or preimmune serum for 1 h at room temperature. The samples were mixed with 80 μl of 50% protein A slurry and incubated for 1 h at room temperature, followed by washing in 80 μl of 1× PBS containing 0.05% Tween 20 for three cycles, each 30 min. Immunoprecipitated proteins were eluted and analyzed on immunoblots using anti-FoxO1 and anti-PPARα antibodies, respectively.
Immunoprecipitation of FoxO1-Δ256 and PPARα complex was performed. FoxO1-Δ256 is a FoxO1 dominant-negative mutant that contains the amino domain (1–256 amino acid residues), as described (3, 39). HepG2 were transfected with 4 μg of pPPARα plasmid in Vitacell culture medium (American Type Culture Collection) in six-well plates. Four hours later, culture media were renewed with prewarmed media supplemented with adenoviral vector expressing FoxO1-Δ256 at a multiplicity of infection of 100 plaque-forming units/cell, as described (3). After 48-h incubation, cells were harvested and lysed in 100 μl of M-PER buffer supplemented with 1-μl protease inhibitor cocktail (Pierce). Protein lysates were subjected to immunoprecipitation by rabbit anti-FoxO1 antibody or preimmune serum, as described above. Each condition was run in triplicate. Immunoprecipitates were analyzed by immunoblot assay using anti-FoxO1 or anti-PPARα antibody.
Effect of fenofibrate on FoxO1 and PPARα interaction was determined as follows: HepG2 cells were cotransfected with FoxO1- and PPARα-expressing plasmids (2 μg each plasmid). After 24 h of incubation, cells were incubated in the presence and absence of 50 mM fenofibrate in culture medium for 16 h, followed by immunoprecipitation using anti-FoxO1 antibody. Immunoprecipitated proteins were subjected to semiquantitative immunoblot assay by anti-FoxO1 and anti-PPARα antibodies, respectively.
Fast protein liquid chromatography fractionation of lipoproteins.
Aliquots (500 μl) of plasma were applied to two head-to-tail linked Tricorn high-performance Superose S-6 10/300GL columns using a fast protein liquid chromatography system (Amersham Biosciences), followed by elution with PBS at a constant flow rate of 0.5 ml/min. Fractions (500 μl) were eluted and assayed for TG and cholesterol concentrations using the Thermo Infinity TG and cholesterol reagents (Thermo Electron).
Liver tissue from euthanized hamsters was embedded with Histoprep tissue embedding media (Fisher Scientific). Frozen sections were cut (8 μm) and subjected to immunohistochemistry using rabbit anti-FoxO1 antibody (dilution at 1:1,500). The second antibody was Cy3-conjugated goat anti-rabbit IgG (dilution 1:500, Jackson ImmunoResearch Laboratories). The nuclei of hepatocytes were visualized by staining with TO-PRO-3 dye (Molecular Probes, Eugene, OR). Specimens were examined under a laser scanning confocal microscope (Nikon E800, Nikon).
Liver histology.
Liver tissue was embedded in the Histoprep tissue embedding media and snap-frozen. Frozen sections (8 μm) were cut for fat staining with Oil red O, as described (19).
Plasmid transfection and luciferase assay.
HepG2 cells in six-well microplates were transfected with 1-μg plasmid pHD317 encoding luciferase cDNA under the control of the human APOC3 promoter using the Lipofectamine 2000 (Invitrogen, Carlsbad, CA). In each transfection, 1-μg plasmid pCA35-LacZ was included, and the amount of β-galactosidase (β-gal) activity was used as control for the normalization of transfection efficiency. After 48-h incubation, cells were collected for luciferase and β-gal activity assays as described (2).
FoxO1 promoter-directed luciferase reporter system.
The 2-kb mouse FoxO1 promoter [−1,748/+407 nucleotide (nt)], including the 5′-untranslated region, was cloned from Balb/C mouse genomic DNA (BioChain Institute, Hayward, CA) into the TA-cloning vector pCR2.1 (Invitrogen) by PCR using specific primers (for forward reaction, 5′-GATCTGGGGAAAGCTTTAGGAAAAC-3′; and reverse reaction, 5′-CAGAGGGCCATGAAGAGACGAC-3′). After verification by DNA sequencing, the KpnI-XhoI DNA fragment harboring FoxO1 promoter was subcloned upstream of the luciferase gene in the pGL3-basic plasmid (Promega, Madison, WI).
RNA isolation and RT-PCR.
Total RNA preparation from HepG2 cells for RT-PCR analysis are as described (3). The primers for PPARα are 5′-AAGGGCTTCTTTCGGCGAAC-3′ (corresponding to a conserved region of mouse and human PPARα cDNA 367–386 nt) and 5′-TGACCTTGTTCATGTTGAAGTTCTTCA-3′ (mouse and human PPARα cDNA 644–670 nt). Primers for FoxO1 and β-actin mRNA have been described (3). All primers were obtained commercially from Integrated DNA Technologies (Coralville, IA).
Chromatin immunoprecipitation.
Chromatin immunoprecipitation (ChIP) was performed as described (2). HepG2 cells (1 × 106 cells) were transfected with pFoxO1 (2 μg) alone or in combination with pPPARα (2 μg). Both pFoxO1 and pPPARα plasmids express the respective transgene under the control of the cytomegalovirus promoter, as derived from the pCR3.1 vector (Invitrogen). They were cloned from C56 BL/6J mouse liver RNA by RT-PCR using specific primers flanking FoxO1 (forward 5′-TCCTAGGCACGAACTCGGAG-3′ and reverse 5′-TTAGCCTGACACCCAGCTGT-3′) and PPARα coding regions (forward 5′-ATCACAGCTTAGCGCTCTGT-3′ and reverse 5′-TCAGTACATGTCTCTGTAGATC-3′). To compensate for the difference in the amount of DNA used for transfection, a control pCA35-LacZ plasmid was included to ensure the same amount of DNA (4 μg) in each transfection. After 48-h incubation, cells were cross-linked with 1% formaldehyde, followed by sonication in a Microson 100-W Ultrasonicator (Structure Probe, West Chester, PA) at 10% of maximum power for 60 pulses, 2 s for each pulse. After centrifugation at 13,000 rpm for 10 min, the supernatant was incubated with 8 μg of polyclonal rabbit anti-FoxO1 antibody, followed by immunoprecipitation using the ChIP kit (Upstate Biotechnology, Lake Placid, NY). As controls, aliquots (1 × 106) of pFoxO1-transfected or pFoxO1/pPPARα-cotransfected HepG2 cells were treated identically for the preparation of cell lysates, which were immunoprecipitated with 8 μg of preimmune rabbit IgG (Genemed Synthesis). The immunoprecipitated DNA was analyzed by PCR using 20-nt primers that flank −675/+1 nt of the APOC3 promoter, as described (2). PCR products were analyzed on 1% agarose gels, and the relative intensity of DNA bands was quantified by densitometry using the NIH Image software, as described (2).
To analyze the potential association between PPARα and APOC3 promoter, HepG2 cells were transfected with 4 μg of pPPARα DNA, followed by ChIP assay using monoclonal anti-PPARα antibody (8 μg, ABR Affinity BioReagents) or 8 μg of preimmune rabbit IgG (Genemed Synthesis). Immunoprecipitates were analyzed by PCR using the APOC3 promoter-specific primers, as described above.
Statistical analyses of data were performed by ANOVA using StatView software (Abacus Concepts). Pairwise comparisons were performed to study the significance between different conditions. Data were expressed as means ± SE. P values <0.05 are considered statistically significant.
Effect of fibrates on metabolism in high-fructose-fed hamsters.
Fibrates are commonly used oral agents for treating hypertriglyceridemia in subjects with obesity and type 2 diabetes, but their mechanisms of action are not completely understood. To define the molecular mechanism by which fibrates improve TG metabolism, we treated high-fructose-induced hyperlipidemic hamsters with either an oral dose of fenofibrate or saline for 4 wk, using one group of hamsters fed on regular chow as control. High-fructose feeding did not result in significant alterations in blood glucose levels (Fig. 1A). However, all hamsters fed on high-fructose diet had significantly higher plasma insulin levels (Fig. 1B), which is indicative of insulin resistance.
To corroborate this finding, we performed a glucose tolerance test. Hamsters fed high-fructose diet were associated with impaired abilities to tolerate intraperitoneally infused glucose (Fig. 1, C and D). But in response to a 4-wk treatment with fenofibrate, this impaired glucose tolerance along with elevated plasma insulin levels in high-fructose-fed hamsters were restored to normal. Based on fasting blood glucose and plasma insulin levels, we calculated ISI using a HOMA as described (7). As shown in Fig. 1E, high-fructose-fed hamsters were associated with markedly reduced ISI, which was reversed to normal after 4-wk treatment with fenofibrate. Fibrate treatment also resulted in a small reduction in body weight, but the mean body weight of fibrate-treated hamsters was not significantly different from that of regular chow-fed controls (Fig. 1F).
To determine the effect of high-fructose diet on lipid metabolism, we determined plasma FFA, TG, and total cholesterol levels. High-fructose-fed hamsters are associated with significantly increased plasma FFA (Fig. 2A), TG (Fig. 2B), and cholesterol levels (Fig. 2C), compared with hamsters fed regular chow. However, these aberrations in lipid metabolism were reversed to near-normal levels after 4 wk of treatment with fenofibrate.
Effect of fibrates on lipoprotein metabolism.
To study the effect of fibrates on lipoprotein metabolism, we subjected plasma pooled from hamsters in individual groups to gel filtration chromatography for the fractionation of lipoproteins. In accordance with their elevated plasma TG levels, high-fructose-fed hamsters exhibited significantly increased VLDL-TG levels (Fig. 2D). The fractional concentrations of cholesterol in VLDL and HDL were also markedly increased in response to high-fructose feeding (Fig. 2E). After fenofibrate treatment, these elevated VLDL-TG levels were significantly ameliorated, but not restored to normal (Fig. 2D). However, fenofibrate treatment reversed elevated VLDL- and HDL-cholesterol levels to normal (Fig. 2E).
To gain insight into the molecular basis of fibrate-mediated beneficial effects on VLDL-TG metabolism, we determined the expression levels of apoC-III and MTP, two functions that catalyze the rate-limiting steps in plasma VLDL-TG metabolism (26, 51). Plasma apoC-III levels were determined by both dot blot and Western blot assays. These two approaches consistently show that plasma apoC-III levels were significantly increased in response to high-fructose feeding and were reduced to normal levels after 4-wk fenofibrate treatment (Fig. 2, F and G). Likewise, hepatic MTP production was markedly induced in response to high-fructose feeding, as detected by Western blot analysis (Fig. 2H). Fenofibrate treatment suppressed excessive MTP production to normal levels in high-fructose-fed hamsters.
Hepatic lipid content in high-fructose-fed hamsters in response to fibrate treatment.
To investigate the metabolic consequence associated with high-fructose feeding, liver tissue from euthanized hamsters was histologically examined after staining with Oil Red O. As shown in Fig. 3, A–C, significantly higher levels of lipid droplets were detected in livers of high-fructose-fed hamsters. This observed increase in hepatic lipid deposition was confirmed by the quantification of overall hepatic fat content. Hamsters fed a high-fructose diet exhibited significantly higher levels of intrahepatic TG content (10.7 ± 0.8 vs. 6.3 ± 0.3 mg/g liver tissue in control diet-fed hamsters, P < 0.001 by ANOVA; Fig. 3D). However, in response to fenofibrate treatment, this increased intrahepatic deposition in high-fructose-fed hamsters was reduced to normal, as revealed by both histological examination and quantitative assay of fat content in liver.
To investigate the molecular mechanism underlying increased fat accumulation in livers of high-fructose-fed hamsters, we determined the expression levels of two key transcription factors in hepatic lipid metabolism, SREBP-1c and its coactivator PGC-1β (31). Hepatic expression of both SREBP-1c (Fig. 4A) and PGC-1β (Fig. 4B) was significantly upregulated, coinciding with increased intrahepatic fat infiltration in high-fructose-fed hamsters. After fenofibrate treatment, hepatic SREBP-1c and PGC-1β expression levels were suppressed to normal, correlating with the reversal of hepatic fat content in fenofibrate-treated hamsters (Fig. 3).
Hepatic expression of FoxO1 in hyperlipidemic hamsters in response to fibrate treatment.
To account for the mechanism of fenofibrate-mediated beneficial effect on hepatic TG metabolism, we determined hepatic FoxO1 abundance in high-fructose-fed hamsters treated with fenofibrate. High-fructose feeding resulted in a more than fourfold increase in hepatic FoxO1 protein levels, which were reduced to normal after a 4-wk treatment with fenofibrate (Fig. 4C).
As control, we studied hepatic expression profiles of PPARα, the nuclear receptor of fibrates. As shown in Fig. 4D, hepatic PPARα protein levels remained at basal levels in high-fructose-fed hamsters. However, in response to a 4-wk treatment with fenofibrate, hepatic PPARα protein levels were elevated about twofold, which correlated inversely with hepatic FoxO1 expression in fenofibrate-treated hamsters (Fig. 4C).
Our laboratory has previously shown that hepatic FoxO1 activity becomes deregulated, culminating in increased nuclear localization in livers with impaired insulin action (2, 3). To determine the potential alterations in hepatic FoxO1 subcellular localization, we performed immunohistochemistry on liver tissue of killed hamsters using anti-FoxO1 antibody. Compared with regular chow-fed hamsters (Fig. 5, A–C), FoxO1 was predominantly localized within the nucleus of hepatocytes in high-fructose-fed hamsters (Fig. 5, D–F). This skewed subcellular distribution of FoxO1 was reversed to normal in response to fenofibrate treatment (Fig. 5, G–I).
Functional interplay between FoxO1 and PPARα in hepatic apoC-III expression.
To study whether fenofibrate-mediated upregulation of PPARα expression in liver contributes to the inhibition of hepatic FoxO1 activity, we determined the potential interaction between FoxO1 and PPARα proteins in liver. Liver tissue (20 mg) from fibrate-treated hamsters was homogenized and subjected to immunoprecipitation using rabbit anti-FoxO1 antibody or preimmune serum, followed by immunoblot analysis. As shown in Fig. 6A, we detected PPARα protein in the product that was immunoprecipitated by anti-FoxO1 antibody, implicating a potential interaction between FoxO1 and PPARα proteins in liver.
To corroborate this finding, we determined molecular association between PPARα and FoxO1-Δ256, a truncated version of FoxO1 that consists of its DNA-binding domain (amino acids 156–256) plus additional 155 amino acids at the NH2-terminus of FoxO1 (3). HepG2 cells were transduced by adenoviral vector expressing FoxO1-Δ256 in the presence of PPARα expression. After 48-h incubation, cells were subjected to immunoprecipitation by anti-FoxO1 antibody, followed by immunoblot assay. As shown in Fig. 6B, a specific protein band corresponding to PPARα was coimmunoprecipitated together with FoxO1-Δ256.
