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3-Carboxy-4-alkyl-2-methylenebutyrolactone (C75), an inhibitor of fatty acid synthase and stimulator of carnitine palmitoyltransferase-1, reduces food intake and body weight in rodents when given systemically or centrally. Intracellular molecular mechanisms involving changes in cellular energy status are proposed to initiate the feeding and body weight reductions. However, effectors that lie downstream of these initial steps are not yet fully identified. Present experiments characterize the time courses of hypophagia and weight loss after single injections of C75 into the lateral cerebroventicle in rats and go on to identify specific meal pattern changes and coinciding alterations in gene expression for feeding-related hypothalamic neuropeptides. C75 reduced chow intake and body weight dose dependently. Although the principal effects occurred on the first day, weight losses relative to vehicle control were maintained over multiple days. C75 did not affect generalized locomotor activity. C75 began to reduce feeding after a 6-h delay. The hypophagia was due primarily to decreased meal number during 6–12 h without a significant effect on meal size, suggesting that central C75 reduced the drive to initiate meals. C75 prevented the anticipated hypophagia-induced increases in mRNA for AgRP in the arcuate nucleus at 22 h and at 6 h when C75 begins to suppress feeding. Overall, the data suggest that gene expression changes leading to altered melanocortin signaling are important for the hypophagic response to intracerebroventricular C75.
- fatty acid synthase
- carnitinepalmitoyl transferase-1
- locomotor activity
obesity results from positive energy balance, with energy intake too high, energy expenditure too low, or both. Calories in excess of requirements for maintaining normal physiological function, regardless of macronutrient source, are stored in fat depots. Thus obesity is defined as a state of elevated fat storage. Recent work has identified potential approaches to obesity treatment by manipulating fatty acid metabolism. 3-Carboxy-4-alkyl-2-methylenebutyrolactone (C75), a synthetic inhibitor of fatty acid synthase (17) and stimulator of carnitine palmitoyltransferase-1 (CPT-1; Refs. 18, 33), reduces food intake and body weight when given systemically to rodents (7, 13, 15, 20, 22, 29, 32–34). We now understand that systemically administered C75 reduces body fat stores by decreasing fatty acid synthesis and increasing fatty acid oxidation.
Our recent work indicates that the mechanism by which C75 reduces food intake involves an increase in hypothalamic ATP with subsequent reduction of hypothalamic levels of the active, phosphorylated form of AMP-activated protein kinase (AMPK) (15). AMPK is a cellular fuel sensor that, when activated in response to stressors that reduce ATP, downregulates biosynthetic pathways that consume ATP and upregulates catabolic pathways that generate ATP (11). Recent work by Minokoshi et al. (23) has identified AMPK as a molecule with broad significance in the hypothalamic control of energy intake.
Decreases in food intake and body weight in response to central C75 have been reported, and intracellular mechanisms through which the actions of C75 are transduced have been proposed. However, how these effects are translated into changes in food intake and body weight have yet to be identified. In this work, we characterize behavioral responses to central C75, focusing on how C75 affects ongoing patterns of food intake, and investigate whether feeding changes can account for the C75-induced alterations in body weight. We then probe for potential brain neuropeptide mechanisms to explain the hypophagia and weight loss responses to C75. Our studies show that intracerebroventricular (ICV) C75 can reduce body weight more than can be accounted for by the hypophagia and that the weight loss is maintained for many days. Furthermore, we show that ICV C75 reduces food intake by decreasing meal frequency not meal size. The decreased appetitive drive coincides with a reduced expression of mRNA for agouti-related peptide (AgRP), implicating changes in melanocortin signaling as a key event downstream of C75's direct actions in the brain.
Animals and Housing
Male Sprague-Dawley rats (200–250 g) obtained from Charles River (Kingston, NY) resided in 22 ± 2°C vivaria on a 12:12-h light-dark cycle. They were housed individually in hanging wire cages or in Plexiglas chambers equipped with pellet dispensers and nesting boxes and were weighed daily. Rats were adapted to these conditions for 1 wk before undergoing cannulation of the lateral cerebroventricle. All animal protocols were approved by the Johns Hopkins University Animal Care and Use Committee.
Chronic Lateral Cerebroventricle Cannulation
Rats were anesthetized with a mixture of xylazine (8.57 mg/kg) and ketamine HCl (57.14 mg/kg) administered intramuscularly. They were then positioned in a stereotaxic instrument with the incisor bar adjusted to achieve a flat-skull position. A hole drilled into the skull 1.0 mm caudal to bregma and 1.3 mm lateral to midline accommodated a 23-gauge stainless steel cannula aimed at the lateral ventricle and lowered to 5.0 mm below dura. The cannula was secured in place with dental cement adhered to stainless steel screws implanted in the skull. A 30-gauge stainless steel obturator inserted into the cannula maintained its patency. Rats received penicillin (60,000 units im) and banamine (1 mg/kg im) to prevent postoperative infection and pain.
ICV Injections
ICV injections were performed with a microliter syringe (Gilmont Instruments) attached to polyethylene tubing and a 30-gauge stainless steel injector, the tip of which extended 1.5 mm past the cannula into the lateral ventricle.
Tests for Cannula Placement and Patency
After rats recovered from surgeries for 1 wk, we assessed cannula placements by measuring water intake in response to ICV angiotensin II (ANG II; Sigma, St. Louis, MO). Rats deprived of water for 1 h were given ANG II (50 ng/5 μl) or sterile 0.9% saline vehicle via the ICV cannula, and allowed 30-min access to water from graduated tubes. Rats whose water intake after ANG II was at least 5 ml greater than intakes after saline were used in the experiments. When the behavioral studies were concluded, cannulas were tested again for patency. We analyzed data only from animals with functional cannulas at that time.
FASgen provided the C75 (mol wt = 254.15). We injected rats with sterile RPMI-1640 1× medium containing 2 g/l glucose (11.1 mM) (Cambrex) as vehicle (RPMI, 5 μl), or half-log- and quarter-log-step doses of C75 (10, 32, and 56 μg; 39, 126, and 220 nmol) dissolved in RPMI in the lateral cerebroventricle 5 min before dark onset and food access in all experiments.
Food intake and body weight.
Ten cannulated rats in hanging wire cages had 22-h access to water and chow beginning at the onset of dark, which permitted 2 h at the end of the light for preparations between trials. Rats received a single ICV injection of RPMI or a dose range of C75 dissolved in RPMI. We measured daily intakes of chow, corrected for spillage, for at least 3 days after each injection and allowed at least 4 days for rats to return to preinjection body weights. C75 doses were given in the following order: 0, 32, 10, 56 μg. Data included in the analyses were from the seven rats with functional cannulas at the end of the study.
Locomotor activity.
We moved 10 rats from hanging wire cages into open-field test chambers (Digiscan; Accuscan Instruments, Columbus, OH) to measure locomotor activity responses to ICV C75. The system consists of a 40-cm2 × 30-cm Plexiglas chamber surrounded by sensor panels that emit infrared beams across the open field. Each beam interruption is detected, and patterns of beam interruptions are analyzed to yield measures of locomotor activity. Activity counts were tallied and stored on file on a computer.
Rats remained in the monitors for 3 days with ad libitum access to food and water. The first day was considered a day of acclimation to the novel environment. On the next day, their activity was monitored in response to the ICV RPMI vehicle, and on the last day, their activity was monitored in response to 32 μg of C75. Injections were given just before onset of dark. Locomotor activity, as the number of beam interruptions in the horizontal plane, was monitored on all 3 days, in 11 bins of 2-h duration, for a total of 22 h each day, allowing 2 h for preparations between trials.
Meal patterns.
In a separate group of rats, we examined patterns of food intake to further characterize the time course and ingestive behaviors underlying the hypophagic response to ICV C75. Six rats were acclimated to ad libitum access to water and 45-mg pellets in cages equipped with computer-monitored pellet dispensers (Med Associates, Georgia, VT) in which an infrared beam detects the removal of a single pellet from the feeding trough and triggers pellet replacement. The times of pellet removals were recorded to the nearest 10th of a second and stored on file on a computer. Files were formatted in Microsoft Excel 98 for subsequent analysis with TongueTwister (version 1.46a) on Macintosh computers (12).
C75 doses were given in the following order: 0, 10, 32, 56 μg. Data were analyzed for 3 days subsequent to drug or vehicle injections for latency to onset of the first meal of the day, as well as for pellet acquisitions, meal number, and meal size during (for each day): 0–24 h, 12–24 h light phase, 0–12 h dark phase, and 3- and 6-h segments of the dark phase. Meals consisted of at least five pellets with intervening intermeal intervals that lasted at least 10 min.
In situ hybridization for hypothalamic mRNA.
Based on results from the food intake and meal pattern experiments, we analyzed C75-induced alterations in hypothalamic gene expression of feeding-related neuropeptides at two time points: 6 h after injection, when hypophagia commences, and 22 h postinjection, when the hypophagia is well established. For the 22-h time point, 18 rats in hanging wire cages were assigned to three groups: 1) RPMI injected, ad libitum fed (ADLIB; n = 6); 2) C75 injected (32 μg), ad libitum fed (C75; n = 6); and 3) RPMI injected, pair fed to the C75 group (PF; n = 6). Each PF rat was given the average C75 group chow intake plus its average amount spilled. PF rats received their allotment of food at lights out and ran out of food in a timeframe comparable with the delayed hypophagia that C75 produced in the meal pattern studies. Injections were given 5 min before onset of dark and chow access. At 22 h postinjection the rats were killed. In the other experiment, we killed six ADLIB and six C75-treated rats at 6 h after injections.
Tissue processing and in situ hybridization.
Brains were removed, frozen quickly in isopentane on dry ice, and stored at −80°C. They were cryosectioned into 14-μm slices in the coronal plane, thaw mounted onto electrostatically charged microscope slides, and air dried. Mounted slices were then fixed with 4% paraformaldehyde, dehydrated with ethanol, and stored at −80°C.
As described previously (2, 3), plasmids with cDNAs for neuropeptide Y (NPY), AgRP, proopiomelanocortin (POMC), and corticotropin-releasing factor (CRF) were linearized by recommended restriction enzymes. Antisense riboprobes were labeled with [35S]UTP (Amersham Pharmacia Biotech) by using in vitro transcription systems with appropriate polymerases according to the manufacturer's protocols (Promega) and purified by Quick Spin Mini Columns (Roche Diagnotics) to yield specific radioactivity of 5 × 108 cpm/μg.
For in situ hybridization, frozen tissue sections were allowed to warm to room temperature, treated with acetic anhydride and ethanol, and incubated in hybridization buffer containing 50% formamide, 0.3 M NaCl, 10 mM Tris·HCl, pH 8.0, 1 mM EDTA, pH 8.0, 1× Denhardt's solution (Eppendorf), 10% dextran sulfate, 10 mM dithiothrietol, 500 μg/ml yeast tRNA, and 107 cpm/ml of [35S]UTP-riboprobe at 55°C overnight. After hybridization, the sections were washed three times with 2× standard sodium citrate (SSC), treated with 20 μg/ml RNase A (Sigma) at 37°C for 30 min, then rinsed twice in 2× SSC at 55°C for 5 min and twice in 0.1× SSC at 55°C for 15 min. Slides were then dehydrated in gradient alcohols, air-dried, and exposed with BMR-2 film (Kodak) for 1–7 days.
Autoradiographic films were scanned (Epson), and the images were analyzed quantitatively with Scion Image (Version 1.62c, National Institutes of Health), by using autoradiographic 14C-labeled microscales (Amersham) as a standard. Data were averages obtained from three sections of the product of area and density of the region of interest. Data from C75 and PF rats in the 22-h experiment were normalized to ADLIB control average. Data from C75 rats in the 6-h experiment were normalized to the ADLIB vehicle control average. Final analyses included data from at least four rats per group (22-h experiment, n = 4 for C75 group CRF mRNA hybridization, all others n = 6).
Statistical Analysis
Food intake and body weight data for each day were analyzed by one-way repeated-measures ANOVA [F(dfbtwn treatments, dfresidual)]. Meal pattern data were analyzed by one-way repeated-measures ANOVA for each time segment. Data from in situ hybridization experiments were analyzed by one-way ANOVA [F(dfbtwn groups, dfresidual)]. Significant effects in the ANOVAs prompted post hoc tests for dose differences by Fisher's least squares means. Locomotor activities for each 2-h bin were analyzed by Student's paired t-test. Significance for all tests was assumed at P ≤ 0.05.
Central C75 Reduces Food Intake
ICV C75 reduced chow intakes on day 1 [F(3,18) = 6.32, P = 0.004; Fig. 1A]. Although 10 μg of C75 did not reduce chow intake significantly compared with vehicle, the 32- and 56-μg doses produced significant and equal decreases of chow intake to 16.4 ± 1.7 and 15.8 ± 1.7 g, respectively (vs. vehicle: P = 0.004 and P = 0.002, respectively). Although reduced, chow intake on day 2 after C75 was not significantly different from intake after vehicle. On day 3, control levels of chow intake were fully restored. Chow intakes measured until day 4 after 32 μg of C75 and until day 5 after 56 μg did not differ from those after vehicle (data not shown).
