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Mucosal inflammation is accompanied by an alteration in 5-HT. Intestinal 5-HT synthesis is catalyzed by tryptophan hydroxylase 1 (Tph1) and we have shown that mice deficient in this rate-limiting enzyme have reduced severity of intestinal inflammation in models of chemical-induced experimental colitis. Here, we investigated the effect of blocking peripheral 5-HT synthesis in generation of intestinal inflammation by a using peripheral Tph inhibitor, telotristat etiprate (LX1606), in models of intestinal inflammation. LX1606 was given orally either prophylactically or therapeutically to mice with dextran sulfate sodium (DSS)-induced colitis or with infection with Trichuris muris. Severity of intestinal inflammation was measured by assessment of disease activity scores, histological damage, and MPO and inflammatory cytokine levels. LX1606 significantly reduced intestinal 5-HT levels and delayed onset and severity of DSS-induced acute and chronic colitis. This was associated with decreased MPO and proinflammatory cytokine levels compared with vehicle-treated controls. In the infection-induced inflammation model, treatment with LX1606 enhanced worm expulsion as well as increased IL-10 production and goblet cell numbers. LX1606-treated mice had significantly lower MPO and IL-1β levels compared with controls postinfection. Our results demonstrate that peripheral 5-HT plays an important role in intestinal inflammation and in the generation of immune responses. Pharmacological reduction of peripheral 5-HT may serve as a potential strategy for modulating various intestinal inflammatory disorders.
- enterochromaffin cells
- experimental colitis
- tryptophan hydroxylase
- inflammatory bowel disease
the gastrointestinal (GI) tract is the largest endocrine organ in the body and is made up of an extensive system of endocrine cells (56). Enterochromaffin (EC) cells are the best characterized subset of enteric endocrine cells and synthesize the vast majority of the body's serotonin (5-hydroxytryptamine; 5-HT) (35, 61). Once synthesized, 5-HT is packaged into granules and stored near the basal border of the EC cell, though some studies have also identified granules near the apical membrane (1, 20). In response to various mechanical and chemical stimuli, including bacterial toxins, 5-HT is released from granules in a calcium-dependent manner (55, 61). 5-HT released from EC cells goes into the surrounding tissue and gut lumen, where it plays important roles in GI motor and secretory function or can be transported into surrounding epithelial cells by the 5-HT reuptake transporter (SERT) and degraded by monoamine oxidase A (21, 26).
EC cells synthesize 5-HT from its precursor, l-tryptophan. Tryptophan hydroxylase (Tph) catalyzes the rate-limiting step of this reaction and has been detected prominently in EC cells (19). It is now established that there are two known isoforms of this rate-limiting enzyme. EC cells contain one form of this enzyme, Tph1, mainly present in the gut and spleen, whereas the second isoform, Tph2, is mainly expressed in the brain stem and enteric neurons (67, 68). Thus 5-HT is synthesized independently in EC cells and neurons by two different rate-limiting Tph isoenzymes. Alterations in 5-HT signaling have been observed in various GI disorders, such as IBD (2, 6, 10, 15, 46), functional disorders such as irritable bowel syndrome (IBS) (5, 10, 13, 32, 51), and various enteric infections (4, 39, 64, 65, 71). Several studies have shown that 5-HT plays a key role in the generation of intestinal inflammation. Mice that are deficient in the rate-limiting enzyme of 5-HT biosynthesis in EC cells (Tph1−/−) exhibit reduced severity of colitis in two different models of experimental colitis [induced by dextran sulfate sodium (DSS) and dinitrobenzene sulfonic acid], whereas replenishing 5-HT levels in these animals upregulates colitis severity (24). In turn, studies have also shown that chemical-induced colitis or spontaneous colitis associated with an IL-10 deficiency is increased in severity when coupled with the 5-HT enhancing effects of a knockout of the 5-HT reuptake transporter, SERT (7, 29).
The aforementioned studies illustrate that reduction in 5-HT synthesis may alleviate intestinal inflammation in experimental models of IBD. Prior approaches aimed at blocking 5-HT synthesis by a pharmacological agent through inhibition of Tph, as with parachlorophenylalanine, have been impeded by adverse effects to brain 5-HT synthesis leading to alterations in central nervous system-mediated functions (58). Telotristat etiprate (LX1032/LX1606) is an orally delivered, small-molecule Tph inhibitor that reduces peripheral 5-HT synthesis. LX1606 was designed not to penetrate the blood-brain barrier, in part as a result of its molecular size. Here, we investigated the effect of LX1606 in the generation of intestinal inflammation using both the DSS-induced model of acute and chronic colitis and the Trichuris muris infection-induced inflammation model with a view to validate peripheral Tph as a target for modulating gut inflammation.
C57BL/6 mice (Taconic, Cambridge City, IN) were kept in sterilized, filter-topped cages under specific pathogen-free conditions and fed autoclaved food. All mice were male aged 8–10 wk. All experiments were approved by the animal ethics committee of McMaster University and conducted under the Canadian guidelines for animal research.
Telotristat etiprate (LX1032/LX1606 hippuric acid) was supplied by Lexicon Pharmaceuticals (The Woodlands, TX). The compound was formulated in 0.25% wt/vol methylcellulose (Sigma, Mississauga, ON, Canada) and administered to mice once daily via oral gavage at 300 mg/kg. Preparations of formulations of LX1606 were corrected for salt content (salt correction factor 1.31).
Induction of DSS-induced colitis and treatment with telotristat etiprate (LX1032/LX1606 hippuric acid).
Acute colitis was induced by giving 5% DSS (wt/vol) (molecular mass 40 kDa; ICN Biomedicals, Solon, OH) in drinking water for 5 days. Mean DSS consumption was noted per cage each day. Chronic DSS-induced colitis was induced by a previously published method (37). LX1606 was administered prophylactically and therapeutically. In the prophylactic treatment protocol, mice received vehicle or LX1606 at a dosage of 300 mg/kg body wt orally every day starting 1 day prior to administration of 5% DSS and were euthanized on day 5 post-DSS to assess disease severity, MPO activity, and inflammatory cytokines. In the therapeutic treatment protocol, mice received vehicle or LX1606 every day starting 48 h after DSS administration. For chronic colitis, mice were treated with vehicle or LX1606 (300 mg/kg body wt per day) for 6 days starting 1 day before the beginning of the 2nd and 3rd DSS cycle and were euthanized on the last day of the 3rd DSS cycle (therapeutic strategy). All control mice received vehicle and water without DSS.
Assessment of colitis severity.
Disease activity index (DAI) is a combined score of weight loss, stool consistency, and fecal bleeding and was blindly assessed by using a previously published scoring system (23). This scoring system was defined as weight loss: 0, no loss; 1, 1–5%; 2, 5–10%; 3, 10–20%; 4, 20%+; stool: 0, normal; 2, loose stool; 4, diarrhea; and bleeding: 0, no blood; 2, Hemoccult positive (Hemoccult II, Beckman Coulter, Fullerton, CA); and 4, gross blood (blood around anus). DAI was measured on all 5 days of DSS treatment. To assess macroscopic damage, mice were euthanized 5 days post-DSS or at the end of the last cycle of water for chronic DSS-induced colitis. Upon euthanasia, their abdominal cavities were opened, and observations on colonic distension, fluid content, hyperemia, and erythema were recorded. The colon was removed and macroscopic damage was immediately assessed on the full section of the colon. Macroscopic scores were blindly assessed by using a previously described scoring system for DSS colitis (11, 23). To assess for histological damage, formalin-fixed colon segments were paraffin embedded and 3-μm sections were stained with hematoxylin and eosin (H&E). Colonic damage was blindly scored using a previously published scoring system that considers changes in crypt architecture, cellular infiltration, goblet cell depletion, and crypt abscess (11, 22).
Determination of colonic 5-HT content.
Colon samples were weighed and longitudinal length was recorded. Samples were homogenized as previously described (52). 5-HT content was analyzed by enzyme immunoassay using a commercially available kit (Beckman Coulter, Fullerton, CA) and expressed as a function of wet weight (nanogram per milligram tissue).
Measurement of colonic MPO activity and cytokine levels.
Colonic MPO activity and cytokine levels were measured according to a published protocol (38). In brief, for MPO measurement, colonic tissue samples were homogenized in ice-cold 50 mmol/l potassium phosphate buffer containing 0.5% hexadecyl trimethyl ammonium bromide (pH = 6.0) (Sigma). Homogenates were centrifuged and the supernatant was removed, and an aliquot was then added to a solution containing potassium phosphate buffer, O-dianisidine, and hydrogen peroxide (Sigma-Aldrich). The absorbance was measured at 450 nm by a spectrophotometer (model EL808, BioTek). MPO activity was expressed in units per milligram of colon tissue, where one unit is defined as the quantity of enzyme able to convert 1 μmol of hydrogen peroxide in water per minute at room temperature. Cytokine levels from colon lysates were determined by using commercially available ELISA kits according to the manufacturer's instructions (Quantikine Murine; R&D Systems, Minneapolis, MN).
Parasitological technique.
Trichuris muris parasites were harvested and ova collected and maintained as previously described (66). All infected mice received ∼300 T. muris ova in distilled water (200 μl) by oral gavage. Mice received vehicle or LX1606 at a dose level of 300 mg/kg body wt per day, orally starting 3 days prior to infection, and were euthanized on various days postinfection (PI) to examine changes in inflammatory and immune responses; worm burden was assessed by counting the number of worms present in the cecum.
Histological analysis and immunohistochemistry.
A segment of the proximal colon of infected animals was fixed in 10% neutral buffered formalin and stained with periodic acid-Schiff (PAS) stain to detect intestinal goblet cells. For immunohistochemistry, formalin-fixed, paraffin-embedded colonic segments were sectioned to 5 μm in thickness, deparaffinized by heating at 60°C for 30 min, cleared with CitriSolv (Fisher Scientific, ON, Canada), and rehydrated in a graded ethanol series of decreasing ethanol concentrationss. Sections were subjected to heat-induced epitope retrieval (10 mM sodium citrate buffer-0.05% Tween 20, pH 6.0), blocked with 2% goat serum in PBS containing 1% BSA-0.1% Triton X-100-0.05% Tween-20-0.05% sodium azide, and incubated with a polyclonal antibody raised against Muc2 (2.67 μg/ml; sc-15334; Santa Cruz Biotechnology) overnight at 4°C. Sections were washed with PBS-0.5% Tween-20 and incubated with Alexa Fluor 594-conjugated goat anti-rabbit IgG (2 μg/ml; no. A-11037; Molecular Probes/Invitrogen). Sections were mounted with ProLong Gold antifade reagent containing 4′,6′-diamidino-2-phenylindole (DAPI) (Molecular Probes/Invitrogen). Images were captured by using a Nikon Eclipse 80i through NIS-Elements Basic Research imaging software. Fluorescence filters used were blue (DAPI, Hoechst), excitation filter 340–380 nm, emission filter 435–485 nm; red (TRITC, RFP), excitation filter 540–580 nm, emission filter 600–660 nm. The number of PAS- and Muc2-positive goblet cells was quantified by analyzing at least 40 crypts from each individual colon cross section and was expressed per 10 villus crypt units. Investigators were blinded to the study groups.
Western blotting.
Colons isolated from the mice were homogenized in Tris-buffered saline containing protease inhibitor solution (P8340, Sigma). The total protein concentration in each solution of homogenized tissue was determined using the Bio-Rad DC Protein Assay Kit (cat. no. 500-0116, Bio-Rad). Prior to loading onto SDS-PAGE gels, the samples were diluted 1:1 (vol/vol) with 2× Laemmli sample buffer (Bio-Rad) without reducing agent and heated for 5 min at 100°C with a dry block heater. Equal amounts (15 μg) of protein homogenates from each group were loaded and electrophoresed onto 7.5% SDS-PAGE and transferred to a PVDF membrane at 400-mA constant current for 4 h at 4°C. Membranes were blocked with 5% milk blocking buffer (5% wt/vol nonfat milk in 1× wash buffer containing 50 mM Tris-base, 150 mM NaCl, 1% Tween-20, 1% Triton X-100) overnight at 4°C and then incubated with primary antibodies against: Muc2 (0.2 μg/ml) (sc-15334; Santa Cruz Biotechnology) or Muc5ac (1:1000) (M5293; Sigma) for 2 h at room temperature. Membranes were washed with 1× wash buffer, incubated with either anti-rabbit horseradish peroxidase (HRP)-linked antibody (1:5,000, no. 7074, Cell Signaling Technology) or anti-mouse HRP-linked antibody (0.08 μg/ml, sc-2318, Santa Cruz Biotechnology) for 1 h. Proteins were visualized by use of Clarity Western ECL Blotting Substrate (Bio-Rad). β-Actin was used as a loading control. Densitometric analysis was performed on Western blots with ImageJ software (version 1.48), normalized to total actin.
Statistical analyses.
All data are presented as means ± standard error of the mean. Unpaired t-test or one-way ANOVA followed by Tukey multiple-comparisons post hoc test or Mann-Whitney U-test was performed with GraphPad Prism version 6.0b for Mac OS X (GraphPad Software, La Jolla, CA). An associated P value <0.05 was considered statistically significant.
Peripheral Tph inhibitor, LX1606, significantly reduces intestinal 5-HT levels.
To verify that oral administration of LX1606 was able to deplete intestinal 5-HT, colonic and jejunum 5-HT levels were assessed from mice on day 5 post-DSS-induced colitis. Administration of LX1606 significantly decreased 5-HT concentrations in both the colon and jejunum compared with vehicle-treated controls (Fig. 1, A and B, respectively).
Prophylactic and therapeutic treatment with LX1606 delays onset and decreases severity of DSS-induced colitis.
We investigated the effect of LX1606 in an acute model of DSS-induced experimental colitis using a prophylactic treatment strategy (Fig. 2A). Treatment of colitic mice with LX1606 beginning 1 day prior to DSS administration resulted in significantly lower clinical disease activity scores (based on weight loss, fecal blood, and stool consistency) (Fig. 2B). We also observed significantly lower macroscopic scores (based on fecal blood and consistency, rectal bleeding, and erythema) in LX1606-treated mice compared with vehicle-treated mice on day 5 post-DSS-induced colitis (Fig. 2C). H&E-stained colon cross sections of mice that received DSS and were treated with vehicle displayed distortion of epithelial cell architecture, increased leukocyte infiltration, loss of goblet cells, and significant thickening of the muscularis mucosa layer. In mice that received LX1606, histological damage scores were significantly less severe compared with control mice on day 5 post-DSS induction (Fig. 2D). Decrease in colitis severity was associated with significantly lower colonic MPO activity and lower levels of proinflammatory cytokines (IL-1β, IL-6) (Fig. 2, E–G).
We also evaluated the effect of LX1606 on colitis severity using a therapeutic treatment strategy. Here, LX1606 was administered orally on day 2 after DSS administration (Fig. 3A). LX1606 treatment resulted in significantly reduced whole colon tissue 5-HT levels (Fig. 3B), and a modest decrease in total disease activity scores (Fig. 3C). Treatment with LX1606 also resulted in a modest decrease in macroscopic damage scores (Fig. 3D) and less severe histological damage (Fig. 3E). This was associated with lower MPO activity and colonic IL-1β and IL-6 levels (Fig. 3, F and G). In turn, mice treated with vehicle had significantly higher macroscopic and histological damage on day 5 post-DSS, including crypt distortion, inflammatory cell infiltration, and muscle thickening (Fig. 3E).
Therapeutic treatment with LX1606 decreases disease severity in a chronic DSS-induced colitis model.