To address whether FoxO1-PPARα interaction is enhanced by fenofibrate, HepG2 cells were transfected with FoxO1 and PPARα expressing plasmids. After 24-h incubation to allow FoxO1 and PPARα production, cells were incubated in the presence and absence of 50 mM fenofibrate in culture medium for 16 h, followed by immunoprecipitation using anti-FoxO1 antibody. Using semiquantitative immunoblot assay, we detected similar levels of PPARα protein in the immunoprecipitated complex of fenofibrate- and mock-treated cells (Fig. 6C). These results suggest that fibrates did not significantly enhance FoxO1 and PPARα interaction in HepG2 cells.
To address the functional interplay between FoxO1 and PPARα in VLDL-TG metabolism, we studied the effect of FoxO1 on hepatic apoC-III production in the presence and absence of PPARα production in HepG2 cells using a predefined human APOC3 promoter-directed luciferase reporter system (2). Our laboratory has previously shown that FoxO1 stimulates human apoC-III expression via direct binding to its target site in the APOC3 promoter (2). As shown in Fig. 7A, such an APOC3 promoter-directed luciferase expression system in pHD317 was transfected to HepG2 cells that were pretransfected with vectors expressing FoxO1 or PPARα alone or both in combination. Consistent with our previous observations, FoxO1 markedly stimulated APOC3 promoter activity, as evidenced by significantly increased luciferase activity in response to elevated FoxO1 production in HepG2 cells (Fig. 7, B and C). However, this stimulatory effect of FoxO1 on hepatic apoC-III expression was abolished in the presence of elevated PPARα production (Fig. 7, B and C). These results revealed a novel mechanism by which PPARα counteracts the effect of FoxO1 on hepatic apoC-III expression in modulating plasma VLDL-TG metabolism.
To strengthen the above findings, we performed a similar study using a mutant version of the APOC3 promoter. As a result of mutations in the insulin-responsive element (IRE), this mutant APOC3 promoter no longer responds to FoxO1 (2). We transfected this mutant promoter-directed luciferase expression system into HepG2 cells in the presence of FoxO1 or PPARα expression alone or both in combination. As shown in Fig. 7D, mutations in the IRE abolished FoxO1-mediated stimulation of APOC3 promoter activity and also abrogated PPARα effect on ApoC-III expression in HepG2 cells. Furthermore, elevated PPARα production alone did not result in significant changes in the mutant APOC3 promoter activity.
To address whether PPARα suppresses FoxO1 expression at the transcriptional level, we cloned the 2-kb FoxO1 promoter using FoxO1 promoter-specific primers. After verification by DNA sequencing, the FoxO1 promoter was subcloned into a pGL3-basic luciferase reporter system. This FoxO1 promoter-directed luciferase expression system was transfected into HepG2 cells, together with pPPARα or control pGL3-basic plasmid, followed by analysis of luciferase activity after 24 h of incubation. As shown in Fig. 7E, PPARα production resulted in a slight induction of FoxO1 promoter activity. In addition, we determined endogenous FoxO1 mRNA levels using semiquantitative RT-PCR assay in PPARα expressing and control cells. No significant difference in FoxO1 mRNA levels was detected in HepG2 cells that were transduced with either PPARα or control plasmid (Fig. 7F). These data indicate that PPARα did not directly suppress hepatic FoxO1 expression.
Mechanism of PPARα-mediated antagonism of FoxO1 activity.
To define the mechanism of PPARα-mediated counterregulation of FoxO1 activity, we postulated that PPARα, when associated with FoxO1, interferes with FoxO1 binding to target promoter DNA, resulting in inhibition of gene expression. To test this hypothesis, we determined the molecular interaction between FoxO1 and APOC3 promoter DNA in FoxO1-expressing HepG2 cells in the presence and absence of PPARα production. HepG2 cells were transfected with FoxO1-expressing plasmid alone or in combination with PPARα-expressing plasmid. After 48-h incubation, cells were subjected to ChIP assay. Consistent with previous observations (2), a specific DNA fragment corresponding to the human APOC3 promoter DNA was immunoprecipitated by rabbit anti-FoxO1 antibody in FoxO1-expressing HepG2 cells (Fig. 8A). Using the same assay, we detected a similar APOC3 promoter-specific DNA in HepG2 cells expressing both FoxO1 and PPARα (Fig. 8A). But the relative amount of APOC3 promoter activity in FoxO1- and PPARα-coexpressing cells was more than fivefold lower than in cells expressing FoxO1 alone, as determined by semiquantitative PCR assay (Fig. 8B). As control, no APOC3 promoter-specific DNA was detected when rabbit preimmune IgG was used in the ChIP assay (Fig. 8A). FoxO1 stimulates hepatic apoC-III expression via specific binding to its target site (CCAAACA) in the APOC3 promoter DNA (2). These data suggest that this association between FoxO1 and APOC3 promoter DNA was significantly reduced in response to PPARα production, which correlated with the inhibition of APOC3 promoter activity in PPARα-expressing HepG2 cells (Fig. 7, B and C).
To investigate whether PPARα alone binds to APOC3 promoter DNA, we subjected pPPARα-expressing HepG2 cells to ChIP assay using anti-PPARα antibody, followed by PCR analysis using the same set of APOC3 promoter-specific primers, as described (Fig. 8A). No specific PCR DNA was produced. Although PPARα is known to bind specifically to a highly conserved DNA sequence that comprises 2-hexamer repeats with one nucleotide in between (AGGTCAXAGGTCA) in target promoters (11), sequence analysis did not reveal the presence of such a consensus PPARα binding site within a 5-kb DNA region of the APOC3 promoter (−5,000/+1 nt). These data were consistent with the lack of significant alterations in APOC3 promoter activity in response to PPARα production in HepG2 cells (Fig. 7, B and C), suggesting that PPARα modulates hepatic apoC-III expression by counteracting the stimulatory effect of FoxO1 on APOC3 promoter activity (2).
The goal of this study is to determine the role of FoxO1 in the pathogenesis of hypertriglyceridemia and address whether FoxO1 mediates the beneficial effect of fibrates on VLDL-TG metabolism in high-fructose-fed hamsters. We show that high-fructose feeding resulted in marked elevations in plasma FFA, TG, and total cholesterol levels, accompanied by significantly elevated plasma insulin levels and impaired glucose tolerance. Interestingly, fasting blood glucose levels and body weight remained unchanged in high-fructose-fed hamsters. These data indicate that hamsters fed a high-fructose diet, as opposed to regular chow, developed insulin resistance and hypertriglyceridemia in the absence of fasting hyperglycemia and excessive body weight gain. Thus high-fructose-fed hamsters represent a nonobese model of insulin resistance with altered TG metabolism.
Our present studies indicate that hepatic FoxO1 activity becomes deregulated, culminating in markedly elevated production along with increased nuclear localization in livers of high-fructose-fed hamsters. Similar observations have been made in insulin-resistant livers of high-fat-induced obese mice (unpublished data) and diabetic db/db mice (2, 3). These data unveil an association between hepatic FoxO1 deregulation and impaired hepatic metabolism. Indeed, FoxO1 gain of function, as a result of adenovirus-mediated hepatic FoxO1 production or transgenic expression of its constitutively active allele in liver, is associated with impaired glucose metabolism in mice (40, 46). Conversely, FoxO1 loss of function, caused by hepatic expression of its dominant-negative allele in insulin-resistant liver, is associated with significantly improved fasting glycemia and amelioration of hyperinsulinemia in diabetic db/db mice (3). FoxO1 haplo insufficiency is sufficient to protect mice from developing high-fat-induced insulin resistance (41) and rescue the diabetic phenotype in insulin receptor substrate 2-deficient diabetic mice (43). Furthermore, targeted FoxO1 inhibition by anti-sense approach improved hepatic metabolism and peripheral insulin action in high-fat-diet-induced obesity (47). Although high-fructose feeding is associated with hypertriglyceridemia, the underlying mechanism remains elusive. Our present data suggest that aberrant hepatic FoxO1 function is a contributing factor for metabolic abnormalities in high-fructose-fed hamsters.
Consistent with this interpretation is the revelation that plasma apoC-III levels were significantly elevated, correlating with increased hepatic FoxO1 activity in high-fructose-fed hamsters. We have previously shown that FoxO1 mediates the inhibitory effect of insulin on hepatic apoC-III expression, and FoxO1 deregulation links loss of insulin inhibition to unrestrained apoC-III production, contributing to the pathogenesis of hypertriglyceridemia (2). This predicts that a selective inhibition of FoxO1 activity will suppress apoC-III production in high-fructose-fed hamsters. Indeed, we show that hepatic FoxO1 deregulation was corrected in high-fructose-fed hamsters in response to fenofibrate treatment. This effect parallels the normalization of plasma apoC-III levels and amelioration of hypertriglyceridemia in fenofibrate-treated hamsters. Thus modification of FoxO1 transcriptional activity represents an important mechanism by which fibrates curb apoC-III overproduction and improve TG metabolism in subjects with hypertriglyceridemia.
In addition to FoxO1, we observed that multiple factors, such as PGC-1β and SREBP-1c, contribute to high-fructose-induced hypertriglyceridemia. A coactivator of SREBP-1c, PGC-1β has been shown to bind and augment SREBP-1c transcription activity in stimulating lipogenesis, contributing to elevated hepatic VLDL-TG production and secretion and the development of hyperlipidemia in high-fat-induced obese mice (31). Likewise, we detected a significant increase in hepatic fat content in high-fructose-fed hamsters, which correlated with augmented hepatic PGC-1β and SREBP-1c expression. These observations, along with the induction of hepatic MTP production, help explain previous observations that high-fructose-fed hamsters are associated with inappropriately increased hepatic VLDL-TG production (10). Increased fat infiltration in organs other than adipose tissue, such as liver and skeletal muscle, is closely associated with insulin resistance (9, 17, 29, 48–50, 54). Our present findings provide important insights into the mechanism of fructose-induced insulin resistance, suggesting that an increased intrahepatic lipid deposition plays a causative role in the development of insulin resistance, as reflected in hyperinsulinemia and glucose intolerance in high-fructose-induced hamsters. In keeping with this conclusion, we show that fenofibrate treatment suppressed hepatic PGC-1β and SREBP-1c expression to basal levels, resulting in the normalization of hepatic fat content in high-fructose-fed hamsters. These data suggest that fenofibrate-mediated suppression of PGC-1β and SREBP-1c expression also contributes to the reversal of insulin resistance and amelioration of hypertriglyceridemia in high-fructose-fed hamsters.
Although it is known that hepatic PPARα activity is upregulated by fibrates (8, 13, 21), the molecular link between upregulated PPARα activity and improved TG metabolism remains undefined. We show in high-fructose-fed hamsters that PPARα and FoxO1 are differentially regulated by fibrates. Hepatic PPARα levels were significantly increased, accompanied by a corresponding decrease in hepatic FoxO1 levels in fenofibrate-treated hyperlipidemic hamsters. Although inappropriately increased FoxO1 activity in liver is associated with abnormal hepatic metabolism (1, 34, 46), these observations raise the possibility that fenofibrate-mediated activation of PPARα activity counteracts the effect of FoxO1 on hepatic apoC-III production, contributing to improved VLDL-TG metabolism in high-fructose-fed hamsters. Implicit in this assumption are recent studies by Dowell et al. (20), who showed that PPARγ, another member of the PPAR nuclear receptor subfamily, interacts with FoxO1 and antagonizes its function in kidney epithelial cells. To underpin this hypothesis, we show that PPARα associated with FoxO1 interfered with FoxO1 binding to APOC3 promoter and diminished the ability of FoxO1 to stimulate hepatic apoC-III expression. It follows that PPARα contributes to improved VLDL-TG metabolism in response to fibrate treatment by counterbalancing the effect of FoxO1 on hepatic apoC-III expression. We would like to acknowledge the limitation of coimmunoprecipitation used in our studies, as this assay does not allow the distinction of a direct interaction between FoxO1 and PPARα from indirect association via a third partner. Likewise, FoxO1-Δ256 used in this study contains FoxO1 DNA binding domain (amino acids 156–256) plus 155 amino acid residues of FoxO1 NH2-terminal domain. It remains unknown whether PPARα counteracted FoxO1 via specific interaction with FoxO1 DNA binding domain. Further studies are needed to characterize the underlying mechanism by which PPARα antagonizes FoxO1 function in improving hypertriglyceridemia in animal models with altered TG metabolism.
In addition to its activation of PPARα (21, 32, 37, 38), fenofibrate has been shown to display pleiotropic effects on the expression of genes in lipid metabolism. Fibrates upregulate lipoprotein lipase expression (18, 21). This effect, along with the suppression of apoC-III overproduction, accounts for enhanced clearance of lipoprotein remnants. Furthermore, fibrates are shown to enhance carnitine palmitoyltransferase I expression, accounting for increased fatty acid oxidation in liver and muscle and contributing to improved insulin sensitivity (37).
Increased consumption of fructose, a major ingredient of corn syrup used in soft drinks, is associated with the development of insulin resistance and dyslipidemia, but the underlying mechanism is unknown. Our studies highlight the importance of hepatic FoxO1 deregulation along with augmented PGC-1β production in the pathogenesis of high-fructose-induced insulin resistance and hypertriglyceridemia and, furthermore, elucidate a novel molecular antagonism of PPARα against FoxO1 in mediating the effect of fibrates on the reversal of hypertriglyceridemia. These data provide evidence that selective inhibition of FoxO1 activity in liver can be explored as a distinctive mechanism for better management of hypertriglyceridemia.
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-066301.
We thank Drs. Steve Ringquist, Fiona D'Souza, and Robert O'Doherty for critical proofreading of this manuscript. We also thank Dr. Bruce Spiegelman for providing anti-PGC-1β antibody. This study has been orally presented at the 65th American Diabetes Association Scientific Session (2005), San Diego, CA.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2007 by American Physiological Society