Central C75 Produces Long-Lasting Weight Loss in Excess of Feeding Reduction
Rats gained 4.4 ± 1.2 g by the end of day 1 after ICV injection of RPMI vehicle. Single ICV injections of C75 reduced body weight dose dependently on day 1 [F(3,18) = 10.637, P < 0.001; Fig. 1B]. Doses of 32 and 56 μg of C75 significantly reduced body weight, by 8.0 ± 3.8 g (P = 0.005 vs. vehicle) and 16.6 ± 5.2 g (P < 0.001 vs. vehicle), respectively. Although reductions in chow intake were equal after the 32 and 56 μg doses of C75 (Fig. 1A), body weight after 56 μg was significantly lower than after 32 μg (P = 0.041; Fig. 1B).
Although the principal weight losses with C75 occurred on day 1, reduced body weights were maintained over multiple days (Fig. 1B) [day 2: F(3,18) = 9.219, P < 0.01; day 3: F(3,18) = 7.697, P = 0.002; day 4: F(3,18) = 4.327, P = 0.018; day 5: F(3,18) = 6.521, P = 0.004]. Rates of weight gain or regain across doses over days 2-5 were comparable, such that doses of 32 and 56 μg resulted in significantly lower weights than vehicle consistently across days 2-5 (day 5: 32 μg, P = 0.002; 56 μg, P = 0.007). At day 5, the weight difference between the 56 μg dose and vehicle was 21.4 g, so a weight loss of ∼5% was maintained for 5 days after a single ICV injection of C75.
Central C75 Does Not Alter Physical Activity
Rats exhibited essentially the same levels of activity in the horizontal plane, whether given vehicle or 32 μg of C75 ICV, during each of the 2-h bins of data collection on the day after injection (Fig. 2). Total counts of horizontal activity after C75 did not differ from those after vehicle during either the 0- to 12-h dark period [vehicle vs. C75: 42,500 ± 4,200 vs. 37,000 ± 4,600, t(18 df) = 0.887] or during the entire 0- to 22-h period of data collection [vehicle vs. C75: 54,100 ± 4,400 vs. 47,500 ± 4,900, t(18 df) = 1.002].
Central C75 Decreases Meal Frequency
Day 1 pellet intakes.
ICV C75 reduced the acquisition of pellets on day 1 in the meal pattern experiment (Fig. 3, top) in a dose-response pattern consistent with that seen in the chow intake experiment (Fig. 1A). C75 did not produce significant feeding or pattern changes on days 2 or 3. C75 decreased the number of pellets acquired during the entire 0- to 24-h period of day 1 [F(3,15) = 4.237, P = 0.023], with significantly reduced and equal intakes after 32 and 56 μg (339 ± 63 and 325 ± 60 pellets, P = 0.031 and 0.022, respectively) compared with vehicle (528 ± 28 pellets).
Delayed hypophagia on day 1.
Analyses of food intake patterns in 3- and 6-h bins revealed that C75 did not significantly alter pellet intake during the 0–3 h, 3–6 h, or the first 6 h of dark [0–6 h: F(3,15) = 0.0646], but C75 reduced pellet acquisition during 6–9 h [F(3,15) = 3.426, P = 0.045], 9–12 h [F(3,15) = 3.688, P = 0.036], and the last 6 h of dark [6–12 h: F(3,15) = 5.719, P = 0.008] (Fig. 3). During the 6- to 12-h period, C75 doses of 32 and 56 μg significantly reduced pellet acquisitions (88 ± 37 and 84 ± 26 pellets, P = 0.017 and 0.014, respectively) compared with vehicle (210 ± 29 pellets) (Fig. 3).
Delayed decrease in meal frequency.
The C75-induced reduction in pellet intake appeared most clearly related to a decreased number of meals (Fig. 3, middle) rather than a reduction in meal size (Fig. 3, bottom). C75 decreased meal number during 0–24 h [F(3,15) = 3.63, P = 0.038], with significantly reduced and equal numbers of meals after the 32- and 56-μg doses (5.8 ± 1.4 and 6.0 ± 0.05 meals, P = 0.021 and 0.027, respectively) compared with vehicle (9.0 ± 1.3 meals). C75 did not decrease the number of meals during the first 0–6 h of dark, but did reduce meal number significantly during the 6- to 12-h period [F(3,15) = 4.479, P = 0.02], due to a reduction at the 56-μg doses of C75 (1.5 ± 0.04 vs. 3.3 ± 0.06 meals, P = 0.032).
Central C75 Decreases AgRP mRNA
At 22 h after injection and food access, rats pair fed (PF group) to the levels of food intake by hypophagic C75-injected rats [food intakes: ADLIB = 26.2 ± 2.1 g, C75 = 10.6 ± 1.6 g, PF = 9.1 ± 0.2 g; F(2,14) = 40.174, P < 0.001; PF vs. C75 not significant] had a significantly increased hybridization signal in the arcuate nucleus for AgRP mRNA compared with the ADLIB controls [F(2,13) = 6.123, P = 0.013; PF = 234 ± 32% of ADLIB, PF vs. ADLIB, P = 0.005] (Fig. 4A). In contrast, C75-injected rats, though hypophagic, had AgRP mRNA signal levels comparable to those of ADLIB (140 ± 30% of ADLIB, not significant) and significantly lower than those of PF (P = 0.034). Although reduced, the hybridization signal for NPY mRNA after C75 was not significantly different from the signal seen in ADLIB. Levels of hybridization to arcuate nucleus POMC mRNA and to paraventricular nucleus CRF mRNA did not differ among treatments.
At 6 h after injection, a time when food intakes did not yet differ (ADLIB = 10.2 ± 1.5 g, C75 = 11.4 ± 0.6 g), rats given C75 had decreased a hybridization signal for arcuate AgRP mRNA compared with that of vehicle-injected rats [t(10 df) = 2.212, P = 0.05; Fig. 4B]. Hybridization to arcuate mRNAs for NPY or POMC, and to paraventricular CRF mRNA, did not differ between treatments at this time point.
This study characterizes the time courses and patterns of hypophagia and weight loss in response to brain administration of the fatty acid synthase inhibitor and CPT-1 stimulator C75 in a rat model. The data suggest that these changes are achieved through altered melanocortin signaling. C75 reduced food intake by decreasing meal frequency. It took at least 6 h for a single ICV injection of C75 to decrease meal frequency and food intake. We showed that just before these behavioral changes, gene expression for AgRP was reduced. These data suggest that in the rat, central administration of C75 reduced feeding by decreasing de novo production of this orexigenic hypothalamic neuropeptide and altering melanocortin signaling.
The hypophagia produced by ICV C75 had a delayed onset. The 6- to 9-h period after injection was the earliest 3-h dark-phase bin to show a significant reduction in pellet acquisition. The hypophagic response might be delayed because C75 affects the de novo production of hypothalamic feeding-related neuropeptides. Consistent with data from mice (13), 1 day after ICV injection of C75 the rats, though hypophagic, did not exhibit the increase in arcuate nucleus expression of mRNA for AgRP seen in PF controls (Fig. 4A). Thus in opposition to gene expression changes due to an imposed food restriction, C75 decreases the expression of arcuate orexigenic neuropeptides (16). However, the question remained whether such C75 alteration of gene expression could drive the changes in feeding behavior. C75 decreases the level of expression of mRNA for AgRP at 6 h (Fig. 4B), just as the compound begins to reduce feeding. The delay in hypophagic response to C75 may include the time required for C75 to diffuse to critical sites in sufficient amounts. It is also possible that the biochemical or other changes occurring downstream of pharmacological fatty acid synthase inhibition and CPT-1 stimulation with C75 are subordinate to other physiological influences during the early dark phase.
In mice, C75 decreases the level of mRNA for NPY in the arcuate nucleus (5, 13, 15, 16, 29, 34). In these rat experiments, C75 tended to reduce levels of NPY mRNA. C75 prevents the expected hypophagia-induced increases in c-Fos in medial arcuate nucleus neurons that contain both NPY and AgRP (22). Results from recent experiments suggest a mechanism of action in which C75 increases hypothalamic ATP, reduces levels of gene expression for pAMPK, pCREB, and NPY, and reduces the levels of these proteins in mouse hypothalamus (15, 16). None of the experiments to date have examined the possibility that, in vivo, C75 alters synaptic release of neuropeptides or other neurotransmitters involved in food intake control, an action that could produce rapid changes in feeding behavior. Mice, unlike rats, reduce their food intake rapidly in response to ICV C75 (9, 15).
AgRP is an endogenous melanocortin antagonist at melanocortin-3 and -4 receptors (MC3R, MC4R) (8, 27, 35). The brain MC4R is most clearly involved in the control of food intake (14, 21). Recent reports suggest that AgRP (fragment 18-132) (Refs. 10, 26) and shorter fragments (6) also act as inverse agonists, keeping the MC4R in an inactive conformation and preventing their agonist-dependent activation and internalization (30). C75 decreased levels of AgRP mRNA at 6 h. We hypothesize that this should result in less AgRP signaling, so that MC4R previously held at the extracellular membrane by AgRP would be less likely to be occupied by AgRP. In such a case, neither POMC gene expression nor its processing to melanocortins would have to increase to achieve an increase in melanocortin signaling "tone," and to result in decreased food intake.
At the level of individual meals, feeding reductions can occur via decreased meal size or decreased meal frequency. The melanocortin feeding system has not been extensively tested for effects on meal pattern. One report shows that ICV administration of the MC-3/4-R agonist melanotan-II decreases food intake in rats by decreasing meal duration and size selectively (1). However, other data have demonstrated a decrease in meal number as well (25). Central C75 reduced pellet acquisitions in the meal pattern experiment during 0–24 h, specifically during 6–12 h. The 0- to 24-h reduction in pellet intake was clearly characterized by a reduction in the number of meals during 0–24 h. The reduced meal number occurred specifically during 6–12 h, with 56 μg of C75. Although C75 did not produce a significant reduction in meal size, subtle reductions in meal size may contribute to the overall feeding reduction. However, our data are more consistent with the notion that C75 acts in the brain primarily to reduce the drive to initiate and reinitiate energy intake, rather than to truncate meals once they have begun.
Although hypophagia was a major contributor to weight loss in rats given C75 centrally, additional factors cannot be discounted. Although 32 and 56 μg of C75 produced the same level of hypophagia on day 1, the 56-μg dose produced the greater weight loss. Furthermore, the 56-μg dose reduced food intake by 7 g, yet produced 22 g of weight loss relative to vehicle control. The present experiments do not examine hydration, overall metabolic measures, or carcass composition. They do show that ICV C75 did not alter the level of physical activity. This is consistent with other data showing that C75 alters brain c-Fos activation only in hypothalamic and hindbrain sites involved in the control of feeding and involuntary energy expenditure (9, 22) without altered c-Fos in cortex, cerebellum, or other brain regions (22). Thus, although C75 has been termed a "nonspecific neuronal activator" in some in vitro studies (31), this seems unlikely in vivo. It has been suggested that C75 decreases feeding and body weight secondary to illness (7, 28, 31). Relevant to the present study, ICV C75 does not produce conditioned taste aversion in rats (7).
Until very recently, effects of central C75 administration on peripheral tissue metabolism had not yet been explored. Cha et al. (4) report that ICV C75 increases whole body fatty acid oxidation in mice in vivo and in mouse skeletal muscle in vitro at an early 2-h time point. Muscle is a large organ that primarily uses fatty acids for fuel, so it seems reasonable that increasing fatty acid oxidation in skeletal muscle could be one way that central C75 reduces body weight. Notably, intrahypothalamic injection of leptin also increases fatty acid oxidation in skeletal muscle (24). Leptin is also one of several anorexigenic treatments recently shown to decrease hypothalamic AMPK activity (23), as does C75 (15).
The feeding and weight changes after C75 are unusual in that there is no rebound hyperphagia and that the weight loss initiated on day 1 is sustained for many days, without return to preinjection baseline body weight (Fig. 1). The present study did not include measures of hypothalamic mRNA beyond a 22-h time point. It would be interesting to know whether AgRP mRNA remains decreased in C75 treated rats for several days or whether other events downstream of altered melanocortin signaling are affected at later time points.
Perspectives: C75, AMPK, and AgRP/Melanocortin Signaling
Our data suggest that ICV C75 decreases the drive to initiate energy intake. The sequential timing of C75's reduction of AgRP gene expression and the hypophagia suggest that altered melanocortin signaling is important for the hypophagia. A recent report has demonstrated that the increased AgRP in response to a low-energy state requires the activity of AMPK (19). Conversely, decreased hypothalamic AMPK activity decreases mRNA for AgRP and reduces food intake and body weight (23). Thus the decreased appetitive drive with ICV C75 may derive from its ability to increase hypothalamic ATP and decrease the activity of AMPK (15). This in turn may reduce AgRP gene expression and AgRP blockade of MC4Rs to increase melanocortin signaling "tone."
FASgen, Inc. provided the C75 for these experiments. Under a licensing agreement between FASgen and the Johns Hopkins University, G. V. Ronnett and F. P. Kuhajda are entitled to a share of royalties received by the University on sales of products described in this article. F. P. Kuhajda owns FASgen stock. G. V. Ronnett and T. H. Moran have an interest in FASgen stock that is subject to restrictions under University policy. The Johns Hopkins University manages the terms of these agreements in accordance with its policies on conflict of interest.
This work was supported by National Institutes of Health Grants DK-068054 (to S. Aja), DK-19302 (to T. H. Moran), CA-91634 (to J. M. McFadden), DC-02979 and DK-64000 (to G. V. Ronnett), and CA-87850 (to F. P. Kuhajda).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2006 the American Physiological Society