To investigate the effect of LX1606 treatment in a chronic model of colitis, mice were administered three cycles of DSS solution and treated with LX1606 for 6 days starting 1 day prior to the beginning of the 2nd and 3rd DSS cycles (Fig. 4A). Treatment with LX1606 significantly reduced whole colon tissue 5-HT content compared with vehicle-treated controls (Fig. 4B). Following treatment with LX1606, there was attenuation of disease severity, indicated by lower disease activity scores during the periods of DSS administration (Table 1). Mice were euthanized on day 37 following the last day of the 3rd cycle of DSS administration and colons were excised to assess for macroscopic damage. There was reduced macroscopic damage in LX1606-treated groups compared with controls on day 37 post-DSS administration (Fig. 4C). DSS-induced colitis is accompanied by a shortening of overall colon length. The colon length of mice treated with LX1606 was significantly increased compared with vehicle-treated mice post-DSS (Fig. 4D). There was also less severe histological damage (less distortion of epithelial cell structure, decreased inflammatory cell infiltrate, less significant thickening of the muscularis mucosa) in LX1606-treated mice compared with vehicle-treated controls (Fig. 4E). Delay in disease onset and disease severity in LX1606-treated mice was associated with lower MPO activity and reduced IL-1β levels (Fig. 4F).
LX1606 administration decreases inflammatory response postinfection with nematode T. muris.
T. muris is a natural nematode parasite of mice that resides in the cecum and colon. Different strains of mice display varying resistance to infection with T. muris whereby resistant strains mount a protective Th2 response and susceptible strains mount a Th1 response and cannot expel the worm (16). During infection, the large intestine becomes inflamed as macrophages and other leukocytes accumulate within the tissue (45). This study evaluated the effect of oral administration of peripheral Tph inhibitor in reducing colonic inflammation in relation to reduction of gut 5-HT content. There was no difference in weight loss between LX1606 and vehicle-treated groups with or without infection (data not shown). We assessed the effect of LX1606 on inflammation by measuring MPO activity and production of cytokines. We observed significantly reduced colonic MPO activity in infected mice treated with LX1606 compared with vehicle-treated controls (Fig. 5A). Investigations on cytokines in colonic tissues revealed lower levels of proinflammatory cytokines, IL-1β and IL-17, and higher levels of immunoregulatory cytokine, IL-10, on day 21 PI (Fig. 5, B–D). There was no significant difference in the levels of IL-13, IL-33, and thymic stromal lymphopoietin (TSLP) between the LX1606-treated mice compared with vehicle treated after infection (Table 2).
LX1606 administration promotes worm expulsion and upregulates goblet cell numbers.
Goblet cells reside throughout the GI tract and are the main source of mucins in the gut (34). Parasitic infections, including T. muris, are associated with changes in mucus composition and stimulation of mucus production by goblet cell hyperplasia and increased mucin expression (28, 31, 33, 50). Changes to mucus secretion and mucin expression are correlated to parasite expulsion. Assessment of worm burden in the large intestine of LX1606-treated mice showed acceleration in worm expulsion compared with vehicle-treated controls on day 14 PI (Fig. 5E). To determine whether this was due to enhanced mucus secretion, we used PAS staining to stain goblet cell mucins on formalin-fixed colon sections from uninfected and T. muris-infected mice at days 14 and 21 PI. We observed no changes in PAS staining in colon sections of samples taken from uninfected mice (Fig. 5F). A significant increase in PAS staining was observed, however, in tissue sections of samples taken at days 14 and 21 PI (Fig. 5F). Muc5ac is a mucin that is induced by T. muris infection and plays an important role in the expulsion of these parasites (27). We assessed Muc5ac expression to see whether LX1606-treatment postinfection induced any changes compared with vehicle-treated controls. As assessed by Western blot, we observed a relative increase in Muc5ac on days 14 and 21 PI compared with uninfected mice. We did not observe, however, any changes in Muc5ac levels between LX1606- and vehicle-treated mice on either day (Fig. 5G). Muc2 is a major secreted mucin within the colon and has previously been shown to be correlated with worm expulsion and protective against enteric infections (28). Using Western blot and immunostaining, we assessed changes in Muc2 expression. Muc2 expression is significantly increased in infected mice compared with uninfected mice on days 14 and 21 PI. On both days, there was an increase in Muc2 expression in LX1606-treated groups compared with vehicle-treated control groups (Fig. 5, H–J).
In this study, we tested the hypothesis that an orally delivered Tph inhibitor would confer protection against both chemical- and infection-induced inflammation. The selectivity of LX1606 for inhibition of Tph1 in the GI tract is based on the distribution of the compound and its failure to cross the blood-brain barrier (which is, in part, a result of its molecular size). The inability of the compound to cross the blood-brain barrier and affect central 5-HT stores is important because deletion of Tph2 in the brain is associated with alterations in behavior (59). In turn, deletion of intestinal Tph2 in the enteric nervous system is followed by significant defects in GI motility as well as abnormal development of enteric neurons (43).
A recently published study by Margolis et al. (48) showed oral administration of LX1606 (AKA LX1032) significantly depleted intestinal 5-HT levels compared with vehicle-treated controls. LX1606 administration also induced a significant decrease in blood 5-HT concentration but not in brain 5-HT level. Margolis et al. also evaluated the effect of LX1606 (LX1032) on neuronal 5-HT stores using immunocytochemical techniques and found that LX1606 did not affect the proportion of myenteric 5-HT-immunoreactive neurons or the area of myenteric plexus occupied by 5-HT-immunoreactive nerve fibers. This suggests that, although LX1606 significantly depletes 5-HT stores from EC cells, entire neuronal 5-HT stores are maintained and, therefore, LX1606 and similarly related peripheral Tph inhibitors appear to fail to enter the myenteric plexus and/or inhibit enteric neuronal Tph2. In addition, the safety and efficacy of LX1606 have been recently evaluated in patients with diarrhea associated with carcinoid syndrome (40, 54). Despite the differences in treatment periods (4 wk vs. 12 wk, respectively), both studies demonstrate that patients that receive LX1606 treatment have improvements in bowel movement frequency and reduction in 5-HT production, as measured by a reduction in the metabolic breakdown product of 5-HT, urinary 5-hydroxyindoleacetic acid (40, 54). These studies suggest the benefit of telotristat etiprate/LX1606 in intestinal conditions such as carcinoid syndrome in addition to colitis. In our study, we provide further evidence of a beneficial role for these small molecule inhibitors in experimental models of intestinal inflammation.
We evaluated the effect of LX1606 using both a prophylactic and therapeutic treatment strategy in DSS-induced colitis. Some of the pertinent features of the DSS model of colitis may include weight loss, blood in stools, diarrhea, and anemia (14, 18, 53, 63). Upon euthanasia, mice that have been administered this DSS regimen have shortened colons and feces that are soft and poorly formed. Microscopically, colonic tissue from DSS-treated mice is characterized by inflammatory cell infiltration of the mucosa/submucosa, distortion of crypt architecture, goblet cell depletion, and thickening of the muscle layers (11). Administration of LX1606 significantly depleted colon and jejunum 5-HT content (which includes both EC cell and neural contributions) and reduced the severity of DSS-induced acute colitis albeit to a lesser degree when administered therapeutically. Disease activity scores were significantly lower in mice treated with LX1606 compared with vehicle-treated controls. LX1606-treated mice had significantly lower macroscopic and histopathological damage scores. This was associated with a decrease in MPO activity (an enzyme released by granulocytes such as neutrophils, serving as a surrogate marker of inflammation) (62), and a decrease in the levels of proinflammatory cytokines IL-1β and IL-6. IL-1β is primarily secreted by monocytes and macrophages upon activation and is upregulated in the inflamed colon of patients with IBD and DSS-induced colitis (44, 53). Secreted IL-1β binds to and signals through the IL-1 receptor to activate the NF-κB signal-transduction pathway, resulting in the upregulation of other proinflammatory mediators, including IL-6 (41, 57). These results corroborate with a recent study that evaluated LX1606 (in addition to a related peripheral Tph inhibitor, LP-920540) in a tri-nitrobenzene sulfonic acid (TNBS)-induced colitis model (48). Administration of LX1606 significantly ameliorated the severity of TNBS-induced colitis and reduced expression of proinflammatory gene expression of IL-6 and IL-1β. We also tested the effect of LX1606 using a therapeutic strategy in a chronic model of DSS-induced colitis whereby mice receive repeated cycles of DSS and water. Mice that received LX1606 and were euthanized 1 day after the last day of DSS administration had significantly reduced colon 5-HT levels and improvements in disease activity scores (an additive score considering weight loss, stool blood, and stool consistency) throughout the DSS cycles in the chronic colitis model. However, when mice were euthanized 11 days after the last day of DSS administration we did not observe a difference in jejunum or colon 5-HT levels in LX1606-treated mice (data not shown). This is consistent with previous observation that 5-HT levels return to baseline after discontinuation of drug treatment, asserting that continuous treatment is necessary to maintain the reduction of 5-HT levels.
We also evaluated the effect of LX1606 in an infection-induced model of inflammation using the nematode T. muris. This parasite is very similar to the human parasite Trichuris trichura and is a commonly used murine model of intestinal nematode infection-induced inflammation. Infection with embryonated T. muris eggs is strain specific whereby strains resistant to chronic infection (such as C57BL/6) expel the parasites beginning on day 14 PI and are able to fully clear the parasite by day 35 PI through the generation of the Th2 type immune response. Susceptible strains (such as AKR) generate Th1 immune response, fail to expel worms, and develop chronic infection (12, 52, 69). Once infected, these eggs reach the cecum, hatch (in the cecum and proximal colon), and embed in the mucosal epithelium (9, 25). Once in their intraepithelial niche, the worms fully mature and affect intraepithelial cell homeostasis, and endocrine cell hyperplasia, resulting in the accumulation of inflammatory cells such as macrophages within the tissue (8, 16, 17, 45). In this study, we treated resistant (C57BL/6) mice with either LX1606 or vehicle once daily starting 3 days prior to infection to assess the effect of LX1606 in infection-induced inflammatory responses. Administration of LX1606 reduced intestinal inflammation in the colon of infected mice as indicated by a reduction in proinflammatory markers MPO, IL-1β, and IL-17. IL-17 has been implicated in the pathogenesis of many inflammatory conditions and IL-17 levels and genes in the Th17 pathway have been shown to be upregulated following nematode infection (42, 70). Treatment with LX1606 also increased immunoregulatory IL-10 production in intestinal tissues in infected mice compared with that in vehicle-treated mice. Therefore, it seems very likely that the treatment with LX1606 modulated inflammation by upregulation of IL-10 production. However, the treatment may have an additional indirect effect on inflammation by reducing worm burden. These findings demonstrate that LX1606 is able to reduce severity not only in chemical-induced colitis but also in enteric parasite-induced inflammation. The intestinal mucus serves as a significant component of the host response to nematode infection. Mucins act as the main structural component of the intestinal mucus layer and are secreted mainly by goblet cells that are dispersed throughout the epithelial layer (36). Changes in goblet cell response and mucin production are observed in many intestinal infections, including T. muris, and play an important role in worm expulsion (28, 49). Previously, we demonstrated that an increase in the major intestinal mucin, Muc2, correlates with worm expulsion following T muris. infection and there is a significant delay in early-stage worm expulsion in its absence (28). Interestingly, an increase in Muc5ac, a mucin normally expressed in the airways and stomach, is observed in the colon following infection and has since been shown to play a critical role in the expulsion of T. muris, in addition to affecting worm viability (27, 28). In addition to reducing intestinal inflammation in infected mice, we wanted to investigate the effect of LX1606 treatment on host defense in enteric infection. Previously, our laboratory has shown that infection of resistant C57BL/6 mice with T. muris upregulates the number of EC cells and 5-HT content in the colon (47, 52, 69). Treatment with LX1606 promoted worm expulsion on day 14 PI and resulted in an increase in PAS-positive goblet cell numbers. There was an increase in Muc2 and Muc5ac expression postinfection compared with uninfected mice. As assessed by immunoblotting, we observed no discernible difference in Muc5ac expression between LX1606 and vehicle-treated controls. Interestingly, we did, however, observe an increase in Muc2 in LX1606-treated mice on days 14 and 21 PI. These results suggest that LX1606 treatment leads to an increase in the expression of Muc2 glycoprotein in infected wild-type mice, perhaps as a host defense mechanism. These findings suggest that although Muc2 and Muc5ac may act in concert to promote worm expulsion, upregulation of Muc2 by LX1606 was sufficient to promote worm expulsion in this infection despite no changes in Muc5ac expression. To understand the mechanism by which LX1606 enhanced goblet cell responses, we investigated other cytokines (IL-10, IL-13, IL-33, TSLP) which are shown to be upregulated in T. muris infection (3, 30, 60) and observed a significant increase in IL-10 production after LX1606 treatment on day 21 PI. In our previous studies, we have shown that IL-10 plays an important role in upregulation of intestinal goblet cells numbers (49). These findings suggest that the increase in goblet cells and Muc2 expression that we observed by LX1606 treatment may be in part mediated by IL-10 and warrants further investigation into the direct mechanisms underlying this observation.
Small molecule Tph inhibitors, such as LX1606, represent a novel class of drugs that has the potential to improve inflammatory conditions associated with increased production of 5-HT. The present observations in this study further confirm the ability of selective pharmacological reduction of peripheral (EC-derived) 5-HT to reduce the severity of intestinal inflammation. Importantly, LX1606 is selective to the periphery and thus central effects are avoided. This class of compounds has potential not only in IBD, but also in other intestinal inflammatory conditions associated with increase in 5-HT, such as IBS and carcinoid diarrhea.
This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and Crohn's and Colitis Canada (to W. I. Khan), by funding from Lexicon Pharmaceuticals, Inc., and by an Ontario Graduate Scholarship (to J. J. Kim). W. I. Khan is a recipient of CIHR New Investigator Award.
B. Zambrowicz and Q. M. Yang are employees of Lexicon Pharmaceuticals, Inc.
J.J.K., H.W., and J.D.T. performed experiments; J.J.K., H.W., and J.D.T. analyzed data; J.J.K. and W.I.K. interpreted results of experiments; J.J.K. prepared figures; J.J.K. drafted manuscript; J.J.K., H.W., J.D.T., B.Z., Q.M.Y., and W.I.K. approved final version of manuscript; B.Z., Q.M.Y., and W.I.K. conception and design of research; B.Z., Q.M.Y., and W.I.K. edited and revised manuscript.
The authors thank Dr. Richard Grencis (University of Manchester, Manchester, UK) for providing T. muris and Ivana Sunjic for technical support.
↵* J. J. Kim and H. Wang are both first authors.
- Copyright © 2015 the American Physiological Society