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I've just learned that the nastiest bullies I've yet to meet in Social Media Land, the first two people I was forced to block on Facebook, are being publicly shamed for screwing their employees out of thousands of dollars. The irony of this is nothing short of astounding, because these self-righteous social justice warriors have been branding themselves as paragons of left-wing virtue for the last decade. If you live in progressive Montreal, this is every bit as riveting as that moment in 2006 when the anti-gay pastor of a megachurch was caught smoking crystal meth with a gay prostitute. I must confess that I'm finding it a little bit hard to resist the schadenfreude, because these bullies have delighted in publicly humiliating people for years. A woman I know from our reading group had a full-on breakdown after a particularly nasty Social Media Land pile-on which was orchestrated from start to finish by these two individuals. She was hospitalized a day later. Spent a few weeks in the Douglas. The damage that these two trolls have done is remarkable. But it looks like they're getting a taste of their own medicine.
—John Faithful Hamer, The Myth of the Fuckbuddy (2017)


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- 62 years old
- Date of birth: Feb 1, 1947
- Date of passing: Nov 21, 2009
|Let the memory of Mary Margaret be with us forever
"Mary it's been since 2009 since you left us. Miss you as much today as I did the day you left us 11-21-2009. You are at Peaxe now, no more pain.
Love you my friend, remember when we first met, at BHS."
"Mary, well it's been six years since you passed. Today you would be 70. You are missed everyday my friend."
"Wel Mary it's been 6 years since you left us. I miss you dearly. I think of you often. Love susie"
"Wel Mary it's been 6 years since you left us. I miss you dearly. I think of you often. Love susie"
"Happy birthday Mary, my dear friend. Missing you."
"Well yesterday was your birthday. I miss you my friend. Always"
"Mary you are missed more & more each day. Love you Susie"
"Well today is your birthday. Happy Birthday my friend, you are missed more and more everyday. I pray you are at peace and resting. love you Mary. Always Susie"
"It's been two years since your passing I miss you as much today as I did two years ago. Mary my friend Wilma is coming home to be with our Lord. If you see her tell her hello from me. She is a kind person just like you, I know you'll become good friends. All my Love Susie"
"Mary was the best friend I ever had. She is missed more than words can explain. Mary was a kind loving person. I met Mary when we were in the 7th grade and remained friends with her until her untimely death. RIP my fiend."
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Miraculum | 2014
The destinies of several people intersect as they prepare to board a plane bound for Cuba.
Jump to
Item 7
The destinies of several people intertwine: A nurse who is a devoted Jehovah's Witness, begins to doubt the existence of God when her companion's health deteriorates and she grows fond of a plane crash survivor. A man and woman in their sixties, he a bartender and she a parking attendant, decide to fulfill their passionate love. A conservative couple drowns their disappointments about life in alcohol and gambling. And finally, a man who is returning from exile tries to make amends for an irredeemable action, and brings us to a plane bound for Cuba. They are each waiting for a miracle and are forced to make decisions that will inevitably affect their lives.