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Lexicon Welcomes Back Kennedy Placek to 2016 Internship Program
Lexicon welcomes back Kennedy Placek to our summer internship program
Lexicon Founder David Placek Weighs in on Kraft Dinner Rebrand
Most people would not consider changing their name to Sweetie Pie or Honey Bunny just to demonstrate that they are loved. But for a brand that depends on people's affection for its existence, it may just make sense to take a term of endearment and make it official.
Meet Our First 2016 Summer Intern: Sarah Schechter
This summer's internship program features four bright thinkers from top universities across the nation.
Lexicon Branding Featured on CBS Sunday Morning
If you are in the business of launching a new product, the name is everything. David Placek is a professional "namer, whose Sausalito, Calif.-based company, Lexicon, has named some of the biggest products around. Lee Cowan finds out about the genesis of such well-known names as Outback, Dasani and Swiffer.
Lexicon Opens Office in Amsterdam
Our new office allows us to expand our client service offering to Europe and the UK and is a core part of our strategy to develop Lexicon's European client base. Our primary focus will be on creating next generation brands in the technology and consumer categories.


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Sales Development Manager ( 1 - 2 yrs)
Corporate Resources
RS 1,75,000 To 2,00,000 Panaji, Chiplun, Kolhapur, Malegaon, Nashik, Pune, Ratnagiri, Sangli - Miraj & Kupwad
1. Identification of potential FCs as per the company norm. 2. Recruit minimum expected number of FCs within three months of joining. 3. Be a coach and guide for FC in sales calls and in prospecting new customers. 4.Prepare day to day sales and DI...
Key Skills : sales,head sales,marketing,business development
Sales Officer For India ( Fresher)
Itm Group of Institution
RS 1,50,000 To 1,75,000 Ahmadnagar, Jalgaon, Malegaon, Nashik, Pune
We Offers A Great Opportunity For Freshers To Build A Career In Banking Sector With Leading And Renowned Banks . We Recruit Graduates As A SALES OFFICER Throughout Maharashtra And Goa. Contact - 09699504070
Key Skills : sales,client relationship executive,business banking executive,area sales officer,sales officer,sales manager,area sales incharge,branch sales...
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Key Skills : marketing,public relation,business developer,sales executive,distribution,business development executive,regional manager,head sales,channel sales