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McCullough I385 weed whacker Friction Drive
This is the first motored bike I built. It moves right along at gleeful speeds. I don't have a speedo yet so if I guess it feels like 20-25mph speed, but who cares I like it.
jjstanza, Apr 23, 2009
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Beyblade: Bakuten Shoot Episode 4 English Subbed
You are watching Beyblade: Bakuten Shoot Episode 4 English Subbed from the Beyblade: Bakuten Shoot Anime Show. Watch or Download Beyblade: Bakuten Shoot Episode 4 MP4 English Sub and other episodes of Beyblade: Bakuten Shoot Streamed for Free.
"The Qualifier Begins"
Stream Beyblade: Bakuten Shoot Episode 4
Episode Summary: The Beyblade Regional Qualifying Tournament is underway as Tyson, Max, Ray and even Kenny are entered to see if they can dethrone Kai, the reigning champion. As our announcers, Brad Best and A.J. Topper rev up the crowd, Kenny is first into battle but without a Bit Beast in his blade, he falls quickly to Kai. The tension builds as Tyson takes on the Blade Sharks in the next round. His biggest competition is against Carlos who breaks team ranks and decides to go it on his own. As the battle progresses, Tyson realizes Carlos is the toughest competitor he's ever faced, Yet with the odds stacked against him, Tyson manages to squeak through to the next round and still to come in the tournament... both Ray and the undefeated Kai.