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Burnt Mills Washout April 2014
On Wednesday, April 30, 2014, 4-5 inches of rain fell on the Northwest Branch watershed. At Burnt Mills, where Colesville Road crosses the Northwest Branch, considerable damage was done due to flooding.
The brown strip is the result of flooding.
Water sat for an extended period quite far into the grassy area.
Photo by Dave Kerst
Upstream side of the Colesville Road bridge
Photo by Dave Kerst
Downstream side of the Colesville Road bridge - the river is 50 feet to the left. The river flowed over a parking lot and dumped into the grassy area.
Photo by Dave Kerst


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Early years
Griggs was born Elbert Sutton Griggs (he later changed the order of his given names) in 1872 in Chatfield, Texas, to the Rev. Allen R. and Emma Hodge Griggs.[1] His father, a former Georgia slave, became a prominent Baptist minister and founder of the first black newspaper and high school in Texas. Sutton worked closely with his father on the National Baptist Convention's Education Committee. He wrote frequently later in life of his deep respect for his parents' characters and accomplishments.[2]
Sutton Griggs attended Bishop College in Marshall, Texas and Richmond Theological Seminary. Upon graduation, he became pastor of the First Baptist Church in Berkley, Virginia. There he married Emma Williams, a teacher, in 1897. In 1899, he became pastor of Tabernacle Baptist Church in East Nashville and corresponding secretary of the National Baptist Convention.
Griggs was a prolific author, writing more than thirty books and pamphlets in his lifetime and selling them door-to-door or at the revival meetings at which he preached. His first novel, Imperium in Imperio, published in 1899, is his most famous. In 1901, Griggs founded the Orion Publishing Company to sell books to the African American market. None of his four subsequent novels achieved the success of Imperium in Imperio, but he produced a steady stream of social and religious tracts, as well as an autobiography.
An admirer of W. E. B. Du Bois and a supporter of the Niagara Movement and the National Association for the Advancement of Colored People, Griggs was strongly influenced by contemporary social theory. He believed that the practice of social virtues alone could advance a culture and lead to economic success.[3] The more radical ideas expressed in his novels, particularly Imperium in Imperio, have led him to be sometimes characterized as a militant separatist in the mold of Marcus Garvey. During his lifetime, however, his integrationist philosophy and courting of white philanthropy earned him the scorn of self-help advocates.[4]
Griggs's careers in both the church and social welfare sphere were active and itinerant. In Houston, he helped establish the National Civil and Religious Institute. In 1914, he founded the National Public Welfare League. From 1925 to 1926, he served as president of the American Baptist Theological Seminary, which his father helped found. His longest tenure—19 years as pastor of Tabernacle Baptist Church in Memphis—saw him act on his belief in the social mission of churches, providing the only swimming pool and gymnasium then available to African Americans in the city.
Death and legacy
The Wall Street Crash of 1929 stripped the Tabernacle of investment funds and led to its bankruptcy. Griggs returned to Hopewell Baptist Church in Denison, Texas, then to a brief pastorship in Houston. Shortly after resigning that post in 1933, he died in Houston, and was buried in Dallas.[1]


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With First Tutors: Music you can search for a Wellington tin whistle tutor. Tin Whistle lessons are a brilliant method to start a fun new hobby, pick up a new skill and attain confidence in tin whistle. Try our site to find Wellington tin whistle teachers and select which best matches your requirements so you can enjoy your tin whistle tuition in Wellington straight away!
First Tutors: Music is the fastest way to discover Wellington tin whistle tutors in the UK, helping you find Wellington tin whistle tuition in your area and Wellington tutors to assist with any instrument, for example, piano, violin or guitar. We can help you find Wellington tin whistle tuition or a Wellington tin whistle tutor to prepare for tin whistle grades and improve your tin whistle skills! We order Wellington tin whistle teachers in your area according to their tuition prices and distance from you.
If you are a tin whistle teacher and would like to offer your tin whistle tuition services in Wellington or throughout the UK, please register with First Tutors: Music or find out more about us here. Becoming a Wellington tin whistle teacher is a wonderful way to improve your own knowledge by giving tin whistle tuition while helping others, all in your local Wellington area!