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Love, Mystery, and Family Dysfunction in "Julieta"
Pedro Almodóvar's gorgeous (and 20th!) film is why movie theaters still exist, people—so see it while you can.
30-Second Synopsis: Julieta is planning to move out of Madrid with her boyfriend, Lorenzo, but her plans change when she runs into Beatriz, a childhood friend of her daughter, Antía. Julieta hasn't seen her daughter in years; Antía left one day for a spiritual retreat and never returned. Jumping between the past and the present, Julieta tells the story of its title character and how she attempts to reconcile her relationship with her daughter.
The Auteur: Spain's Pedro Almodóvar, known for such films as All About My Mother, Volver, Women on the Verge of a Nervous Breakdown, and Talk to Her.
The Source Material: Almodóvar, who wrote and directed the film, based it on three short stories by Alice Munro ("Chance," Soon," and "Silence"), all of which appear in her 2004 book, Runaway.
The Stars: As the present-day Julieta, Emma Suárez is a perfect Almodóvar heroine: conflicted, mysterious, and beautiful (and with a touch of huskiness to her voice—Almodóvar is partial to dialogue delivered with just the right degree of breathiness). She is perfectly matched by Adriana Ugarte, who plays Julieta in her younger days.
Who Almost Starred in Julieta: Meryl Streep. Almodóvar temporarily considered making this his first English-language film but, in the end, could not resist making it in his native tongue.
Charming Proof of How Much Almodóvar Loves This Movie: The 13-page document of his notes on the film, handed out to everyone who attended the screening.
Almodóvar's Words on the Film: "Julieta is about the mother's struggle to survive uncertainty. It is also about fate, about guilt complexes, and about that unfathomable mystery that leads us to abandon the people we love, erasing them from our lives as if they had never meant anything, as if they had never existed."
The People Doing All That Abandoning: First, Julieta is abandoned by her daughter—then, Julieta herself abandons her longtime boyfriend when presented with the first lead on her missing daughter in 12 years.
Make Sure You Don't Blink When: A young, distraught Julieta has her hair tended to by Antía and her friend Beatriz. It's a quick, clever, transformative moment you won't want to miss.
Artists Whose Fingerprints Are Happily Evident: Master director Alfred Hitchcock, Patricia Highsmith (who's even mentioned by Lorenzo at one point), and, of course, Alice Munro.
Why Almodóvar Remains So Vital: There simply are not enough directors in the world who try to get as much out of every frame as Almodóvar does. From the opening shot to the closing moments, he infuses his beautiful images with layers of subtext, and the viewer can't escape the feeling that this artwork is deftly placing itself in dialogue with the canon, and adding something crucial to the conversation. In short, it feels good to leave yourself in the hands of an artist as capable as Almodóvar.


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California Auto Centers
ReScore Reviews™ (1)
98% Would Recommend
Latest Review about 5 hours ago
Review for California Auto Centers
GUADALUPE L. on 02/09/2014
"Wont give up until the problem is found and corrected"
Electrical issues are the worst. Todd and the team working on the car didn't give up until they found the problem and the solution. This makes my life a lot more comfortable knowing that when my daughter drives this car, she is safe.
Vehicle: Chevrolet Cavalier
Service Date: 02/07/2014
Review Created: 02/09/2014 08:03 AM


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LOOK:Tuwang tuwa si Jim Paredes sa pagkakatalo ni Manny Pacquiao
Legendary OPM artist Jim Paredes expressed his happiness after he saw the defeat of former WBO Welterweight Champion and Senator Manny Pacquiao against his fellow Aussie Jeff Horn.
On Saturday, Manny Pacquiao faced one of the biggest upsets of his career after he lost to the undefeated Aussie boxer.
"Pacquiao lost!! What a great day!!" Paredes said in his two tweets after the boxing match.
Paredes also criticized the Filipino boxing champ for his beliefs and he called Pacquiao a Pro-Extrajudicial Killing, Pro-Death Penalty and Anti-Gay politician.
He also reminded the Senator to pay his taxes.
"You used to unify us. The whole nation.. Not anymore. EJK, anti-gay, death penalty got in the way.
After u rest I hope you pay your taxes." Paredes tweeted.
After u rest I hope you pay your taxes." Paredes tweeted.
The tweets of Jim Paredes against Pacquiao sparked outrage to the netizens especially from Pacquiao fans.
"And you so – called yourself a FILIPINO????" @joancharmed said in a tweet.
But netizen @iamcessyg reminded @joancharmed that Parades is already an Australian Citizen.
"He's not. He's Australian. And that puzzles me why he keeps meddling with Filipino issues." @iamcessyg said in her tweet.
@cjamado23 also criticized Paredes for mocking the boxer who represented the country for decades.
"Man i do not like manny the politician but to mock manny the boxer representing your country is just low." CJ Amado told Paredes.
Loralaine Pascual also informed Paredes that he got a new hater for tweeting against Sen. Pacquiao
"Jim Paredes gained a lot of haters and I'm one of them. What a great day!" Pascual tweeted.
Another Netizen annoyed Jim Paredes and the former artist decided to block him in his twitter account.
"Dapat sayo jim binabato sa marawi" @donmupz told Paredes.
Paredes responded "Dapat sayo binoblock! DONE!"
Another netizen who supported Paredes in his advocacy for a long time, expressed his disappointed for showing too much hate against the boxing champ.
"Sir kasama nyo po ako sa ilang adhikain nyo but this time, this is just too much and out of line. Godbless." @nicko_pogi12 tweeted.
Meanwhile on Facebook, Paredes also received criticisms from the netizens.
"Because he embraced and love his australian citizemship..what ashame of people like you..dpat doon k n lang sa Australia manirahan matandang hukluban.." Juvy Baco said in her FB comment.
Mocha Uson also slammed Paredes for his tweet against Senator Pacquiao. She believes that Paredes already corrupted by his hate towards the Duterte administration.
"Ano nangyari sayo Mr. Jim Paredes???? Nakakaawa ka na, yung bitterness mo kay tatay Digong naging ganyan ka na sa bansa natin." Mocha Uson said in her post.
Since Senator Pacquiao expressed his support to the reforms of the Duterte administration, Jim Paredes started to hate the Filipino boxing champ.
In his past tweet, he even called the Senator 'crazy' for begging Indonesian leader Joko Widodo to save Mary Jany Veloso from death penalty.
Pacquiao was considered as a national treasure of the Philippines because of his contribution in sports.
So tweeting against Manny Pacquaio may be a wrong move, especially there are many people who were still sad by the result of the match between the Filipino boxing icon and Jeff Horn.[source]


text: There have been a number of discussions on this general subject, but I want to do something opposite to those threads. With a bluetooth rcvr on my systen located next to the hdtv, I would like to use my phone and its keyboard (flipside) and little mouse pad to controll the computer. Anyone seen or heard of an app that can do this?? Martyn


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So, 5 weeks left to meet at Space/ID Bologna! And we are getting ready to laugh, dance, move, and enjoy our time together! This is easy…
Meanwhile, as we are also going to creatively start to explore intersectional justice, sexual citizenship, public space and European citizenship, safer space, community space and public space through arts and direct action practices, we will propose suggestions to get into the mood and give the possibility to have a wider – and as horizontal as possible – exchange before the meeting (mostly) through QueerArtLAB FB group and by email.
– sharing knowledge
we will propose materials and readings about intersectionality, privilege, art interventions and public space, and everybody is more and welcome to add comments, links and suggestions.
we'll publish our picks in Resources.
The common language within the group that will meet in Bologna is English, but materials in other languages (possibly with a brief introduction in English) and on local context related to the themes are more than welcome as we recognize the limits of linguistic (and cultural) monopoly of anglophone-centered analysis and discourse. Beyond English and mother-tongues (Polish, Danish, French, British English, Castellano, Italian), more than one person in the group can understand French, Castellano, Catalan and Italian as foreign language. So, please, enjoy!
– figure out our know-how on DIY (do it yourself), and DIT (do it together)
there's a lot of simple stuff (or considered as such) that we've been doing and that can be of great value to be shared: you know how to make bread, or to make molds, printing, stencil with basic materials, or how to make a zine, or to apply make up to whomever and make them uniquely gorgeous, or to work on open source, or…
the list might me be infinite… so, let's start to put together our magic!
– sharing experiences
of course, we will do that during the meeting. Nevertheless sharing information about works we've been doing collectively or individually, as well as other projects that inspire us with links or short descriptions, images, sounds etc, are a great way to start to have an in-depth and diversified approach to arts and how to create communities and challenge power relations with them.
– sharing responsibilities
as organizers, we do have some responsibilities that are up to us (e.g. selection, practical arrangements, definition of the draft programme, final report), nevertheless some arrangements can be already defined within the group in a participatory way: for instance, the definition of materials and food; space and time arrangements; as well as content and skills sharing during Space/ID.
Last but not least, contributions to the different parts of the preparation are highly recommended but not compulsory, and are not limited to actual participants to the training (except for sharing responsibilities).
How does it sound? 😉
If you have doubts or questions, please ask the group!
QAL Team