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3D Album - Romantic Journey
After Effects Project \ 3D Album Slidshow \ Wedding \ Photo Displays
After Effects Project - 3D Photo Album - Magical Journey by XiYing @ JingHaiYu
After Effects Project \ 3D Album Slidshow \ Wedding \ Photo Displays
- A nice project for After Effects, which will save you a lot of time. The one thing you need is to replace the project baseline data (text, video, images) on your personal and start render.
- Music included.
Nightingale and the Rose
Spring Night, quiet garden dim moonlight,
A nightingale singing in the East rose bushes.
But the lovely roses have no feelings, listening is not listening,
But in praise of love under the wind rocked into the dream.
You do not also the case for the cold beauty sing?
Clear it, the poet! What should you desire?
She did not listen to the poet's passion,
You see her blossom Tuyan; call her, but no response.
Ah, rose girl!
Ah, rose girl, I lost my freedom,
However, I do not wear your shackles shy.
Similarly, the laurel leaves of the nightingale,
King of birds in the woods of the star,
In the proud, beautiful roses side,
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Despite being away from Bakken, New England is experiencing a resurgence
NEW ENGLAND -- There isn't a producing oil well within 15 miles of New England.
But just like many other western North Dakota communities, the small town in northwestern Hettinger County is seeing a revitalization thanks in large part to the economic impact of the Bakken oil boom.
Several new homes are being built, and the city's population has increased from 460 a few years ago to an estimated 700.
Business isn't exactly booming, but it has seen a noticeable uptick with more sales tax dollars being generated, longtime community businesses building new facilities and new businesses opening along a once-decaying Main Street.
All are great signs for a small town that only a few years ago seemed relegated to watching businesses close as its population grew older and dwindled.
"Main Street in New England hasn't probably looked this good in 30 years," New England Mayor Marty Opdahl said.
Preparing for a boom that never cameChanges to the community
Thought of by many -- including its own mayor -- as a "bedroom community" for Dickinson 25 miles to its north, New England is beginning to embrace the label.
Jung, who helps new residents sign up for utilities, said most newcomers work in Dickinson or in the oil industry. A few others just wanted to escape the high prices of housing elsewhere.
"When I first started here, it was definitely considered an elderly town. There has kind of been a shift in that," said Jung, a single father who moved home to raise his daughter after working for IBM in Minneapolis and the Mayo Clinic in Rochester, Minn. He is now the head coach of the New England girls' basketball team and wears several hats around town alongside his auditor duties.
"I wouldn't consider New England an elderly town right now. We have some really good, young progressive people here that like to get things done. It seems like a lot of projects we have, it's been a good community effort. That's what it takes for a small town to grow."
Chris Cooper, 30, moved to North Dakota from Fort Myers, Fla., to work as a subcontractor and is one of New England's newest citizens. He said he loves the small-town atmosphere for raising his family.
"I really do like it," said Cooper, who has two young children. "It's a very family-orientated atmosphere. It's a slower pace. You can actually breathe."
Cooper has built two houses here and has acquired a vacant piece of land on the city's north side where he plans to construct seven more and an apartment building with the help of out-of-state financiers.
"Some people don't want to be in Dickinson, they just don't want to be there," Cooper said. "There's too much going on, too much hustle and bustle. They want to be here, and we're close enough to the boom that we're not getting all the riff-raff, but we're still picking up some of the money from the boom."
Even longtime New England residents like Harold and Sharon Maershbecker are putting money into helping revitalize the town.
They are constructing a two-story storefront building on Main Street that will also have eight apartments. It is being built on the site where the town's general store once stood.
"The buildings there were in very bad shape, needed to be taken down," Sharon Maershbecker said. "We didn't want to leave another hole in Main Street. We kept racking our brains, trying to think of something we could do to help the community, and that was what we came up with."
'A very good location'
If the oil industry eventually moves south and inundates Slope, Bowman and Hettinger counties like it did areas in northwest North Dakota, New England expects to be at the heart of the activity because of its location.
The city is at the junction of Highways 21 and 22, is 12 miles west of busy Highway 85, and is the only city with room to grow and the amenities to support oil-related development between Dickinson and Bowman.
"We're in a very good location," said Rep. Mike Schatz, a New England native and retired history and government teacher who also coached the school's now nonexistent football team to four 9-man state championships. "I've lived here all my life. I'm one of those people who have been here from birth until now. We've seen it go up and down a bit. Until the boom started, it was mostly down. ... Now, there is some real optimism on Main Street."
Though New England and its surrounding area is on the fringe of the Bakken formation, it is in the middle of the Three Forks and Tyler formations, meaning oil development could come slowly. Marathon Oil Corp. noted in its 2012 media packet that it holds leases in Hettinger and Slope counties.
Opdahl said the city has spoken with the North Dakota Department of Transportation about moving its water depot from inside city limits to its edge along Highway 21 when the road undergoes improvements next year. That would help divert potential water truck traffic related to the oil industry.
Future projects, the mayor said, could include sewer, water line and street repairs -- especially if New England continues to grow. Opdahl said the city could handle about 1,500 people if it had to.
"We have to ask some hard questions," Opdahl said. "These are questions we just don't ask ourselves as city officials. We have to ask the residents, are they willing to go to the future?"
No one knows whether the oil industry will have a long and lasting impact on the New England area.
One way or another, Opdahl said New England will be prepared. He noted the city has been through its share of booms and busts.
About 100 years ago, New England touted itself as the grain capital of the world. In the mid- to late 20th century, it was a vibrant community with two schools that thrived off the surrounding agricultural industry.
As time went on, the railroad pulled up tracks, grain elevators and farm implement dealerships closed and, eventually, so did the St. Mary's School.
Now, after almost 20 years of downturn, New England is finally showing signs that it isn't just another dying North Dakota small town.
"Many times I've heard people say, 'New England is dead now. This is the nail in the coffin,'" Opdahl said. "The difference is, you have to know the people of New England. The people from New England are residual, they never quit, they never die."