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I took a couple of these just for fun (C;mon, who hasn't?) and this one turned out to really capture a feeling of immediacy or 'presence', I thought. I gave it more of a film feel to capitalize on that impression! And I left all that dirt on the mirror, because those dusty roads are an essential part of the journey, wouldn't you say?
Canon 50D
Canon 50mm f/2.8 "Nifty Fifty"


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Loons and Logs Day
Saturday, July 16th
With activities for everyone in the family, all are welcome to discover the natural and cultural history of the Adirondacks through hands-on, nature-based programming and events.
10:00 am Northern Forest Nature Walk
Learn about the history of logging on the Huntington Wildlife Forest as we visit the site of an old log boom. We will learn what types of trees that were harvested in the area and the fate of these logs as they traveled from Rich Lake, down the Hudson River, to the paper mills below.
2:00 pm Artist in Residence Sculpting Demonstration
George Bumann, our 2016 Artist in Residence, will create a sculpture of the bird of the day - the common loon. You'll be able to watch George work and learn about loon biology as he creates this piece of art
3:00 pm 5th Annual Rubber Loon Race
Release the Loons! The only race of its kind, our custom designed and made in America loons tumble into Rich Lake outlet and race 400 yards to the finish line. Prizes donated from local businesses will be awarded to the first four loon s across the line.
2016 Grand Prize Packages
The Artist Package
- An afternoon of instruction with local artist Frances Gaffney, a set of compact watercolors and other equipment to get you started on a new hobby.
The Heart of the Park Package
- Overnight accommodations at the Hoot Owl Lodge, a guided bike or boat trip from Cloud Splitter Outfitters, a round of golf at High Peaks Golf Course, and a gift Certificate from Scoop's Great Ice Cream and more.
The Loony Package
- A pair of Eagle Optic binoculars, a guided kayak trip on a private lake to observe loons (and maybe chicks!), a loon book and print.
The Fishing Package
- Fly rod, fly box with assorted flies and instruction with Professional Fly Fishing Guide Rick Kovacs
Sponsoring a Loon in the Race
Sponsor a loon and you can be a winner! As you watch the front runners swim through the finish line, have your fingers crossed that it's your sponsored loon. Sponsors of the top loon finishers win one of the prize packages listed on the right. Prizes are generously donated by local businesses.
You can also purchase your very own loon! By doing so you are not only bringing home a piece of the Adirondacks, but you are also supporting the one-of-a-kind programming offered here at the AIC!
All funds raised through the sponsoring and purchasing of our rubber loons directly support the unique, exciting and place-based public programming we offer at the AIC.


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A major benefit of masturbation is having the opportunity to explore your own body for ways to enhance your own–and your partner's–pleasure during sex. You can learn a lot from trying new things on yourself, and knowing the location of your erogenous zones gives you a road map for doing just that.
Your Erogenous Zones
The word "erogenous" comes from the Greek "eros," which means "love," and the English "genous," which means "producing." Your erogenous zones are areas of you body that have heightened sensitivity and responds sexually when touched at the right time by the right person. The most common erogenous zones on men are the neck, lips, ears, nipples, scrotum, perineum, and, of course, the almighty penis. Lesser-known erogenous zones include the eyelids, the feet and ankles, and the area just below your belly button.
But not everyone responds the same to these erogenous zones. Some people may not respond at all when they're touched, while others may knock your socks off and contribute to an explosive orgasm when they're properly manhandled during the deed. It just depends on the individual, which is why experimenting on your own can help open doors to better sex during the real deal. Here, then, are four ways to experience sexual pleasure in exciting new places.
1. Stimulate your nipples.
Try experimenting with nipple stimulation when you masturbate. Try lightly touching or flicking them, and try squeezing or rolling them. Notice when the stimulation feels the best, such as just before or during orgasm. If you end up getting a shock of pleasure from nipple action during sex, adult novelty stores stock all sorts of clamps, pumps and vibrating pads to elicit the response you're looking for.
2. Press your perineum.
The perineum is the area between your anus and scrotum, and it's a hotbed of sexual pleasure if you're willing to experiment. This particular spot is rife with perineal nerves whose job is to convey sexually pleasurable sensations from the genitals to the brain. Try stroking or pressing on your perineum as you masturbate, and increase the pressure just before and during orgasm. But be warned: Once you experience the jolting pleasure, you may never be able to go back to plain old sex.
3. Squeeze your scrotum.
The pouch containing your testicles is rife with nerve endings that make it a powerful erogenous zone. You never know what kind of touch will do it for you, so experiment with different sensations, such as squeezing, stroking, or even touching it lightly with ice. If your playtime elicits shocking results, you can buy a vibrating ball pouch to free up your hand for other kinds of exploration.
4. Map Your Body
Body mapping is a technique of self-exploration that you can use during masturbation to find other erogenous zones, including some you may not have known you have. Lightly touch all of the areas of your body, and when you feel a sexual response, experiment with different pressures and speeds to come up with the perfect cocktail of pleasure.Back


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Lloyd's Glass
ReScore Reviews™ (2)
96% Would Recommend
Latest Review 18 days ago
Review for Lloyd's Glass
Beth H. on 08/15/2012
My only suggestion would be that the technician's do a better job cleaing the outside of the windshield when they're done. I had to drive home in the rain that afternoon and there was some kind of film on the glass and so when the wipers hit them, it didn't really push the rain away like normal and I couldn't see a thing. It was kind of scary.
Category: Glass
Service Date: 07/23/2012
Review Created: 08/15/2012


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ImagesClick to Enlarge
Additional Information
Rated 5 out of 5 by Gmaz from Great product!! I've had several types of id tags for my pets, but without doubt, THIS tag surpasses them! The engraving on the tag is easily legible, and it's obviously a quality tag. The BEST feature, in my opinion, is the way it slips on the collar and stays there. No more tag hanging down for my dog to try an pull off, chew, or lose!!! I plan on replacing my other dogs' id tags with this one!! I highly recommend this product, paws down!!
Date published: 2017-04-10
Rated 4 out of 5 by Patti from These tags stay on! Although the tags I bought for my dogs don't seem to lay flat on their collars (they stand up), it's fine. They stay on. My dogs wrestle with each other all day long and we are constantly losing dog tags in the grass or wherever?!? These tags have survived at least 3 months so far, so I am grateful.
Date published: 2017-05-12
Rated 3 out of 5 by Joski from Dog tags Great looking tags that fit very nicely on the collar. The rubber could be stronger as one side broke when cought on a branch while running on a path in the woods. I bought two. The second collar is holding up nicely
Date published: 2017-05-27
Rated 5 out of 5 by Monica from Great dog tag! I bought 3 of these tags for our 3 dogs. Even though they are all microchipped, this is a little added assurance in case one of them gets lost.
Date published: 2017-04-23
Rated 5 out of 5 by Linda from Great product! My order was delivered quickly and looks great. Its wonderful. Not hearing the tags rattle.
Date published: 2017-03-01
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Dog IDmeBAND is rated out of 5 by 5.
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When will these be available again?
We do not expect to have the Dog IDmeBAND back in stock any time in the near future. Our apologies for any inconvenience. Thank you!
Date published: 2017-11-13
Does this fit on collars with the plastic clip closure?
Thank you for your question. The loops on either end of our Dog IDmeBAND are flexible silicone, which allows you to slide it onto on almost any 1" wide collar, including those with the plastic clip closure.
Date published: 2017-04-20
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Pearson's Mint Patties
|The Original Mint Patties from Pearson's. Made only with the finest ingredients, including real oil-of-peppermint, Pearson's Mint Patties contain real dark chocolate with 66% cacao. Packaged in a 240 count jar or a 25lb bulk case. Approximately 50 pieces per pound in the bulk case. Gluten Free.
There have been no reviews