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You can now download iOS 8.1.3 ipsw through the Software Update section of the native Settings app on iPhone or iPad. It is also possible to update through iTunes on a Mac or PC.
This new update primarily focuses on bug fixes, but also increases general stability of iOS as well. It is recommended for devices that run prior versions of iOS 8 to install iOS 8.1.3 using direct links.
For users whose iOS devices have less available storage, the iOS 8.1.3 may be very useful because it is said to reduce the amount of free storage space available to install an available software update.
The total reduction is currently unknown, but users who have limited device's storage capacity have been able to install the update with as little as 500MB free. It is really less than prior iOS updates often required several GB of storage capacity to be available.
The full release notes of iOS 8.1.3
This release includes bug fixes, increased stability and performance improvements, including:
Reduces the amount of storage required to perform a software update.
Fixes an issue that prevented some users from entering their Apple ID password for Messages and
Addresses an issue that caused Spotlight to stop displaying app results
Fixes an issue which prevented multitasking gestures from working on iPad
Adds new configuration options for education standardized testing
The easiest way for most users to install iOS 8.1.3 is through the Software Update within the Settings app on their iPhone, iPad or iPod touch. Please backup your devices before installing software updates :
Step 1. Open the "Settings" app and then go to "General" option
Step 2. Choose "Software Update" and when iOS 8.1.3 appears on the screen, pick "Download & Install" option
The update will be downloaded from Apple servers and will be installed on device and rebooting it automatically to complete the software update.
Users can also choose to download iOS 8.1.3 ipsw install it using the direct links below:
iPhone 6
iPhone 6 Plus
iPhone 5S CDMA
iPhone 5S GSM
iPhone 5 CDMA
iPhone 5 GSM
iPhone 5c CDMA
iPhone 5c GSM
iPhone 4s


text:
The Professional Teachers' Council NSW office facilities provide quality professional office
space for member associations' use including permanent and casual alternatives.
Conveniently located within walking distance from Lidcombe Station, bus, M4 and Parramatta Road the spaciousness of the office allows PTC NSW and the member associations of English, Geography and Drama to work side by side in a professional environment.
Serviced & virtual offices, with quality fit‐out provide a professional presentation for all
member associations to access either casually for meetings, temporary work space or to
consider as their new home.
Do you require an office or hot desk for 1 or 2 days a week? How about meeting spaces? Or… for a few hours perhaps, in a professional environment… a work space where you can
download your emails, print documents and host meetings? Our new facility has space just for that purpose.
Long term rental office space?
We have floor space that can be co‐rented, which includes free access to meeting rooms, state of the art kitchen area and dedicated parking spaces. Once this area is rented it is gone! If your association is looking for alternative accommodation, limited small to medium areas are available. Talk to us on 02 9716 0378 or firstname.lastname@example.com to discuss your requirements.
Services @PTC NSW


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View all tyres 205/55 R16
This product was last purchased today at 07:48 PM
We have been collecting information about this tyre for 846 days. In that time we have received 269 reviews. The total distance driven by our customers is 1368000 miles.
The highest rated parameter is: the grip on a wet surface.
This tyre was reviewed by users driving usually in the city.
This tyre was reviewed by drivers who assess their driving style as moderate.
Reviews per page:
Is this review helpful?
6 people
10 people
I've mounted the Nokian WR D4 tyres over 2 months ago. I drove a little more than 750 miles on them with a 150 bhp car weighing
1.5 tons. Usually in the city. First thing that got my attention was the smell of rubber compound. That's very unusual. From
what I've read Nokian added canola oil to the mixture, maybe this caused such an unusual effect. These tires really smell like
no other. I don't pay much attention to the appearance of the tread, for me it's completely irrelevant. For me, the tyre needs
to be effective when it comes to draining water, mud and snow as well as breaking distance. On second place i'd put the noise
level and the third thing is rolling resistance. But I must admit that this tread is unique in appearance and looks quite nice.
As for traction; On the dry the tyre firmly grips the road and is very quiet, not squealing on curves. At high speeds on the
highway tyre noise did not bother me at all, it is minimal and for that Nokian is to be commended. I had the opportunity to
ride in the city during really heavy rains which turned roads into rivers and so I am delighted how well this tire can cope
with the water.At 45mph in such conditions, I only heard sough of traversed water, and the car felt like it was sticked with a
glue. Rut with water? For those tires it does not matter. Braking? At the 45 mph, in these rainy conditions, the car felt like
if it was driving on the dry road. As for the winter conditions of snow it was maybe a couple of days and the tires were good.
On the slush also all great. But it is not enough to somehow verify their effectiveness and to issue reliable opinions. As for
the rolling resistance is not noted a higher combustion When you change summer tires (Pirelli) with these winter tires, but i
refrain from evaluation because of a small run on these Nokian WR D4. I won't judge thei durability neither because of
distance. In my opinion premium tires all have similar parameters. If you have a slow 300-400 pounds and wish to buy winter
tires then i honestly recommend them. If not, try Barums, but in my opinion it is worth investing in Nokians, in the end is the
only part of the car which directly connects it to the surface ... Final statement - since i usually have little time to get to
work in the morning i'm very glad Nokian WR D4 can take me there swiftly and safely.
2 people
1 people
The Nokian WR D4 keeps cool as well fitted on the car with more than 300 hp. First impression - at above + 10 ° C during
braking from high speeds the tyre terribly bends (i know it should be used when it's colder but still) - enough so that you
think that you are driving on the rims. They also make strange sound during braking (something like this specifically hums and
whistles, oddly enough from the beginning I thought that I did keep coming brakes) Second thing is that Nokian WR D4 are rather
durable. A few days driving in dodatnch temperature, some faster braked suddenly have 10 thousand miles instead of 8 mm tread
close to 7 mm. Any super-aggressive driving, most highway and is classified as the biggest downsides of the tire. On the plus
side? Adhesives for dry better than a summer tire type Dunlop Sport Max On wet at all a revelation because I virtually can ride
as if there was no water on the road. Overally: you should buy them even if you hadn't heard of them before, but if You are
driving on a lot I'm sure the will last a few seasons so it's hard not to recommend them.
2 people
0 people
I bought Nokian WR D4 to replace Pirelli Winter Snowcontrol 185/60 R15, and during summer i use of Michelin Energy Saver in the
same size. I decided to buy Nokian in "XL" version with a load index 88 instead of 84 to get more support and I do not regret
the choice at all. This new Nokian rubber proved to be a very good decision. In terms of grip on dry, wet and snow, all
compared to the old Pirelli, Michelin is compared to the summer, with respect to which these Nokian also offer lower fuel
consumption and noise levels slightly lower, despite the winter geometry and the greater load index. My car now offers great
comfort with the soft suspension, but it gives great opportunity for sports maneuvering, as the tread a little 'tight;
nevertheless, I found more grip than the Michelin summer, which amazed me. Throughout the winter, in which I have traveled
about 10,000 miles, the tread has worn by ONE millimeter. Ultimately, I could not claim to be more happy with this purchase.
Last, but not least, the Oponeo service was good and fast.
1 people
5 people
Hello, there were many positive reviews I have to express my opinion on Nokian WR D4 tires. Traction and breaking on snow as
well as wet is pretty good but i was hoping it'd be a bit better. The noise a little quieter than my Michelins primacy Hp. And
that would be enough. Now a negative impression. The tire is the index of H, but goes on it above 140km / h (weather conditions
good and dry road), unfortunately the car gets unstable sometimes but probably because it's quite heavy and even Michelins felt
that way. Otherwise the traction is satisfactory . I've never experienced anything like this for the summer, so on dry pavement
advise against. To 140km / h the tire meets your expectatnions but above that Nokian WR D4 werent so good during July /
September 2015 (but still that was the time when summer tyres should've been used so i got those fitted little too early.
1 people
1 people
It is true that I do not have Nokian WR D4 for long, but I managed to do 1500 miles already. I tested it both out and in the
city, because I traveled a lot lately. On a dry surface they behave really well. For wet (and a lot of rain recently) I was
very pleasantly surprised, because I did not feel much of a difference. But most surprised me is how the tires allow you to
correct mistakes on the slippery surface whether it's snow or soft ice. I have repeatedly made the mistake of giving too much
gas while cornering (at this point it's probably just the spikes would have helped), the car began to fly, but after rapid
correction of gas and counterattacks on wheels - Nokian WR D4 immediately caught traction again. Really highly recommended
Nokian - I will recommend them to my faily and friends.
Nokian WR D4 205/55 R16 91 H RUN ON FLAT
The presented tyre is marked with 3PMSF symbol (Three Peak Mountain Snow Flake). It means that the tyre meets the EU requirements for winter tyres. The symbol is awarded after thorough tests of a tyre model in terms of snow grip.
Technology description: Do you need a durable and reliable winter tyre that can deal with extreme weather conditions? This innovation from the Finnish leader on the tyre market provides excellent driving quality, safety and the comfort of travelling.
Its optimised tread pattern guarantees an excellent grip and precise driving no matter the surface type. Each tread block and sipe was designed individually, so the tyre perfectly performs its function on wet, snowy and icy surfaces.
Driving precision and control is also supported by the tyre's central rib, sectionally equipped with sipes.
With this, the tyre quickly responds to the movements of the steering wheel, even when travelling on the most demanding surfaces.
Each side of the rib is supplied with small tread blocks, densely notched with sipes. It's thanks to these that its performance isn't affected in the snow. The grooves lead the tyre across the surface and, at the same time, ensure that the whole tread maintains its stiffness and, therefore, complete performance in such conditions.
Slush? Nokian WR D4 winter tyre also has a solution for this.
The quick and effective removal of slush and regular water is ensured by the polished grooves located on the sides of the tyre.
Driving in deep snow, on straight roads and on bends is taken care of by the deep bevels on the sides of tyre shoulders.
If you appreciate an economical drive and you are not indifferent to environmental conditions, then the Nokian WR D4 is a good solution. With the use of Nokian Twin Trac Silica rubber compound, which contains natural rubber, rape oil and silica, rolling resistance has been reduced. Consequently, fuel consumption is lower and less carbon dioxide is emitted into the atmosphere.
What's interesting, is that the tyre is also fitted with a tread wear indicator. The numbers presented in the photo stand for the deepness of the tyre's main grooves in mm. Individual digits wear off along with the wear of the tyre tread. The snowflake remains on the tyre as the last symbol. It's visible when the tyre tread is at least 4 mm deep, and once it disappears, the tyre no longer ensures the full safety.
Information on the manufacturer: Nokian is the only manufacturer worldwide that specialises in winter tyres designed for extreme northern conditions. Since the tyres are adapted to changing weather conditions, they also perform excellently in the variable weather prevailing in Poland. It is the first company in the world to supply winter tyres and the first one to produce ecological tyres with the use of low-aromatic oils. Nokian Tyres was founded in 1988, but its history dates back to 1898 when they established a Finnish rubber factory called Suomen Gummitehdas Oy.
Fuel efficiency is rated from A to G on a colour-coded scale. The highest fuel efficiency rating is A (green; the lowest rolling resistance), while the lowest fuel efficiency rating is G (red; the highest rolling resistance). Rolling resistance influences fuel consumption and vehicle emissions; the lower the resistance, the lower the fuel consumption and exhaust fume emissions.
Wet grip is the tyre's ability to adhere to the road surface in wet conditions. The EU rating focuses only on the wet braking performance of the tyre. Wet grip is rated from A to G, where A represents the best braking performance and G represents the worst. It is one of the most crucial safety parameters.
Tyres contribute to the amount of noise a vehicle generates. Choosing a tyre with a good noise rating will lower the impact of your driving on the surrounding environment.
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I Love My Own Private Time
Personal Stories, Advice, and Support 139 People
Desiderata Poem-- written by Max Ehrmann in the 1920s -- Not "Found in Old St. Paul's Church"! -- see below Go placidly amid the noise and the haste, and remember what peace there may be in silence. As far as possible, without surrender, be on good terms with all persons...
burwi333 36-40, M 0 Oct 29, 2010
It Is Few and Far BetweenHaving my two gorgeous children most of the time has killed the whole " me time " aspect ofmy life . but im slowly getting it back and im using it to work on my book im starting . Or my self help .
starstruck2xtrme 26-30, F 1 Jun 22, 2008
I love hanging with friendsbut enjoy even more my me time. I love just catching up on shows, reading, and listening to music by myself.
TheTruth94 22-25, M 1 Mar 25, 2015
PeaceFor me it's a pretty rare commodity. I am rarely alone in the house and my private time is usually when I can go out alone especially when I can walk with my dog in the countryside, which I do love to do. My own space is very important to me and even though I am rarely...
womaninbliss 51-55, F 3 Responses 1 Jun 10, 2011
I can do whatever I want at night,it's nice :P
ErraticSarcastic 31-35, F 5 Nov 19, 2015
After a busy day at workand when my kids are still at school, i would like to just lay around relaxing and reading the news or just surfing the net.. While enjoying my cup of coffee.. I really hate it when my cousins next door bang at my door.. They do that all the time.. Cant they just leave me alone...
thesimpletruth77 36-40, F 2 Jul 28, 2014