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Green Mining Declaration Indonesia
Usha Mill For Coal,Crusher USA
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How mining and burning coal affects South Africa . New documentary from Friends of the Earth South Africa and Friends of the Earth InternationalRead More
Importing and Exporting,Ministry of Finance and the Economy
The Customs and Excise Division of the Ministry of Finance is responsible for approving all imports to and exports from Trinidad and Tobago. How do I export goods? ... Fill out a Customs Declaration Form (C82 Form) ... Duty-free capital goods e.g. mining, ...Read More
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text: Hi everyone - I was just wondering about formula and the airport security. Can we take powder? Can we take liquid formula in a sealed container? I got some small 2ounce premade enfamil from his ped. What about dry cereal and baby food? Is water still a no go too? Thanks for the advice in advance. Does a stroller count as one of your carry ons? How strick are the air lines with carryons? We are not buying my 5 month old a ticket. We are taking his infant seat hoping that there will be an extra seat. We are flying on delta. Any info or tips would be greatly appreciated. We are taking the red eye so i hope he sleeps. Thanks again, Jennifer


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Terra Group Celebrates Groundbreaking Of Grove At Grand Bay With On-Site VIP Ceremony & Party In Coconut Grove
Terra Group's Pedro and David Martin oversee proceedings: guests include starchitect Bjarke Ingels, landscape visionary Raymond Jungles, City of Miami Officials & real estate titan Alicia Cervera
Jun 11, 2013, 05:00 ET from Terra Group
COCONUT GROVE, Fla., June 11, 2013 /PRNewswire/ -- Pedro Martin and David Martin, founders and owners of leading Miami real estate development company Terra Group, celebrated the groundbreaking of Grove at Grand Bay with a ceremony and private reception on Wednesday, June 5. Notables in attendance to mark construction of the project, heralded as the most significant residential development in Coconut Grove in more than a decade, included Grove at Grand Bay's architect and winner of Wall Street Journal's "Architectural Innovator of the Year" award Bjarke Ingels and landscape architect Raymond Jungles.
Also in attendance were City of Miami Commissioner Francis Suarez; City of Miami Commissioner for District 2 and Chairman of the Miami Downtown Development Marc Sarnoff; Philip Freedman, Director of Sales for Grove at Grand Bay; Cervera Real Estate founder and chair, Alicia Cervera, Sr. and Managing Partner Alicia Cervera Lamadrid, Jr.; Coconut Grove historian Dr. Paul George; President and CEO of the Miami Science Museum, Gillian Thomas; daughter of Raymond Jungles, Amanda Jungles; famed restaurateur and reality television personality Fabian Basabe; and socialite Jillian Jacobson.
Located at 2675 South Bayshore Dr., the twin spiraling towers will rise above the lush flora and fauna for which The Grove is known, offering pristine waterfront views of Sailboat Bay and the marina. More than 90 percent of the units in the North Tower have sold in less than one year; sales for the South Tower launched in March 2013.
"Grove at Grand Bay will serve as an area landmark, setting the bar for future development in Coconut Grove," says Pedro Martin, Terra Group's Chairman, Chief Executive Officer and Founder who, together with Co-Founder David Martin, is developing the project. "Since Grove at Grand Bay launched, we have sold more than $250 million worth of inventory, a figure that shows buyers' eagerness to become a part of this exciting new wave of design."
David Martin adds, "Among South Florida's most in-demand communities, Coconut Grove has a unique history renowned for embracing the arts and nature. Some of history's most creative minds have made Coconut Grove their home over the decades, including Robert Frost, Alexander Graham Bell, Tennessee Williams, Neil Young and Howard Hughes."
"Our vision was to create an eco-conscious residential project so sculptural and visually spectacular that it would become a statement for a new Coconut Grove. There was no architect in the world better suited to realize this than Bjarke Ingels," continues Martin, who is committed to bringing world-class architecture and design to Miami.
Bjarke Ingels, founder of BIG (Bjarke Ingels Group) is an award-winning architect acclaimed for designing buildings "as programmatically and technically innovative as they are resource-conscious." Bjarke's singular vision for the LEED-certified Grove at Grand Bay has resulted in the creation of a modern masterpiece: Two glass-and-steel-encased towers rising in the sky 20 stories high, elegantly twisted at a 38-degree angle and housing 98 expansive residences. "There are some architects who only care about their sculpture," said David Martin, president of Terra Group. "Bjarke, on the other hand, approaches things in a genuine, humble manner and is conscientious and respectful."
"Grove at Grand Bay is inspired by 'engineering without engines,' or using contemporary technology to create buildings that look different because they perform differently," says Ingels. "By creating balconies at an unprecedented 12 feet tall and 12 feet deep, we combine generous views and outdoor space with natural shade, maximizing daylight and optimizing shade. The sliders are also hurricane-proof, something all South Floridians can appreciate."
Individual condominium units are spacious and designed to integrate interior living space with Coconut Grove's natural splendor, featuring floor-to-ceiling sliding doors that open to terraces offering panoramic views of Sailboat Bay and the marina, as well as the Miami skyline and coastline. Priced from $3 million, these residences in the sky are tailored to a modern lifestyle that values both family life and entertaining at home, with living, dining, kitchen and family rooms configured in a continuous rectangular space.
Central to the project's architecture is the 're-Groving' of the site, led by award-winning landscape architect Raymond Jungles, whose vision will be translated into a flow of lush vegetation through shared lobby spaces, walkways and terraces to reinforce the idea of continuity.
Grove at Grand Bay's amenities include a multi-lingual butler, on-site chef, curator-maintained art gallery, a gym and spa with separate facilities for men and women, a pet spa, and four pools -- a 25-meter lap pool, 25-meter swimming and lounging pool, and two rooftop pools with covered cabanas. "As a development company, our goal is not only to learn to innovate architecturally, but to create environments and services that change our residents' lives," says David Martin. "Whether it's our pet spa, our amazing chef or the central walkway connecting Bayshore Dr. to 27th Ave., we designed everything with families in mind."
For additional information about the property or to inquire about sales, visit www.groveatgrandbay.com.
About Terra Group
Led by father and son owners Pedro and David Martin since 2001, Terra Group is known for developing design-driven projects marked by originality and attention to detail that enhance the quality of community life. The award-winning company is comprised of highly trained leaders in the field, including architects, builders, developers, lawyers, businessmen and designers. Terra Group has transformed South Florida's landscape with residential and commercial projects in Coconut Grove, Miami Beach, Doral and the Midtown Miami area. Terra Group's properties include Grove at Grand Bay, Glass, 900 Biscayne Bay, Quantum on the Bay, Metropolis, Nautica, Las Sevillas and Las Ramblas, The Reserve, Doral Cay, Vintage Estates and Vintage Place, Modern at Doral, Atlantic 15 in Sunny Isles . Corporate offices are located in Coconut Grove, FL. For more information, visit www.terragroup.com.
About BIG-Bjarke Ingels Group
BIG is a Copenhagen- and New York-based group of architects, designers, builders and thinkers operating within the fields of architecture, urbanism, research and development. BIG's projects span throughout Europe, North America, Asia and the Middle East. BIG was founded by Bjarke Ingels, who has received numerous awards and honors, including the Danish Crown Prince's Culture Prize in 2011, the Golden Lion at the Venice Biennale in 2004, and the ULI Award for Excellence in 2009. In 2011, the Wall Street Journal awarded Ingels the Architectural Innovator of the Year Award. In 2012, the American Institute of Architects granted the 8 House – a BIG project – its Honor Award, naming it "a complex and exemplary project of a new typology." Alongside his architectural practice, Ingles taught at Harvard University, Yale University, Columbia University, and Rice University and is an honorary professor at the Royal Academy of Arts, School of Architecture in Copenhagen.
To schedule a site tour and interview with David Martin, please contact Nick D'Annunzio and Karina Atala at TARA, Ink.at firstname.lastname@example.com and firstname.lastname@example.com, 305.864.3434 ext. 101/153
SOURCE Terra Group


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WEDDINGS in Nigeria have gone way past the normal ceremonies. It now involves a lot of fanfare, side attractions, variety of foods, extravagant decorations, grand entry for couple, etc. Every bride that wants the best on her big day pays attention to every detail. Some hire wedding planners from the outset, others do the planning and vendor hiring, then employ the services of an event coordinator to make sure all vendors cooperate and do what is to be done.
Whichever the case may be, brides should be careful, know what they want so as to avoid wedding planning mistakes.
ENCOMIUM Weekly brings you more mistakes to avoid when planning your wedding.
When planning your wedding, it is normal to log on to Instagram and check for ideas and inspirations for how your wedding should turn out or look. While at it, you have to put yourself in check so you don't get carried away by what you see on bellanaija, wedding digest and other Nigerian wedding pages on Instagram. Always remember that individuals are different and the fact that someone's wedding looked good with a particular theme does not mean yours will look same. The only thing you should do while on Instagram is look up ideas and not get totally carried away by what you see. Have in mind that things are not always what they look like.
We are not saying you shouldn't hire family, but rather be careful when considering to hire them, so it doesn't become a decision you wished you didn't make.
First, there's always that little activity you want family members to oversee on your wedding day. When you hire them as your wedding vendor, they won't be able to help with that little activity and they also won't be able to enjoy your party like everyone else. Second, if they mess things up, it may be awkward and you might not be able to scold them as you'd want to. Imagine if you had your aunt as the caterer at your wedding reception, and you paid her for variety of food for 500 people and the food doesn't go round your 350 guests.
This is one wedding disaster always waiting to happen because people would ask what plans you've made and would try to convince you to try this or that or hire a vendor they know. The moment you listen to everyone and do everything that is suggested, you might end up with a disastrous wedding party. Whatever plans you make should be between you, your husband and the wedding planner.
Music is the life of every party, so you have to make sure the band will dish out entertaining and danceable songs, and also the DJ would play trendy songs back to back, so people don't get bored.
Early callers to the wedding reception would not be bored or get tired of waiting for the party to start. Once the party starts and the music plays, they would dance till their feet hurt.
The master of ceremonies is also a key part of the wedding as he would be doing a lot of talking. Be sure that he is witty, polite and won't be insultive to your guests when making jokes.
Aside coming to celebrate your big day, people are coming to eat and have fun at your wedding. Yes, a lot of people look forward to the food at the party. Ensure that the food goes round and is more than enough for the guests. Availability of variety of food is important. Desserts and finger foods are also wedding must haves. Guests are not happy when they don't eat or have enough to eat at your wedding. That is why it is essential to make sure you invite only the number of people you can cater for.