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Title: All Time Low's Autograph Signing Session this Wednesday
Written by Kevin Pableo
Hey Hustlers! Get ready! IT'S ON! All Time Low will be having an autograph signing session this Wednesday at The Block Atrium in SM North Edsa. All you have to do is to buy All Time Low's "Dirty Work" album CD + DVD which will be released by MCA Music this Sept. 21. You must buy the album at the venue and have your CD signed by the band! The event will start by 6pm. Visit www.facebook.com/astroplus1 for more details. Don't miss it! See you all there!
This autograph signing session is brought to you by Ovation Productions, Dayly Entertainment, Astroplus and SM North Edsa The Block.
For tickets, call Ticketnet: 911-5555 or visit www.ticektnet.com.ph
This concert was brought to us by Ovation Productions and Dayly Entertainment.
Sunday, September 18, 2011
All Time Low's Autograph Signing Session this Wednesday.
Posted by Manila Concerts at 11:04 PM
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William Hurt
News about William Hurt, including commentary and archival articles published in The New York Times.
Review: In 'Goliath,' Billy Bob Thornton Plays a Down-and-Out David
In this new legal series for Amazon by David E. Kelley and Jonathan Shapiro, Mr. Thornton portrays a seedy lawyer up against his old firm.
October 13, 2016, Thursday
MORE ON WILLIAM HURT AND: Web-Original Programming , Television , Thornton, Billy Bob , Kelley, David E , Goliath (TV Program) , Shapiro, Jonathan (Television Producer) , Arianda, Nina , Hurt, William (1950- )
Review: 'Humans' Contemplates When Robots Are Routine Accessories
This AMC premiere asks what happens to the role of humans if robots live alongside them?
June 26, 2015, Friday
MORE ON WILLIAM HURT AND: Television , Hurt, William , Humans (TV Program) , AMC (TV Network) , Chan, Gemma (1982- )
A Chekhovian Bird of a Different Feather
Christian Camargo's "Days and Nights" is a modern reworking of Chekhov's "The Seagull."
September 25, 2014, Thursday
MORE ON WILLIAM HURT AND: Movies , Camargo, Christian , Janney, Allison , Hurt, William , Jones, Cherry , Rylance, Mark , Holmes, Katie , Days and Nights (Movie)
Fatal Film Accident Prompts Wrongful Death Suit
Sarah Jones, a camera assistant, was killed by a train on a movie set in February while working on a Gregg Allman biographical film in Georgia.
May 22, 2014, Thursday
MORE ON WILLIAM HURT AND: Jones, Sarah Elizabeth (1986-2014) , Georgia , Movies , Suits and Litigation (Civil) , Railroad Accidents and Safety , Occupational Safety and Health Administration , Open Road Films , National Transportation Safety Board , CSX Corporation , Miller, Randall M (1962- ) , Hurt, William
The Space Shuttle That Fell to Earth
William Hurt stars as the physicist Richard Feynman in "The Challenger Disaster," the Science Channel movie about the 1986 crash.
November 16, 2013, Saturday
MORE ON WILLIAM HURT AND: Challenger (Space Shuttle) , Hurt, William , Science Channel , Television
A New Romeo for Classic Stage Company Production
Julian Cihi, a recent New York University graduate, will star opposite Elizabeth Olsen in "Romeo and Juliet" Off Broadway.
September 4, 2013, Wednesday
MORE ON WILLIAM HURT AND: Alagic, Tea , Hurt, William , Shakespeare, William , Wittrock, Finn , Classic Stage Company , New York University , Theater
In Search of Her Romeo, This Juliet Gains a Friar Laurence
Finn Wittrock has dropped out of the Classic Stage Company's "Romeo and Juliet," and William Hurt has signed on as Friar Laurence.
July 31, 2013, Wednesday
MORE ON WILLIAM HURT AND: Classic Stage Company , Shakespeare, William , Wittrock, Finn , Romeo and Juliet (Play) , Hurt, William , Theater
Age, They Hope, Won't Wither Them ... Quite Yet
"Late Bloomers," starring William Hurt and Isabella Rossellini, is a romantic comedy about a married couple dealing with the indignities of aging.
April 12, 2012, Thursday
MORE ON WILLIAM HURT AND: Movies , Hurt, William , Rossellini, Isabella , Gavras, Julie , Late Bloomers (Movie)
This Sunday: Actors Turn Villainous
A history of the Great Performers portfolio.
December 9, 2011, Friday
MORE ON WILLIAM HURT AND: McGinley, Ryan , Hurt, William , Franco, James , Paltrow, Jake , News , Sundsbo, Solve , Theron, Charlize , Winslet, Kate
Ahab Has a Wife and a Heart. Oh, and a Whale.
Encore's two-night mini-series "Moby Dick" takes liberties with the novel, including a family back story for Captain Ahab.
August 1, 2011, Monday
MORE ON WILLIAM HURT AND: Television , Melville, Herman , Hurt, William , Anderson, Gillian , Hawke, Ethan , Sutherland, Donald
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Mussee Kata Boutique's Website Makes Phuket Reservations Quicker and Easier
Booking rooms online at Mussee Kata Boutique in Phuket is now easier with the hotel website's direct booking feature.
Tourists and travelers need not phone customer service or visit a travel agency to book accommodations at this boutique hotel in Phuket. By following just a few easy steps, they can secure rooms in just minutes. The reservation system, powered by DirectWithHotels, features a currency converter, and convenient bookmarking and printing buttons for easier reference as guests sort options.
To begin the direct reservation, guests must log on to http://musseekataboutique.com/
This loads the page where potential guests will be shown the Phuket accommodation types available for their stay. They choose by clicking the number of rooms they need in their preferred design. This page also shows the room rates, current promos, and in-room inclusions. Go to the final step by clicking "Reserve Now."
Prospective visitors will then be asked to provide personal information and credit card details, so they can submit the 10% prepayment. They then complete the process by clicking "Confirm Reservation."
The prepayment serves as a deposit to secure the reservation. The remaining balance is settled directly at Mussee Kata Boutique upon guests' arrival or checkout. The booking system will automatically give instant confirmation via email to report that the payment has been received and the rooms have been booked.
All transactions made using the website and booking system are safe, private, and monitored by trusted Internet security systems Trustwave and VeriSign.
Phuket's Mussee Kata Boutique offers guests a rewarding and comfortable holiday through lavishly appointed accommodations and superb guest services. Guests will also enjoy the swimming pool with jacuzzi, free Wi-Fi in public areas, the 24-hour guest service center, tour desk, motorbike and car rentals, and an overall laid-back lifestyle in one of the world's most illustrious beach destinations.
This boutique hotel in Phuket's location further gives an opportunity to savor the beaches of Kata and Chalong, plus the nightlife through the many bars found in Kata Plaza.
For more information about the wonderful Phuket accommodation at Mussee Kata Boutique, visit its website at http://musseekataboutique.com/
Mussee Kata Boutique
100/81 Kata Night Plaza, Kata Rd, Muang
Phuket 83100
Phone Numbers: (66) 76 330118
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Premature babies left unattended
AT LEAST 53 premature babies were left unattended in some Gauteng hospitals during the public sector strike on Monday, Premier Nomvula Mokonyane told the legislature yesterday.
"When I visited some of the hospitals that were severely affected by the strike, I was told shocking stories of 53 premature babies who were left unattended when striking workers forced nursing staff to leave their posts," she said.
"Some of the babies were literally locked in the wards with no one bothering to make alternative arrangements for their care."
Mokonyane said while she understood that workers had a right to strike, it was wrong of them to disrespect the rights of babies.
"We all respect the right of workers to strike, but they must also respect the Constitutional right of these babies to live," she said.
Mokonyane said the government was grateful and thankful for the support it received.
"Government is very heartened by the volunteers, including professionals who selflessly offered their services to care for those in need when the striking government workers abandoned their posts.
"From the bottom of our hearts we say thank you for what you are doing to help us through this difficult period."


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Strong Black Woman Trailer (2013)
"Life is a series of moments" 28 November 2013 Drama
Veronica, a 27-year-old black woman, runs her house very well. Veronica has a college degree in corporate law and works for a popular firm. Darnell is a freelance photographer. A series of moments changes the course of the marriage. Veronica has choices to make as she decides whether she wants to continue on the path she's on in her marriage or learn to become a stronger woman.
Watch the official Strong Black Woman 2013 trailer in HD below or find more Strong Black Woman videos on Vidimovie.


text: Greetings I am trying to make the move the Etch. Before I can make the move I need to insure I can get on the internet. (Much of my college work is on the internet.) I am attempting to connect to my ISP with wvdial. The instructions I found states that I should run wvdialconf command. I did. It sets a few settings for you. The instructions state that I should now change the phone number in the wvdial.conf file to the appropriate settings. I did that. I then ran the wvdial command per instructions and the dude takes off and dial out and appears to establish a connection. I try to ping my college's server and nothing. I tried to view a web page with a browser and nothing. (I did all the above as root.) The ifconfig seems to show that I am connected. Running the route command shows that there is an entry for ppp0. Now am I missing something? No messing around with the resolve.conf file of hosts file? Is there a default route that I am missing that needs to be changed? Connecting to the internet is now the only barrier that keeps me from making the move to Etch, and removing the SuSE 10.3 (which has a slew of odd problems) from my system. Any information will be helpful. Best Regards Walt L. Williams I have a 1.2 GHZ AMD Athlon, with an external USR V-Everything modem.