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Support to organizations
Family Literacy Day
On the initiative of ABC Life Literacy Canada, January 27 is Family Literacy Day. In addition to celebrating the joy of reading and learning as a family, this Day is a chance to incorporate learning into the family routine. All across Canada, parents, community and literacy organizations, libraries, and schools are invited to organize family learning activities.
Once again this year, the Literacy Foundation is collaborating in Family Literacy Day by distributing the promotional materials developed by ABC Life Literacy Canada to literacy training organizations and community-based family resource centres.


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United Methodist Church of New Canaan
- UMC celebrates Laity Sundayncadvertiser.com
- UMC 'pit stop' welcomes Halloween trick-or-treatersncadvertiser.com
- New Canaan: UMC kids carry picture of Jesusncadvertiser.com
- Methodist book study: 'Pray Like Jesus'ncadvertiser.com
- Methodist Church welcomes associate pastorncadvertiser.com
- Methodist to bless animals April 23ncadvertiser.com
- Methodist Church celebrates Holy Weekncadvertiser.com
- John C. (Jack) White, 89, lifelong resident of New Canaanncadvertiser.com
- Methodists celebrate Habitat for Humanityncadvertiser.com
- Fabric and yarn drive for area refugeesncadvertiser.comWeston , Syria , United Kingdom , New Haven , New Canaan
- Afternoon book study starts Jan. 25ncadvertiser.com
- Service Sunday provides cheer to homebound seniorsncadvertiser.com
- Turkey Dinner amusementsncadvertiser.com
- Obituary: Joan Starr, 87wiltonbulletin.comLakeview , Scottsdale , Norwalk , New Canaan , Los Angeles
- Book study at Methodist Churchncadvertiser.com
- Rally Day Sept. 11 at United Methodist Churchncadvertiser.com
- Story event at United Methodist Churchncadvertiser.com
- Obituary: Douglas G. Noiles, 91, resident, engineer, inventorncadvertiser.com
- Walbert to be honored for community servicencadvertiser.com
Frequent names
Newstral's extraction of names of people and organisations from the world's news is completely automated. If you do not want your name to appear here, please contact us. We will be happy to look at your request.


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ATLANTA - Georgia Tech football coach Chan Gailey will turn over control of the offense this fall, he announced Thursday.
Patrick Nix, Gailey's top offensive assistant since 2003, will coordinate the offense and call the plays. Nix has held the offensive coordinator's title the last two seasons, but Gailey has overseen the unit and handled all the play-calling except the two-minute drill.
The time is right for Nix to assume the full duties, Gailey said.
"Patrick has some good ideas about what our guys can do," Gailey said. "We've been around each other long enough now he knows my general thoughts about what's important and he will incorporate that into what he does.
"I think its a good time to put some new ideas and some new thoughts into our offense."
Nix described his approach as one of "controlled attack." He prefers to pressure opponents with his play-calling without being reckless.
Nix admitted Georgia Tech's offense won't be drastically different with him in control instead of his boss. Gailey's conservative bent the last three years - the Yellow Jackets have averaged fewer than 22 points a game during the span - will still be reflected in the offense.
"I've been around a lot of coaches who understand you can't have turnovers, you have to control the ball, and you can't give the game away," Nix said. "That's the thing I've learned in this game is make the other team beat you, don't beat yourself. There are a lot of very good risks. You can score points and move the football, but at the same time don't get your team beat."
Nix is an experienced play-caller despite being just 34 years old. He called the plays as the passing game coordinator at Jacksonville State in 1998 as well as during his two years as the head coach at Henderson State. His Henderson offense set 18 school records, four Gulf South Conference marks and three Division II records.
The former Auburn quarterback also called Samford's plays for the final six games of the 2001 season.
Nix's role at Georgia Tech has evolved since he arrived as a member of Gailey's first staff in 2002. He was hired as a recruiting coordinator and running backs coach. Gailey promoted him to running game coordinator and quarterbacks coach a year later after offensive coordinator Bill O'Brien left for Maryland.
Nix assumed the offensive coordinator's title in 2004 and also took over the play-calling in the Yellow Jackets' two-minute drill. Gailey has told Nix for years he eventually wanted the assistant to take over the offense.
"The process just kind of continued on until he decided, 'Hey look, I want to step back more' and then finally 'I want to step all the way out of if and let you run the offense,'" Nix said. "I'm excited and looking forward to the opportunity."
The changeover began this spring, with Nix running the offense during spring practice. Gailey said neither his health - he suffered a heart attack last spring - nor his new five-year contract, signed in March, factored into the timing of the move.
Gailey delayed announcing the change until the completion of spring drills to keep from tipping off the Jackets' opponent for the season opener, Notre Dame. The Fighting Irish visit Atlanta on Sept. 2.
"They'll be some wrinkles that are different. Anytime you have somebody else doing something, it doesn't matter what line of work you are in, there are things that are done differently," said Gailey, whose team experimented with a handful of new formations and personnel groupings during spring practice. "The general concepts are the same. But there are a few different looks to things."
Wide receiver Calvin Johnson is among the players who welcome the changes based on the offensive success in spring practice. The Yellow Jackets scored nine touchdowns in their final spring scrimmage last week.
"It was something new, but it was very productive," Johnson said. "We had a good spring, so whatever he did, he did a good job."
Philip Wheeler won the middle linebacker's spot in the spring, Gailey said Thursday. Wheeler started at outside linebacker last fall and made 64 tackles, 11.5 for loss, including four sacks. He also tied for the team lead in interceptions with four. ... The Yellow Jackets will not make any adjustments in their defensive philosophy because of their injury-riddled secondary, Gailey said. Starting strong safety Joe Gaston suffered a season-ending knee injury in the spring, forcing cornerback Jamal Lewis to switch positions and leaving four players with little experience to compete for Lewis' cornerback spot. Georgia Tech will continue to play aggressively on defense, blitzing from nearly every position, Gailey said. "We have to have those guys step up and play well," Gailey said. "Defensively, we're not going to change anything."