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This is a brief facilitator's guide to run a LEGO simulation to teach Scrum - one of the Agile product development frameworks.
This teaching game is widely used by the Scrum trainers community worldwide including various certification classes, in-house trainings, formal business programs and team workshops.
The initial variant of the game is developed by Alexey Krivitsky back in 2009. Here you can download the newest guide.
Please note that this brief guide is becoming slightly obsolete. For the most recent updates check the new book lego4scrum 3.0.
Also available in other languages.
Check out the new book!
The book is released early 2017.
It contains all recent ideas on lego4scrum. Including using user story mapping and how to scale the simulation to a hundred participants and more:
This work is distributed under a Creative Commons Attribution 3.0 Unported License.
Have questions? Talk to us: firstname.lastname@example.com


text:
Product Description
Quick Charge 2.0 AUKEY Wall Charger with Micro-USB Cable for Samsung S7/S6/Edge, LG G4, Moto X, Blackberry Priv | Qualcomm Certified
Product Description
Color: Black
Benefit from the next-generation in fast charging; reduce smartphone and tablet downtime significantly with advanced Qualcomm® Quick ChargeTM 3.0 Technology.
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Aukey's best selling Quick Charge 2.0 Charging adapter now gets upgraded with Quick Charge 3.0 technology, making it compatible with both existing Quick Charge 2.0 devices and future Quick Charge 3.0 devices. You device can get up to 80% of battery in as short as 35 minutes.
Quick Charge 3.0 employs Intelligent Negotiation for Optimum Voltage (INOV), an algorithm which allows your portable device to determine what power level to request at any point in time, enabling optimum power transfer while maximizing efficiency.
Truly Universal Design
While offering blazing fast charging for our expanding number of compatible devices, the innovative charger is equally fast in charging non-compatible smartphones and tablets with its 5V/2A maximum current.
Backward compatible with Quick Charge 2.0devices:
Galaxy S6 / Edge
Galaxy Note 4 / Edge
Nexus 6
HTC One M8 / M9
HTC Desire Eye
Moto X (2015)
Droid Turbo
Xperia Z3 / Z3 Compact / Z3 Tablet Compact / Z4 Tablet
Input: AC 100-240V ,
Output:3.6-6.5V/3A 6.5V-9V/2A 9V-12V/1.5A
Dimensions: 3.8 x 3.2 x 0.9 inches (9.7 x 8.1 x 2.3 cm)
Please use your device's original charging cable or Aukey's MFI / Micro Cable for the best possible performance
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Am I alone in my disappointment at how the centenary of 1916 is going? Certainly there is much to admire. The story of 1916 is being recounted in fresh ways, new areas of inquiry have been opened up. We know more about the role of women, more of the innocent bystanders, especially the children who were killed. The O'Brien Press's impressive "16 Lives" series reminds us that sixteen individuals were executed after the rising. Where the focus had once been on the seven signatories of the Proclamation, now we have accounts of other leaders; their backgrounds and motivations. What is disappointing is the level of reflection. An opportunity to learn more of our present problems and predicaments is being lost. I do not suppose that the lessons of history are easily read or that it is the historians' job to teach them. I do suppose that comparison is the best, if not the only way, to study society, culture, politics. Comparing the past with the present gives us a perspective not otherwise available. The material out of which to fashion the comparison is there. It just not being used.
In this post I adumbrate some of what we might expect to learn. My first point is the 'otherness' of 1916. The ideas that motivated the insurgents and shaped the judgments, positive and negative, passed on them are not alive today. The distinction between "mystique" and "politique", between a politics of vision and a politics of power, made by the French thinker and poet, Charles Peguy [1873-1915] , is apposite as we gaze across the chasm that separates us from the lost world of 1916. I discuss that distinction and why Peguy supposed modernity eclipsed mystique.
The 1960s were a turning point in Ireland and elsewhere. We live with the legacy. It is looking pretty tatty. The progressive narrative it ushered in that promised so much in economics, social reform, emancipation, has less and less to contribute. Its guardians who dominate the commentariat have little to say on a Europe in trouble or an Irish democracy struggling to adjust to a changed political landscape. Or rather, what they do say is strong on abuse and weak on analysis. While they know who to blame for the solutions that they dislike, they have no solutions of their own. Except, of course, cries for 'a new vision for a new Republic'; a need they cannot see their way to filling. The resources for reflection and renewal have dissipated. It was good to be around when they were in full flow.
As things get better, ghosts from the past appear and disturb the party. House prices increase, new houses are building, the property supplements fatten and the possibility of another bubble haunts us. The Troika depart the stage, its script completed. The burden of choice and the weight of responsibility descend on the government and their civil servants who must write the script for the next act. No wonder they are nervous, no wonder they seek the assistance of an 'a forum on issues like pay, taxation, and what services can be afforded', no wonder the bien–pensants are troubled by – horror of horrors – the ghost of social partnership. No! No! We are assured, this is not Social Partnership. Social Partnership was a bad thing. This is a good thing.
Now, whether it was a good or a bad thing, social partnership, Irish style, was a failure. Whether the proposed forum is a good or bad thing depends on how we understand the problem it proposes to solve. Given the record of this government it is not surprising that the problem is hardly analysed and barely discussed. Once the problem is stated it is immediately clear that while social partnership was an inadequate solution, the proposed forum barely counts as one.
The problem is not a new one. It is as old as politics. It is encapsulated in this examination question, variants of which featured regularly in my exam papers, and, I guess, politics exams everywhere. No democracy without interest groups; interest groups the greatest threat to democracy. Discuss. Students could approach the question from a number of directions. Those with taste for political philosophy could see it as an opportunity to compare and contrast Hobbes and Rousseau, while Marxists could explain how it exemplifies a contradiction inherent in capitalism and its liberal political order. The political scientists could explore the pluralist model with particular attention to its limitations as discussed by Public Choice theorists in general and Mancur Olson in particular.
It is worth reminding ourselves what we can learn from these lines of enquiry.
Frances Fitzgerald, on taking up office as minister, on June 3 2014, commissioned an 'Independent Review Group' to comprehensively review 'the performance, management, and administration' of the Department of Justice and Equality. The report of the group of 5 was published 27 July 2014. It contains little of interest to the student of our administrative system. It is the same old story, told of the Department of Health in the Travers report [2005] and of the Department of Finance in the Wright report [2011]. The department, it seems, operates as a conglomeration of 'simple structures' [Litton 2006]. Senior management (the MAC) do not combine to provide the strategic perspective and oversight that is supposed to be their role.
On the 14 January last, the Government Reform Unit of the Department of Public Expenditure and Reform published a public consultation paper. It invites the public submit their views on 'Strengthening Civil Service Accountability and Performance'. The paper discusses the ins-and-outs of the topic, presenting us with 19 questions that deserve answers.


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Party Food
Two-Step Caramel Chocolate Chip Cookies
This shop has been compensated by Collective Bias, Inc. and its advertiser. All opinions and soft skin are mine alone.
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Fall is such a delightful season! The warm autumnal colors and cooler weather invite cuddles and coziness. I love roasting hot dogs and s'mores in our outdoor fireplace and curling up in front of a blazing fireplace indoors with a good book. Cider and donuts? Yes, please. More frequent baking sessions are in order, too…maybe caramel stuffed chocolate chip cookies? I guess the only thing that comes with autumn that I don't enjoy is drier skin. Furnace season has always seemed to do an unfortunate number on my sensitive skin. I think this year is going to be different.
While I was at Target last time I picked up a new product, Jergen's Wet Skin Moisturizer. I actually bought two of them: Coconut Oil and Monoi Oil, which has a light gardenia scent (there's also a third variety, Green Tea Oil). Their advertising hooked me but the product performance makes it a keeper! I love what it does for my skin.
You really do apply this Jergen's Wet Skin Moisturizer lotion on wet skin. The recommendation is to use about a dime sized dollop for each arm and a quarter size for each leg, so that's what I did. It instantly absorbs into your skin, and seals in hydration while your skin is at its most moist. You don't need to rinse it off and you can pat yourself dry after applying it if you want, but I didn't find it necessary—a real time saver on busy mornings. This lotion leaves you with really soft skin. I was amazed—I felt like I had my own glow!
The good effects of this lotion last, too. I often feel like I need to keep re-applying lotion to make my skin feel smooth, but that isn't necessary with this lotion. Jergen's Wet Skin Moisturizer really seems to lock in the hydration until you're ready to shower the next day.
How about you? Does cooler weather bring on the dry skin for you? I suggest using Jergen's Wet Skin Moisturizer and then head to your cozy kitchen to make some cookies. You'll both be soft and sweet! These two-step caramel stuffed chocolate chip cookies are quick and super-easy.
- Use premade cookie dough or your favorite chocolate chip recipe.
- Put a caramel inside each cookie.
- Bake. Eat. Smile.
TIP: Be sure to let the cookies set on your cookie sheet for a bit, but remove them before the caramel hardens and sticks to the pan. Otherwise you'll be eating very delicious cookie pieces…which are great with ice cream, BTW!
Want to save time and money? There's a current Target Cartwheel offer: 5% savings on Jergen's Wet Skin Moisturizer. Take a peek at this video and tell me which one you're going to try first!
Stephanie is in love with a boy named Sam. He has taught her that it's okay to jump first and look later, to wear a dirty shirt to the park and to decide that today is a good day to take a nap in your rubber boots. She hangs out here blogging at Spaceships and Laser Beams and at our printable party shop on Etsy.


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Rossignol Bandit B1 Skis
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The Bandit B1 is Rossignol's all-mountain performance ski. A versatile ski, the B1 can handle a wide variety of terrain and speeds. The Bandit B1 is perfect for the intermediate to advanced skier who stays on the trails for the most part but likes the feel of a free ride ski. The B1 has a very smooth controlled feel as its full sidewall allows for effortless edge hold on harder snow and the soft tip allows for easy floatation and the ability to power through crud. Designed to perform 70% on the groomed trails and 30% in softer deeper snow the B1 is an essential skis for those blue-sky days when you want to carve it up right underneath the lift.