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Ponders End is a mid-sized commercial and large residential district in northern London. It's a gorgeous town, filled with marshes and several operating railway stations.
It's home to Wright's Flour Mill, the oldest working industrial building in the London Borough of Enfield. It was built in 1789, though there has always been a mill in its location since the 16th century. The miller's house next to the mill dates back to the 19th century and is as beautiful today as it was when it was first constructed.
Ponders End has always been a commercialized town; some of the first businesses include a dyeing and finishing plant, which opened in 1807. To the south of the town was a factory for making white lead, built in 1893. Even further south was a floor-cloth and carpet producing factory. By 1906, over 2,000 people were employed in factories within Ponders End.
The Overflow Channel, about 3.2 kilometres long, runs through Ponders End and merges with the River Lee Diversion. Parallel to this is the River Lee Navigation, which attracts many anglers each year and supports the existence of the River Lea Anglers Club.
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Mears Michigan Vacation Rentals
Search 2 Mears vacation ski cabins & condo rentals.
Michigan Areas
Lower Peninsula Cities
Country Setting - Yet conveniently located near Silver Lake Sand Dunes, Perfect for Dune buggies, less than 2 mi. to Silver Lake Sand Dune Entrance, 2 Miles to Lake Michigan Beach, affordable and very accommodating, inquire. Spacious yard and fully remodeled home - 4 bedrooms, 2 baths MAIN FLOOR has living room, kitchen, snack bar, dining area. Dining area has a sliding glass door that opens to a large deck with furniture, table and steps to back yard. Main floor also has one full bathroom with tub/shower, 3 bedrooms; one with queen bed, one with a queen bed and a bunk bed set, one with full size bed. LOWER LEVEL has one extra large bedroom with queen bed and 2 twin beds, one full bath, tv area, pool table, ping pong table, and play station. French doors open to large screened in porch with lots of funiture and even TV and Satellite with a movie channel. This 12 x 24 screened porch also has an outside door leading to outdoor patio and picnic table, large back yard with fire pit. Solar Tiki torches and
- type: Home
- beds: 4
- baths: 2
- maximum capacity: 16
Mears Vacation Rentals
Mears Michigan
Mears Michigan
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THERE was one line from Wade Graham in the wake of last night's win that represents everything you have to admire about this Cronulla team.
The Sharks' stand-in skipper was sitting in their post-match media conference, wearing the new sponsor's cap (PainAway, of all things) and thinking over the question just put to him.
Shane Flanagan had just spoken of Andrew Fifita's phenomenal effort.
How Fifita carried the ball 216m coming off the bench with Origin in the back of his mind.
Flanagan said Fifita's performance was "typical" of what the hard-working prop had produced lately.
Then Graham was asked if the against-the-odds win was typical of what this Cronulla team was about?
"At the end of the day," Graham said, "I'd back our team in a dogfight against anyone."
On a wet and miserable Monday night, the Sharks dragged the competition leaders into a dogfight and ate them cold. The final scoreline was 14-12 - but don't be fooled.
Remember, no Paul Gallen, no Luke Lewis, no Michael Gordon. But so many defining moments.
In the eighth minute the Rabbitohs were marching upfield on the back of a penalty when four Cronulla players dragged Dylan Walker 10m sideways and into touch on the first run of the new set.In that moment Beau Ryan, Todd Carney, Jayson Bukuya and Ben Pomeroy came together as one and set a benchmark for the night.
Soon after it was Sam Tagataese's turn when he launched himself at Luke Burgess like a missile to stop a try.
Again, it spoke of the Sharks' commitment to the challenge - and each other.
And the way Fifita aimed up was truly inspirational, one of the great front-row efforts in recent years.
Coming off the bench, he ran for 117m in the first half.
By fulltime his figures were up to 216m from 24 runs and throw in 42 tackles.
All over the park his teammates lifted with him.
Chris Heighington's tackle on Ben Lowe midway through the second half was a ripper.
On the next play George Burgess knocked on. And there were so many of those type of moments last night.
You go back to when the Sharks previously played the Bunnies in round two and their entire world was imploding.
At the time Flanagan had been stood down and four of his support staff sacked.
They lost to the Bunnies 14-12 that night - last night it was the same scoreline in reverse.
But the turning point in their season came after their last loss to the Bulldogs in Gosford.
That was the afternoon Flanagan drew a line in the sand and said there would be no more talk about ASADA and no more excuses.
The next week they beat the Knights in Newcastle after Gallen left the field following his first run with the knee injury that has kept him sidelined since.
The Sharks backed up the next week by beating the Tigers, then the Raiders, then the Rabbitohs last night to claim back a place in the top eight.
Incredibly, Cronulla have now won their past six games at home after starting as outsiders.
Originally published as Sharks triumph in a dogfight


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It's rumored that Chrysler will offer an air suspension for its Ram Heavy Duty pickups. An air suspension features sturdy airbags that replace or supplement the conventional springs and shocks of a truck. In addition, its on-board air compressors change the pressure inside the air springs to correspond to the truck's load.
A lot of attention was given to the Ram Long-Hauler pickup concept because of its extra-long wheelbase and expanded driving range. It could handle big loads with the help of an air suspension at all four corners. In the Long-Hauler, a Kelderman Air Ride setup with a load-sensing system that can self-level the truck had replaced the rear leaf springs.
It also featured a kneeling system that could bring the ride height down to get easier access to the truck and for the purpose of backing up to a trailer. There are two main advantages that air suspensions have over conventional suspensions. These are the improved ride quality and the load-carrying characteristics.
When pickups were still new, the problem affecting heavy-duty trucks was primarily the poor ride quality due to leaf springs. Leaf springs are created by stacking several bands of metal on top of each other so that the loads that are placed on the back of the truck could be managed.
However, this construction leads to a significant level of friction between the springs that is released as the rear flexes. Because of the release of friction, the truck's ride quality becomes poor, more so when the truck isn't carrying passengers or load. As the consumers add more weight, the leaf springs settle down too.
Ram's latest pickups offer improved ride quality by removing leaf springs totally for the coil spring suspension in the 2009-12 Ram 1500 half-ton. On the other hand, Ram added hydraulic body mounts under the cab that work as secondary shock absorbers to keep the truck steady, similar to the case of the 2010-12 Ram 2500 and 3500 HD pickups.


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CSR - a triple whammy!
Thursday November 12, 2015
Caroline White, UX Designer for Purple Cubed, discusses how CSR boosts the 'triple bottom line' - people, planet, profit.
Everyone seems to be at it these days. From McDonald's sponsored initiatives like Capital Clean-up, to CSR meet up groups, to organisations like Thrive who use gardening to change lives – corporate volunteering and CSR has never been so big. I even have a friend who works for Elsevier who offer employees two paid days per year to volunteer for charity.
In our last blog on CSR we pointed out the following benefits:
- Promotes inclusivity and variation in the workplace
- Gives employees ad-hoc development and allows them to learn new skills
- Gives people a sense of belonging and greater good and a deeper affiliation for the organisation
These are great and have proven to send employee engagement levels soaring, though how does this affect the bottom line?
According to Forbes 'your willingness to buy, recommend, work for, and invest in a company is driven 60% by your perceptions of the company—or its reputation, and only 40% by your perceptions of the products or services it sells'. The Reputation Institute report yearly on US companies with the best CSR and it is no coincidence that the top three for 2015 are industry leaders - Amazon, Lego and Levi Strauss. People trust that these companies will look after them and also the environment within which they operate, encouraging investment. As an example, Reuters report that Amazon has recorded record sales this year with total net sales rising 23.2% to $25.36 billion. Some of their projects include making sure products have less packaging and that it is all 100% recyclable, to supporting other organisations with cash and product donations.
CSR is a no brainer. Who can argue with something that hits the triple bottom line, increases employee engagement, boosts profits and actually does some good for the world too? What CSR initiatives are there in your company?