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- Please select a date to see the proper prices!
- Meal can be requested on the spot
Best offer
101 € / person / night, no meal
Description of the accommodation:
Rooms, services Boutique Nazionale Rome is offering eight comfortable rooms to guests looking for accommodation in Rome. Your valuables may be the safely secured in the safe. The hotel is offering wireless Internet connection (WiFi) without charging extra fees, so you may go online anytime with your laptop during your stay. The exact equipment and the exact list of available services of Boutique Nazionale Rome can be read on the information sheet below.
Payment For the reservation you may need to provide advance payment by credit card or credit card guarantee, depending on the exact date, room and price.
Arrival, opening hours The earliest time to check in at the hotel is 14:00, the latest time to check out is 12:00. The personnel of the hotel can speak in Italian and English with you.
Boutique Nazionale Rome rooms Rooms
- Please select a date to see the proper prices!
Accommodation services
Free WiFi in shared places
Pet friendly, Safe deposit box
Desk in the room, Mini-bar


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Mardi Gras
Date of the Mardi Gras season explained
The origin of "Fat Tuesday" is believed to have come from the ancient Pagan custom of parading a fat ox through the town streets. Such Pagan holidays were filled with excessive eating, drinking and general bawdiness prior to a period of fasting.
Since the modern-day Carvinal season is sandwiched between Christmas and Lent, with Christmas Day being December 25 on the Gregorian Calendar as set by the Roman Catholic Church, this means that other Holy Days are "floating" in nature. Easter always falls on a Sunday, but it can be any Sunday from March 23 through April 25, its actual date being the Sunday which follows the first Full Moon after the Spring Equinox.
Mardi Gras is always 47 days prior to this alloted Sunday (the 40 days of Lent plus seven Sundays). The beginning of the Carnival season itself, however, is also fixed, being January 6, which is the Feast of the Ephiphany, otherwise known as Little Christmas or Twelfth Night. Since the date of Mardi Gras thus varies, the length of the Carnival season also varies accordingly from year-to-year.
The origin of the word "Carvinal" is from the Latin for "farewell to the flesh," a time when one is expected to forgo earthly pleasures prior to the restrictions of the Lenten Season, and is thought to be derived from the feasts of the Middle Ages known as carnis levamen or "solace of the flesh."
Mardi Gras New Orleans Website
Future Mardi Gras Dates:
- 2017 Mardi Gras: February 28
- 2018 Mardi Gras: February 13
- 2019 Mardi Gras: March 5
- 2020 Mardi Gras: February 25
- 2021 Mardi Gras: February 16
Links of Interest


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Why Rajkumar Hirani, Madhavan can't afford to miss watching 'Creed'
Heard that Rajkumar Hirani and R Madhavan have been keen to catch up on the Sylvester Stallone-starrer 'Creed' which released last week.
Hirani is tied up with things at his production house and Madhavan was pre-occupied with safety of his family members in the Chennai floods. The desire to watch is because of their upcoming film, 'Saala Khadoos', which is also based on boxing. Madhavan is playing a coach in his upcoming next, so they want to see how Sly mentored the champs.


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Puppy: Saki
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Member Since: August 17, 2008Add to Friends
We got Saki when we went to buy a barbecue! We couldn't resist him. We had been looking for a rescue pup, but fell in love with him. Thanks to his breeding, he's the perfect house dog. He loves to sit on the couch and get massages.View Profile


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Here are my highlights for day four at LonCon3 (Sunday 17th August).
First up, I'd stop off for a cheeky fry-up at the Fox Bar at the Excel to start the day, it has to be the Full Monty right? Bacon, eggs, tomatoes, baked beans, sausage, hash browns, black pudding,& mushrooms with toast & butter. NOM NOM NOM.
But make sure you leave enough room to fit into your lycra, as Day Four at LonCon3 is Hall Costume Day in the Exhibits Hall. Take a camera and a sketchbook to capture the best cosplay around! Sunday evening is also the 2014 Hugo Awards Ceremony. Make sure to practise your "losing gracefully" and "winning!" faces.
Here are my picks of the panels, you will need a Time Turner to fit everything in. Highlights include GRRM, live scorpions, a ton of Tor authors and intriguingly an event entitled The World of Poo. Enjoy! And share in the comments what you are going to see!
Now onto some Sunday highlights...
10am - 11am
On The Blogs: Bloggers Discuss their Roles in the World of YA
Capital Suite 16 (Level 3)
Panellists: Foz Meadows, Patricia Ash, Shaun Duke, Liz de Jager, Erin M. Underwood
Bloggers have become an integral part of YA book promotion. How do authors find these bloggers? Why should readers trust their opinions? What are the best book blogs out there right now and what makes them so useful?
Quidditch UK Demonstration
The Green (Level 0)
Players from Quidditch UK will be demonstrating their sport, and then, if you're lucky, giving you a chance to try it out for yourself. This item will be located on "The Green" in the middle of the Fan Village.
11am - 12pm
Writing and Pitching Comics
Capital Suite 9 (Level 3)
Maura McHugh, Paul Cornell, Mike Carey, Mary Talbot, Debbie Lynn Smith
A discussion about creating comic books from the writer's perspective. Breaking into comic book writing can present a unique challenge for new writers, because the route in is usually different than for artists (there are no portfolio reviews for writers).
Then there are basic issues, such as formatting scripts, which aren't even clear-cut.
How do writers craft the pitches that get them jobs as comic book writers? How do they proceed once they get the gig? What's it like to liaise with artists, colourists, letterers, and editors?
What are the joys and perils of collaborating with so many people?
11am - 12pm
London Suite 4 (Level 0)
With Adrian Tchaikovsky, Charles E. Gannon
11am - 12pm
Mythbusters: UK SF/F by the numbers
Capital Suite 13 (Level 3)
Panellists: Jo Fletcher, Bella Pagan, Jonathan Oliver, Darren Nash, Tom Hunter
Did Iain M Banks' 'popular' SF subsidise his 'worthy' literary output, or vice versa? Who is the biggest genre author in the UK? What does a "best-seller" mean? Which sub-genres sell better than others, have ebook ventures like the SF Gateway and HodderSilver met expectations (and what is the overall market share of ebooks these days)?
Second Stage (Level 1)
George R R Martin talks with friends about Game of Thrones. HELL YEAH
Panellists: Hayden Trenholm, Gregory Benford, Mark Charan Newton, David D Levine, Paul Abell
The development and deployment of technologies that would allow mass migration to other planets and stars can pose major threats to the ecology of the Earth - launching nuclear pulse rockets from the ground for example. If this is the only way to expand into space, should we do it? And to what extent do these arguments apply to other technological developments?
1:30pm - 2pm
I4IS: Starships Inspired by Arthur C Clarke's Fiction
Capital Suite 14 (Level 3)
Kelvin Long, Rob Swinney
Science Fiction is an inspiration driver for imagining future technologies and modes of transportation, to the extent that they can lead to the realisation of those visions by a self- fulfilling prophesy. Arthur C Clarke was a master in this and throughout his many novels he describes various kinds of spacecraft and starship propulsion systems. In this talk we go on a journey through his literature as case studies in space propulsion. We discuss these innovative ideas and consider real world efforts to bring these ideas into reality so that interstellar right may one day be achieved. Kelvin F Long is a physicist, aerospace engineer, author and entrepreneur and is the Executive Director of the Initiative for Interstellar Studies (I4IS).
Zombies, aliens, and monsters from the deep are all very well, but -- unlike climate change and other ongoing environmental damage -- they're not actually likely to cause the downfall of industrial civilisation. Are contemporary TV and film neglecting the apocalypse-in-progress? Where can ecological perspectives be found in SF and fantasy on screen, and how are they portrayed? What are the strengths and weaknesses of visual climate narratives, compared to their prose counterparts?
Detectives in SF
Capital Suite 10 (Level 3)
Panellists: Erin Hunter, Peter F Hamilton, Jan Siegel, Heidi Lyshol, Adam Christopher
The detective character has always been with us, but more and more we're seeing new narrative shapes creeping into the genre as part of a noir movement. What is noir in a literary sense? How is it differentiated from hard boiled? How has the detective had to adapt to survive in a science fictional world? Why such an increase in the prevalence of crime oriented science fiction?
4:30pm - 6pm
The World at Worldcon: SF/F in Australia and New Zealand
Capital Suite 3 (Level 3)
Panellists: Amanda Bridgeman, Tsana Dolichva, Ian Nichols, Ben Peek, Janice Gelb
From afar, Australian SF publishing seems to be in good health, with books such as Nike Sulway's Rupetta (winner of this year's Tiptree Award) and publishers such as Twelfth Planet Press attracting international attention, and writers such as Ben Peek and Rjurik Davidson scoring international publishing deals -- not to mention already high-profile exports such as Greg Egan, Margo Lanagan, and Shaun Tan. To what can the current depth and breadth of the Australian scene be attributed? Which other writers should we be looking out for?
4:30pm - 6pm
Book Covers: The Good, The Bad, and the Ugly
Capital Suite 4 (Level 3)
Panellists: John Picacio, Joe Abercrombie, Irene Gallo, Greg Manchess, Maurizio Manzieri
A panel of artists, art directors, editors, and writers present some of their favourite (and not-so favourite) cover artwork, and discuss why the pictures succeed - or don't!
John Clute's The Darkening Garden (2007) argues for horror as a core mode of twenty-first century fiction. It proposes a narrative "grammar" for horror stories that progresses from SIGHTING through THICKENING to the REVEL and then AFTERMATH. What implications does this structure have for our understanding of horror, as a commercial genre and as a literary form? What works escape its grasp, and why?
The Seriousness Business
Capital Suite 16 (Level 3)
Panellists: Juliet E McKenna, Adrian Tchaikovsky, Saxon Bullock, Emma England, Karen Miller
Perhaps the two most critically acclaimed SF series of the last decade are Battlestar Galactica and Game of Thrones, and in each case the most common reason for that acclaim is their supposed seriousness: here are SF and fantasy with depth and darkness. Why is this the kind of genre material that the mainstream has embraced? Does the presumed "realism" of this approach hold up to scrutiny? Has seriousness become a cliche? And to what extent do these shows, and their imitators, tell original stories, and to what extent do they reinscribe a normative straight white heroism?
What are some of the characters and narratives we've seen enough of? Is it time for the assassin with the heart of gold to take a break? Should the farmer keep farming and stop exchanging his rake for a broadsword? Could the squabbling will-they-won't-they couple just get a room already? More generally, why are tropes used, and what are their structural, stylistic and political implications?
8pm - 11pm
The 2014 Hugo Awards Ceremony
Auditorium (Level 0)
The 2014 Hugo Awards Ceremony is the "do not miss" event of Worldcon. Our attendees have voted, the votes have been counted, and it is now time to find out who are the winners. Join our hosts Justina Robson and Geoff Ryman for a gala celebration of the best of the genre.
9pm - 10pm
The Bottom Up: The Fantastical World of Human Waste
Capital Suite 6 (Level 3)
Rachel Erickson
"What we eat and subsequently excrete plays a major role in human society and especially in what we are pleased to call civilized society."-Miss Felicity Beedle's The World of Poo
Ever wondered where the toilets are on the Starship Enterprise? Thought Terry Pratchett's Harry King was an entirely fictional character? Wanted to make a Tardis Toilet? (Sorry… that's been done and the BBC weren't happy about it!) This talk, by toilet guide and expert Rachel Erickson, explores the underside of science fiction and fantasy, moving away from the traditional future technologies and space travel to look at one of the most basic and un-mentioned aspects of human existence. Come plunge in and explore the wonderful (and often fantastical) world of human waste.
Check out the rest of the LonCon3 programme here
Top Ten Tips for Attending Your First Convention here