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Rebounce Trailer (2011)
REBOUNCE is a colorful, tough and powerful film featuring Frederikke Dahl Hansen in the leading role. She plays opposite Anne Sofie Espersen and Dar Salim, and despite being only 16 years old she portrays toughness, charm, and vulnerability admirably. REBOUNCE is an intense drama. Louise's mother is just out of prison and in the eyes of a teenager she's cool, tough and enchanting. To win her love, Louise follows her lead and enters a world of partying, drugs, fast cash and men. Meanwhile, everyone seems to forget that she is just a teenager
Watch the official Rebounce 2011 trailer in HD below or find more Rebounce videos on Vidimovie.


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I captured this fantastic sunset back in August in Sudak, Ukraine - in my opinion it's one of the best shots from those trip.
wow fantastic shot!
Amazing! Love the colors! This is a great capture
paradise !
very nice picture
Wow, this is a very beautiful shot! Love it :3
Wow thats just... beautiful great job!
Such beautiful colours!
These little waves looks like ice with that perfect reflection ! Awesome work !
wow this is simply beautiful
That's a really great picture... Well done!
A FANTASTIC SHOT BABE!!!!!!! Awesome background for a manipulation for sure!!!!!
Beautiful eye to capture such a lovely scene.
This is beautiful.
Lush!!! Really beautiful!
It is amazing!! I love it
Do you want look at my gallery?
Do you want look at my gallery?


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For many who've been campaigning to get better broadband into the UK's rural areas the Government's Big Society policy agenda is a very welcome opportunity to really make a difference, to fix this problem once and for all.
With BD-UK's programme under way and DEFRA announcing £20m to support rural community broadband things seem to be moving in the right direction – but there are some major challenges ahead.
There is a clear sense that politicians are not just espousing the big society principals, they really believe in it – just look to people like Rory Stewart, Peter Aldous and Jesse Norman, and of course Ed Vaizey.
The challenges, to my mind, lie elsewhere.
Generally, public servants have spent the last decade and more centralising – local government had become a delivery body for central government, spending money as they were told, micro-managed from above.
Localism means the direction of travel between local and central government is being put in reverse; the thinking should now be coming from local authorities in tune with their communities, and with the support of central government
This is very hard if you've not done it before
Whitehall civil servant's natural belief is that they have the big picture.
Local government staff are quite naturally risk averse when confronted with new and difficult decisions which may affect the whole of their community.
It will take some time before Whitehall feels comfortable supporting rather than leading, and it will take equally long before local government feels comfortable sitting in the driving seat, guided by their communities.
In this climate, it is perhaps no surprise that the thinking influencing some local broadband plans is drawing from the known, and appears to be taking those local authorities towards a traditional procurement exercise that will ensure only the biggest, most traditional businesses win, and where community engagement is limited to little more than free marketing support.
Perhaps not surprising but it is disappointing given that the Big Society is a key strand of the Government's policy agenda.
In the way that people like Jesse Norman introduced new thinking which led to a new wave of localism in politics, there is now a need to adopt some new thinking which will lead to localism in our digital society.
And this new thinking isn't radical as in hippy – its radical as in different – its tried and tested in countries that have found the will to move on, and its has room in it for big companies, public bodies as well as communities – in a respectful partnership.
Successful local broadband strategies need to seek a balance:
- Which permits the safety of an established major operator while underpinning the heart and soul of a community initiative
- Which allows industrial scale investment while respecting the local stakeholders at the helm
- Which attract the best national and international services while encouraging local services attuned to the community
There is no shortage of communities wanting to become stakeholders their digital future.
There are respected and experienced organisations that can provide the support that can focus that demand into action.
There are organisations willing to help raise funding to support the demand.
All that's needed is for the processes already in motion to be encouraging of this demand rather the dismissive, and for the industry to try something a little radical.
The reward? A new contract with communities which delivers innovation, investment and opportunities. What's not to like?


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ATLANTIC TENDER CHASSIS-FOR PLASTIC SHELLS- AMERICAN FLYER(21)This auction is for an ATLANTIC TENDER CHASSIS. This chassis is for use with PLASTIC tender shells that have the 2 slots on the front bottom edge of the tender shell. It has dicast metal trucks, pickup wheels, weight and a knuckle coupler. NOTE: These are USED chassis.....expect playwear, chipped paint, a little rust now and then ....... DO NOT expect mint or new parts!!! All items are untested AND All items are sold As Is.......unless otherwise described above. IF YOU HAVE A PROBLEM WITH ANY ITEM PURCHASED FROM ME PLEASE LET ME KNOW BY SENDING AN EMAIL AT ONCE. PLEASE SEND AN EMAIL DIRECTLY TO MY EMAIL ACCOUNT....I DON'T ALWAYS GET EMAILS SENT THRU THE EBAY SYSTEM. I AM SURE THAT WE CAN AGREE ON SOMETHING THAT WILL LEAVE US BOTH SATISFIED WITH THE TRANSACTION. ****************** BEFORE YOU BUY !!!!! ******************** Unless otherwise specified most parts are ORIGINAL AMERICAN FLYER PARTS and are all 45 to 65 years old and are USED parts. Occasionally a reproduction part or two might be included. DO NOT EXPECT THEM TO BE NEW OR MINT PARTS. All items will have varying degrees of playwear as expected because of their age. RETURNS WILL NOT be accepted for reasons of cosmetic condition. Items can only be returned ... read more


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Lunsford Mugen MBX6 Titanium Front Upper Pivot Balls (2)
This item is discontinued and no longer available for purchase. You may want to search our site for a similar item.
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Discontinued Online
This is a pack of two optional Lunsford Titanium Front Lower Pivot Balls, and are intended for use with the Mugen Seiki line of MBX6 1/8 scale vehicles. These pillow bars are designed with the racer in mind. They are made from domestic 6AL/4V Titanium and are CNC machined in-house at Lunsford for the best precision.
This product was added to our catalog on October 4, 2012.


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The Fourth Circuit Court of Appeals recently ruled that a Sarbanes-Oxley Act (SOX) claim initially timely filed with OSHA and then withdrawn falls within 28 U.S.C. § 1658(a), the "catch-all limitations period," which provides a four year limitations period. Jones v. SouthPeak Interactive Corp. of Del., No. 13-2399 (4th Cir., 1/26/15).
To read this blog click here.


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Is is worthwile doing a free website on yolasite. Does yolasite have a good pagerank. I have already sites with weebly and they are doing fine but weebly limits me to only 2 free websites whereas yolasite allows me to have upto 5 free websites. Does anyone have a website on yolasite? If yes, how is the site doing?
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I dont know whether yola is a that good. However I would really recommend that you establish your own website without these website builders.
For a number of reasons....
-Its cheaper
-And you can build a more successful website without having the .weebly ending which makes it look more established
-you wont get those generic templates that they offer
Wordpress is a great platform to do this with.
Hope this helped
(If you dont want to do this cant you create a new email and do it with weebly again?)
You can help the HubPages community highlight top quality content by ranking this answer up or down.
Thanks a lot nightnight. I prefer not to cheat on weebly by using a different identity, they have already offered me so much for free. I agree with you that a paid hosting makes ones site look more established. I'll try to learn how to use wordpress.
I actually liked Yola however eventually I ended up getting paid hosting. The builder that they use is very easy for the beginner and you end up with a nice looking website however the builder was not powerful enough for my needs.
I also found that you could not get ranked well using the free product.
I would recommend getting your own hosting through one of the larger well known companies.
Eventually my needs even out grew that and I now use reseller hosting and offer free hosting for a year for my clients that I build their site for or for those clients that I teach to build their own website.
You can help the HubPages community highlight top quality content by ranking this answer up or down.
Thanks a lot flash167. I think I'll definitely have to shift to a paid service sooner or later as you suggest. By the way, you seem to be expert in website building. Me, I need the drag and drop menus to be able to make my website. I have to learn.
Unfortunately drag and drop options usually create code bloat. If you are looking for an easy to use option without having to learn a lot of coding, I would recommend trying WordPress. WordPress is easy and there are lots of plug-ins.
I'll definitely try wordpress flash167


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Of her work, Allyn writes:
"I strive to create charming scenes and characters to delight and engage children and adults alike! Animals with aspirations, great and small, play a large part in my work. Bright color and a joyful exuberance characterize my work as a whole."
A select group of Allyn's paintings under the title "Little Wonders" is currently on exhibit at Papél, New York, the paperie located at 225 Court Street.
Her prints are available as 8.5" x 11" or 13"x 19" with images centered for framing, prices start at $20.00 a piece. Greeting cards range in size and prices start at $3.00 per card. A full line is available online at www.AllynHoward.com
And check out more of Allyn's work on her blog, Blipadee


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Fuckland Trailer (2000)
20 September 2000 84 mins
Fabián, a magician from Buenos Aires, saves his money from weddings, birthdays, and bar mitzvahs, and uses a hidden camera to document a week-long trip to the Falkland Islands where he has a patriotic plan: to impregnate a British woman. If 500 Argies do this annually, the islands will soon be overrun with children belonging to both cultures. He spends his first couple of days in Stanley doing reconnaissance, setting his sights on Camila, whom he's first seen in church. He chats her up at an Internet café. They go out for drinks, then dinner, then to the see the King penguins and a 1982 battlefield. Back home, editing his Dogma 95 film, he receives a final message from Camila.
Watch the official Fuckland 2000 trailer in HD below or find more Fuckland videos on Vidimovie.