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These items are not for sale and the descriptions, images and prices are for reference purposes only.
You can reduce the number of items displayed by entering a keyword that must be included in the description of the item.
A vintage chromed steel Mickey Mouse car mascot, painted and engraved detail. Height 15 cm
Three Disney figurines Pinocchio, Jiminy Cricket & Timothy mouse, 13.5 cm high (tallest)
Mickey Mouse, Rheinische Gummi Und Celluloid Fabrik Co. Brand, German celluloid, wind-up toy in good condition although right arm attachment is precarious, rare model with five fingers, c. 1930. Height 15 cm. Provenance: Bryan Jackson collection of music b
A Mickey Mouse and Walt Disney porcelain panel topped box. 17 x 13 cm
Movies: Signed photographs of Walt Disney & Sonja Henie; plus 1934-38 postcards (37) from Hollywood studios, many with facsimile autographs.
A collection of sterling silver Charms including Mickey Mouse, London Bus, tiger, boat
Salco 'Mickey and Minnie on the River' no. 85/10 English, circa late 1940's, green painted lead boat with wheels, Mickey and Minnie Mouse figures, two oars and two seats, in illustrated card box, minor paint loss (VG box F)
1932 'Mickey Mouse' by Walt Disney, Book No.1 published by John Sands Ltd [Sydney]
Dean's Rag book Walt Disney Mickey Mouse, 1930s, Reg. On neck 750611, celluloid Goo-Goo eyes, Hands replaced, Repairs, A/F
Two Mickey and Minnie's barrel-Organs, including one blue missing Mickey and one red, and one Crouching Mickey figure (G-VG boxes P-F) (2)
A large Pelham puppet shop display Pinocchio, probably 1960s, An original string puppet made with handpainted moulded composite materials and timber, with felt and cotton clothing, strings to hands, feet and head and attached to a later display stand; bear
Donald duck ceramic figure
Two Gaf Talking View Masters complete with Talking View master Reels, including Superman, Mickey Mouse, Donald duck and Scooby Doo and an Incomplete Bugs Bunny, untested
Disney Modern Ceramic Products, Lulubelle figure, 18.5 cm tall. Unmarked
Ten vintage Walt Disney Uncle Scrooge comics, including Golden Key and Whitman, #187; #188; #191; #195; #163; #171; #170; #165; and others (A L Ot)
Ten vintage Walt Disney Uncle Scrooge comics, including #167; #169; #165; #164 and more (10)
Circa 1950s Mickey & Minnie Mouse Pillow. Wearing jumpsuits & with various toys; frilled edging. Length 38 cm
Mickey Mouse collection: group including toys, figurines, games, brooches, jugs etc. Well worth inspection. 50+ items
Walt Disney toys: 'Mickey's Tractor' & 'Donald Duck & Pluto's Car'. Vintage toys made by Sun Rubber Company, circa 1930's and 40's. Length 12 - 15 cm. (2)
A 14ct gold Pisces charm and Mickey Mouse charm, an another. (3) Weight 2.3g. (incl ref 242, 248)
Tinplate Louis Marx Mickey Mouse & Donald duck hand car with key, mechanism functional When Tested (G-VG box F)
Knickerbocker Toy Co, New York for Disney, Snow white, all composition painted features, original dress 38 cm
Sheet Music: 'Nut-Cracker Suite', illustrated by Ida Rentoul Outhwaite; assorted childrens themes including 'Fairies' (5); Walt Disney (7) featuring nice Mickey Mouse examples 'Mickey Mouse's Birthday Party', and 'Mickey Mouse Silly Symphony' (2). G/VG con
Collection of dolls, including Pedigree doll; Lehmann Tom Monkey; Marina composition Curios Piggy Bank x 2; celluloid faces; Japanese celluloid character dolls, including Mickey Mouse; box of parts and whole miniature bisque figures; Soviet Matroshka dolls
Collection of ephemera, including a rare Wilton Products ash tray/bottle opener with aligator, vintage Mickey Mouse pen holder and Goebel queen of hearts, unboxed (G-E) (4)
Walt Disney lady and the Tramp porcelian plate along with a Wedgwood vase (2)
Pelham puppet electronic theatre, including Mickey Mouse, Minnie Mouse, Goofy, Pluto and Donald Duck, made in England and used for shop display, modified U.S plug, untested (G-VG)
Two Mickey Mouse toy lantern Outfits, one with complete set of slides, the other with boxed sets of slides, A/F (G-VG boxes F-VG) (2)
Mickey Mouse: Mickey Mouse novelty jug & 'Mickey Mouse Treasure Chest' money box. Fair/Good condition. (2 items)
Walt Disney: Bayard alarm clocks, made in France, including Mickey Mouse, Pinocchio, Bambi & Snow White. Fair/Good condition. (4 items)
Radios: Astor 'Mickey Mouse' bakelite radio, version with Mickey Mouse transfer on reverse (made in Australia 1937-40, reportedly under agreement with Walt Disney; later this was challenged and Mickey was removed from the colourful reverse-painted glass di
Pair of Mickey and Minnie Mouse cloth bodied toys, circa 1930's
Linemar clockwork tinplate Disney Mickey Mouse Meteor train, including loco, tender, Three Little Pigs Boxcar, gondola car and Caboose, key not present (F-VG) (5)
Three Mickey & Minney Mouse soft toys 1950's
Set of Mazda Mickey Mouse Lights by the British Thomson-Houston Coy. Ltd. twelve electric Christmas lights with plastic shades decorated with different Disney characters, boxed (G box F)
Mickey Mouse in King Arthur's court. Contributor, Walt Disney Productions. Publisher, Dean & Son, limited with four pop up scenes missing spine
A vintage painted cast iron Mickey Mouse, 24 cm high; a Walt Disney production celluloid Minnie Mouse money box and a Walt Disney production Minnie Mouse doll (3)
Nautilus the Submarine from Walt Disney's '20,000 Leagues Under the Sea', with key, worked well when tested (E box VG-E)
Louis Marx & Co. Mickey the Musician, clockwork mechanism with permanant key (E box F)
Tinplate Disney Ferris Wheel, clockwork mechanism with permanant key, colourful lithography throughout, unboxed, 42 cm x 32 cm (VG-E)
Mattel souvenir Disneyland record set, America, circa 1956, including folding lithographed colour card map of Disneyland with 5 x cut-out Flexible 78 Rpm Records and cut out Disney Play figures, in original colour illustrated Envelope (M packaging E-M)
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Yonkers, NY (PressExposure) December 29, 2011 -- The New Year rings in new hours at Empire City Casino at Yonkers Raceway, with the casino now open from 9:00 AM to 4:00 AM every day. New Year's Day (Sunday, January 1) triggers a month of excitement, beginning with the 2012 Calendar Giveaway for the first 5,000 Empire Club members to visit a promotions kiosk. Guests can also enjoy the New Year's Day Buffet in the Good Time Room from 2:00 PM to 10:00 PM. $19.95* for Empire Club Members and $22.95* for non-members. (*Plus tax & gratuity.)
Mondays are maddening during Mad Money Mondays in the month of January with all existing active Empire Club members receiving a $12 free play by visiting any promotions kiosk on January 2nd, 9th, 23rd and 30th.
Tuesdays in January have been declared "Lucky Ladies" days, with every female Empire Club member eligible for $7 in free play, and a 10% discount coupon for food and beverage purchases. The Ladies fun continues into the evening with two for one drink specials in the Entertainment Lounge from 5:00 PM - 9:00 PM and Karaoke beginning at 7:30 PM. The Tuesday dates are January 3rd, 10th, 17th, 24th and 31st.
Wednesdays are always a big day at Empire City, and January is no different. The popular and customary Young at Heart promotion where Empire Club members age 55 and over who visit a Promotions Booth or kiosk will receive the Young at Heart "Gift Pack," featuring $5 in Free Play, 10% food discount coupons, half price Valet Parking and a different gift each week: a 2012 Calendar with post-its in a leatherette black case, stapler, calculator and portfolio. (One gift per person while supplies last). The January Young at Heart Entertainment, with bands scheduled at both 12:00 PM and 2:00 PM, include: January 4th, New York Exceptions; January 11th, Guss Hayes Band; January 18th, Butch Barbella's Streets of the Bronx; and January 25th, the Peter Lawrence Orchestra.
Patrons will go wild over the new "Crazy Wheel" promotion on January 4th, 11th, 18th and 25th from 9:00 PM to 12:00 AM at the Entertainment Lounge, introducing the new generation of interactive entertainment blending the best of karaoke, trivia, name that tune, clips from favorite TV shows and movies, and prizes for audience participants.
Thursdays will be red hot, featuring both the $2 New York Lottery Hot Cash Scratch Off Promotion and Second Chance Drawing entries on January 5th, 12th, 19th and 26th. The first 4,000 Empire Club Members to visit any Promotions Booth on Thursdays will receive one FREE $2 NY lottery scratch off and an entry into the second chance drawing. The Second Chance Drawing will be held on Thursday, January 26th at 7:00 PM. New York Lottery's popular Yolanda Vega will call 10 Empire Club Members to each win $1,000 cash; if club member is not present then they are awarded $500 cash.
As always, Thursdays will also feature Tribute Bands at the Entertainment Lounge for two performances at 8:00 PM and 10:00 PM. The January lineup includes: January 5th, The Elvis Legend (Elvis Presley Tribute); January 12th, Rag Doll (Frankie Valli and the Four Seasons Tribute); January 19th, Beatlemania Now (Beatles Tribute); and January 26th, Little Deuce Coup (Beach Boys Tribute).
Don't Yawn! Wake Up and Win! On Saturdays January 7th, 14th, 21st & 28th at Empire City from 9:00 AM to 1:00 PM in the Entertainment Lounge, patrons can get their morning paper - a FREE copy of the New York Post - and complimentary coffee and pastry while supplies last.
Comedy Night continues on Wednesday January 11th and 25th in the Good Time Room; doors open at 7:00 PM, and the laugh fest starts at 8:00 PM. Admission is $5 for Empire Club members, and $15 for non-members. All attendees receive one FREE drink ticket.


text:
Rehm, Diane
From Library of Congress Name Authority File
Rehm, Diane
Instance Of
Scheme Membership(s)
Collection Membership(s)
- Aed, Diane, 1936-
Additional Information
Birth Date
- (edtf) 1936-09-21
Has Affiliation
- Organization: Diane Rehm show (Radio program)
Has Affiliation
- Organization: WAMU-FM (Radio station : Washington, D.C.)
Has Affiliation
- Organization: National Public Radio (U.S.)
Birth Place
Associated Language
Field of Activity
Related Terms
Exact Matching Concepts from Other Schemes
- found: Homer Warner, M.D. [VR] 1985: CIP credit frame (Diane Rehm, WAMU-FM, Nat. Pub. Radio Affil., Washington, D.C.)
- found: On my own, 2015: ECIP t.p. (Diane Rehm) data view (hosts The Diane Rehm Show on WAMU 88.5 FM in Washington, D.C., (since 1979); currently it is broadcast to approximately sixty cities across the country, as well as internationally by the Armed Forces Radio Network; widow of John Rehm; she lives in Bethesda, Maryland)
- found: Finding my voice, 2002: title page (Diane Rehm)
- found: Wikipedia.org, accessed 29 December 2015: (Diane Rehm (born Diane Aed; September 21, 1936) is an American public radio talk show host. Her program, The Diane Rehm Show, is distributed nationally and internationally by National Public Radio. It is produced at WAMU, which is licensed to American University in Washington, D.C. Rehm has announced that she plans to retire after the 2016 elections. Diane Rehm was born in Washington, D.C.)
Change Notes
- 1986-06-27: new
- 2016-08-20: revised
Alternate Formats


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In 1913, stricken by tuberculosis, young Anah, Aki, and Leah are sent away from their family for treatment at St. Joseph's, an orphanage in Hawai'i's Kalihi Valley. Of the three, two will die there, and only Anah, the eldest, will survive. But the ghosts of the dead sisters will haunt Anah as she prepares to begin married life away from the orphanage. Desperate for the love of their sister, but jealous of her ability to live in the physical world, they are determined to thwart Anah's happiness. As Anah struggles to appease the dead, it becomes apparent that only through one of her own daughters can redemption be attained.
Poignant, lyrical, and utterly compelling, Behold the Many is a stunning novel that glows with longing and life.
Anah suffers many devastating words and events in the course of this novel. But in Behold the Many , one of our nation's most dynamic literary stylists forces us to stare wide-eyed into the pain until we can see the healing beauty hidden in its folds.