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The EQ7 is a professional, accurate, full-featured scientific calculator designed for the iPhone, iPod touch, and iPad. It offers the powerful features ...
The EQ7 is a professional, accurate, full-featured scientific calculator designed for the iPhone, iPod touch, and iPad. It offers the powerful features of a handheld calculator, with an improved interface to enhance user experiences. While designed primarily for mathematicians, engineers, and students, this calculator is accessible to anyone. Features: • Large multi-lined display with automatically adjusting font size for long equations • Morphing keyboard that accommodates user needs • Equation history • Store favourite equations • Display answers as fractions and mixed numerals • Assign variables and constants • Switch bases: binary, octal, decimal, and hexadecimal • Complex numbers • Conversions • Trigonometry • Probability • Generate random numbers • Calculus (integration, and differentiation) • Solving equations (determine the x value which reduces the equation to zero) • Euclidean and floored division modulus • Greatest common divisor • Least common multiple • Average • Median • Series • Product of a sequence of terms • Sign (sgn) • Sexagesimal (degrees, minutes, seconds) • Polar and rectangular coordinates • Configurable rounding mode for displayed answers • Radians, degrees, and gradians • Normal, scientific, engineering, and fixed notation • Full help documentation (click the advanced button entitled "help") • Customizable Colors
Version: 2.7.10
Size: 30.61 MB
Price: 0,00 €
Developed by Clever Alien
Day of release: 2013-06-18
Recommended age: 4+
Productivity | iPhone, iPad
Educational | iPhone, iPad
Educational | iPhone, iPad
Tools | iPhone, iPad


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October is proving so busy. I'm happy today to be sitting at home by my fire and wearing a sweater! My first sweater outing of the season so far. This week the weather turned suddenly cold and wet and an damp chill hung all over. I dug out my boots today and am making chili tonight. I think the family will all cozy up by the fire and play a board game or watch a funny show. How I love Fridays!
Love the simplicity of the white brick + orange + yellow on my mantle.
This week I had a few friends over for a gathering and was stressing about my home. In all, a good thing because it got me in gear to get my house pulled together for Fall. I made a few new purchases, moved things around and did some deep cleaning. ( Yes popcorn is gone from under the couch cushions now!) Those dead plants and wall scuffs probably aren't even noticed, but it's all I focus on which is stupid.
I also hung up those pictures I had leaning on things. I guess you could say I have a hard time committing! Realizing people may be seeing my house in the warehouse mode, I grabbed a bunch of nails and started hammering items up. The thought just makes my husband shudder. Let me be clear, those 3M sticker deals ( guess whose idea) do not hold up art or baskets with plants. We learned first hand the other night when it sounded like the roof caved in. I was just about asleep. Going to bed, take two. The next day, I brought out the big guns ( large nails- yikes) and holes were made people!
The results, below are a few new items and bits added to the home. Funny thing is, I have a lot of black and orange and thus, hello Halloween! I don't know how that happened, but I'm capitalizing on it now by adding pumpkins of all colors and sizes. I'll tone it down later...Or as Tim Gunn would say, "Make it work." Okay here goes...
The ivy in this pot just kicked it so Jack Be Littles work well instead. I can keep this for Thanksgiving too and add acorns, leaves and twigs perhaps?
Black has a way of making things look a bit sharper. I needed some and this Pottery Barn rug was the answer. I'm loving it in this formerly drab space.
Just in case you were wondering, it's been cat-approved. They couldn't wait to experience it of course. Now our chunky boy, Hobbes can camouflage! This is their Awning Stripe rug and it's wool dhurrie. Very soft and on sale right now...
Just found this for my dining room wall. This color works nicely with the paint in there to brighten it up.
|via this blog- dijeau poage
Some of my favorite books look good at this time of year with the right accessories. Vintage books just have that spooky house vibe. Nature-inspired tomes are even better!
This frame I just found and love too...
Also added a ivy to my dining room wall below. Ivy with tortoise shell, like this frame, always looks so rich together. The frame is a gift given to me long ago from my dear friend Jen.
I hosted a Della Dress party and designer Andrea kindly brought these gorgeous sunflowers.
With these, my home really says Fall. I just can't decide where I like them best! Thank you Andrea, I will enjoy these for a while I think!
Decorating the porch is the most fun to me. I love seeing a neighborhood with pumpkins on stoops. Aren't the Cinderella ones cute? Trader Joes is my go to for those.
Then I've got to get out my special Halloween bits and bobs.
My boys want to put the cotton webs up this weekend. I'm okay with white webs. I try to wait until it's a bit closer to the actual date. It always seems like we have at least one rain after they are up. Then they look pretty bad all stuck to my bushes. I have one rule- cute decor, no gore. I'm not into graveyard stuff or hanging guys from trees. We usually stick with webs, spiders, pumpkins and a rubber rat or two!
Irritated black cat? Check. (Marlo, who we adopted near Halloween 4 years ago.)
Have you yet or do you even decorate for Halloween?


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One of the drums I beat all the time to any creators who'll listen is the importance of not creating your art in a vacuum.
Whether it be through social media, your email list, your blogs and websites, or even in-person groups…
It's important to talk about projects well before you launch them, so that you have a receptive audience when you DO launch.
But, I realized that I've not been taking my own advice.
(I guess this is the wisdom that comes with age. Today is my 38th b-day after all.)
Now, I've mentioned a few times the Kickstarter Page Design Blueprint book that I'm working on. The book is pulling together my own experience, that of my brilliant ComixLaunch guests, as well as crunching the numbers on thousands of successful campaigns to crack the code on Kickstarter page design.
Now, while I'll be working closely with 20 creators to build their Kickstarter pages inside The ComixLaunch Course this spring, I realized I should probably get some more input from the wider creator community.
After all, the time to get input on a book or a product is BEFORE, not AFTER it comes out!
So, I'd love to invite you to go to ComixLaunch.com/pagesurvey to answer a very short survey where I ask you a few questions about Kickstarter page design.
This survey is for all creators, not just those with Kickstarter experience, and I really want to hear from you.
Click here to Take the Short Kickstarter Page Survey
A Few Bonuses for Your Time
I always want to respect the time of my audience, so one of the things that I'm working on is a new for 2017 Kickstarter Page Design Checklist.
Everyone who fills out the survey will get my updated checklist free as soon as it's ready.
And I'll also pull one name from the survey participants and hook them up with a $20 Amazon Gift Card.
Again, I appreciate your input.
I'll consider you taking a few moments to knock out the survey as an incredibly generous birthday present. (Thanks in advance.)
I want ComixLaunch to be the absolute best resource for writers, artists, & self-publishers looking to harness the power of the Kickstarter platform.
The only way to make that happen is to listen to you.
- Identify one creative decision you're having trouble making (cover design, next project, title, character design, etc.)
- Poll your audience (any size audience will do) for feedback on the decision.
Podcast: Play in new window | Download


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As parents, we know that throughout their lives, our children will benefit in so many ways from well-developed reading skills. That's why we start teaching them when they are little, sitting and reading to our kids, pointing out words and pictures. And young children typically experience joy when first learning to read. But as they get older, many kids stop being readers.
As an elementary school teacher, I would often hear from parents that getting their child to pick up a book was a huge challenge. My first question was always: "Do you read?" Unfortunately, more often than not, the reply was "no." As parents, we all know that each minute of the day is precious, and that the to-do list is endless. And we also know that children mimic what the adults in their life do. So, if you knew that it would help your child become a reader, would you make time to read? For most of us, the answer of course is "yes." And the reality is that if the parent is reading, the child often will as well.
Ways to Encourage Independent Reading:
- Incorporate a half-hour of reading time into the bedtime routine. Set up a designated space and time when you are both reading. When you're reading, you're modeling the enjoyment and value of this behavior for your child. Remember to keep distractions to a minimum. You'll quickly find that reading time becomes something you both look forward to.
- Take your child to the library. If you do not have a library membership, look into getting one; oftentimes they are quite inexpensive or even free. Make going to the library a weekly adventure. The library provides access to a large selection of material with various mediums and topics. Allow your child to select what they would like to read, and make sure you are browsing the collection as well. Take advantage of any programs the library has for younger children, as it allows them to interact with their peers and makes going to the library fun.
- Use periodic rewards to keep kids interested. Build a chart using construction paper that can be posted in a visible spot. Let your child put a sticker, or color a square, each time they complete a book. (EDITOR'S NOTE: You can download our free behavior charts by clicking here!) You can use various forms of rewards, depending on the age of your child. Some suggestions are a special snack, a movie night, a little extra time at the playground, or maybe a friend over to play.
- Have kids keep a reading journal. In the journal, put a column for the date, the title and the amount of time spent reading. At the end of each page, total the amount; you'll both be amazed by the number of hours and books! Children often would come to school to tell me they had read 10 hours this month, or finished 20 books. It was a great accomplishment for them.
- Let kids read a variety of formats and materials. One myth that surrounds reading is that it must be a certain type of material to be considered reading. I totally disagree with this! Does it really matter if your child reads a catalogue, a magazine, or a novel? I don't think it does. All formats can encourage them to read. There is nothing that dictates that reading material must be the same for everyone (at home, that is!). Encourage sampling a variety of formats, including magazines and audio books.
Reading skills infiltrate every part of life. Encourage your children at a young age to be readers, and it will serve them their entire life.
About Sandra Steiner
Sandra Steiner is a published Inspirational author, blogger and grandparent. Sandra writes to encourage and inspire those around her to live life to its fullest. She lives on beautiful Vancouver Island in Victoria, BC with her husband and fur babies.


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MyEssayWriting.com - Essay Writing Services.
Science Illustrated is the most commanding magazine about science and the natural world we live in today. This title is for the intellectual with a passion for discovery and the sciences. Science Illustrated will deliver the an upbeat, cutting-edge, visually spectacular range of subjects to the entire family.
Please check your posts and search for the doubles. You have already published some of the issues


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Why Must My Culture Take a Backseat to Christmas?
As the days inch closer to the holidays, plans are being made and schedules are being set. I'm replying to Christmas party invites, and going shopping for gifts, and organizing who I'll visit on Christmas Eve and Christmas Day. But wait a second, I'm Jewish.


text: Please Note: The contents of these emails are usually posted online when sent to the list. An index of articles can be found on http://www.ingridnaiman.com. Contents of the posts may not be posted on web sites nor quoted without permission. Links for contacting Ingrid can also be found on any of her sites.