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Running Riot Trailer (2006)
"The Mission is not Impossible" 14 December 2006 Comedy 95 mins
Tjokkie and Crispin decide to take a bet with their rival, Ratkas Koekemoor that Crispin can beat him in the Comrades marathon.His wife suspect he really wants to go to Durban to fool around, so she hires a private detective to keep an on him. In Durban, he meets and falls for a stunning Russian athlete, but her ex-KGB trainer also has his eye on her. One thing leads to another, and after the race, things come to a head as the competing lovers, coach, and private detective find themselves in compromising and complicated situations.
Watch the official Running Riot 2006 trailer in HD below or find more Running Riot videos on Vidimovie.


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With every progressing phase of the Marvel Cinematic Universe, the stakes have been growing higher and higher. Even though it may not seem possible, the stakes of Captain America: Civil War will be dwarfed come May 4, 2018 thanks to Avengers: Infinity War. Infinity War is the end game of everything so far in the MCU. Of course we'll see Earth Mightiest Heroes, the Avengers, as we have in the previous films, in addition to the Guardians of the Galaxy and some newcomers. The question is: With everything so far in the MCU, where can Marvel go after Avengers: Infinity War?
The Threat Level Of Villains After Thanos Will Be Reduced
Let's recap the previous threats the Avengers face in their movies:
- In Marvel's The Avengers, Loki wanted to subjugate Earth.
- In Avengers: Age of Ultron, Ultron wanted to destroy the Earth.
Now, it won't be known for certain, but I'd bet a shiny buffalo nickel that Thanos's plan is to kill everything in the universe (which explains the involvement of the Guardians of the Galaxy in Infinity War). In the comics, Thanos went around the galaxy, killing everything he could to impress Mistress Death. Call me crazy, but no threat will seem like that big of deal after the Avengers deal with Thanos. Also, don't forget that Infinity War is slated to be a single film after being reduced from a two-part movie, so expect to see the last of Thanos in Infinity War. Marvel hasn't exactly kept villains around for very long in the MCU. That being said, there aren't a whole lot of threats in the Marvel universe as dangerous as Thanos. Even the Infinity War sequel likely won't have nearly as much danger as Infinity War.
The Remainder Of Phase 3 Should Continues To Expand The Scope Of The MCU
This one should go without saying, but expect more and more characters to be introduced to the ever-growing universe that is the MCU. There are several reasons for this. First, there are only so many character arcs you can put a single character through. They are dealing with a limited amount of source material, plus audience fatigue is a real thing.
Second, the contracts of many of the actors are set to expire soon. Not to say they won't be renewing them, but they could look to introduce new characters for cheaper talent who won't be demanding huge sums of money after having been in multiple successful MCU movies (according to Cinemablend, Chris Evans only made $6.9 million for Age of Ultron, and that movie grossed over $1 billion at the box office, so expect him to demand those big bucks when his contract expires, and soon there won't be enough money in the world to pay Robert Downey, Jr. for his roles as Iron Man).
However, the expanded scope isn't a bad thing. Phase 3 has already seen the introduction of Black Panther and Spider-Man. Captain Marvel and the formal introduction of Wasp have already been confirmed as well, and Marvel will likely keep up the rolling out of fan-favorite characters into the MCU.
The Netflix Characters Should Come To The Big Screen
Speaking of fan-favorite characters, expect to see characters from the Netflix series finally appear on the big screen. here is speculation that the characters — who include Daredevil, Jessica Jones, Luke Cage, Iron Fist, and the Punisher — will appear in Infinity War, although you might want to hold off your hopes, as it would make for an overcrowded film.
That being said, I refuse to believe that Marvel will not use these characters on the big screen. The characters are too strong to not include in the films, and fans would eat it up. How cool would it be to see Daredevil fighting alongside Spider-Man? Or how about seeing Luke Cage team up with the Hulk, Hawkeye, and some of the other Defenders from the comics? here would be too many good storylines for Marvel to pass up and not include them in the films.
The MCU Should Have More Films Like Guardians Of The Galaxy
Guardians of the Galaxy was extremely different from what audiences expected out of a comic book movie. Without a marquee hero like Batman or Iron Man, and not really taking a whole lot of inspiration from the comics, Guardians of the Galaxy is easily the biggest surprise in the MCU. Its lighthearted tone combined with its lovable characters and non-stop action make it one of the most memorable and enjoyable MCU movies. Guardians is proof that Marvel doesn't need to be super serious when making a movie, and they could apply that lesson to future films. However, please do not make the villain in any future MCU movie fall victim to the power of dance. It might sound like that last statement is in jest, but it's not. The main takeaway here is that Marvel should not be afraid to take some risks when making MCU movies.
Speaking Of Taking Risks
I walked into the theater for Captain America: Civil War fully expecting someone to get sent to meet their maker (my money was on Hawkeye). Despite there being what appears to be lasting consequences in the MCU, Marvel will have to start letting characters die and not being afraid of it. They are, after all, comic book movies, and while most do not follow the comics perfectly, characters do die in them. With the exception of Quicksilver in Age of Ultron, no Avenger or other Marvel character died. Marvel needs to start putting real danger in their movies in order to keep audiences engaged. If you walk into the theater knowing everyone is going to make it out alive, why see it?
Well, that is my two cents on some direction Marvel should take. Avengers: Infinity War is what the MCU has been building towards since day one, and it will be interesting to see if Marvel shakes things up once it's over.
Let's hope the Marvel heroes are up to the task of saving the planet, unlike these other scenarios in the video below:
Are you excited for Avengers: Infinity War? What about other MCU Phase 3 movies? Let me know in the comments!


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1Way Taxi Cab announce cheap taxi rates into town…
1Way Taxi Cab Cape Town, would like to remind you that we are there to take you wherever you need to go in and around Cape Town. We are a budget taxi (cheaper than Über) and transport service and look forward to welcoming you aboard.
Call us on: 073 027 4664 or email us at: firstname.lastname@example.com or check our website at: www.1waytaxicab.co.za
With the increase in petrol prices, you are better off using us and so the time has come where everyone needs a reliable taxi to take them within and around our city of Cape Town.
Whether you need to get away for a fun night out or need a lift home you will find 1Way Taxi cab prices unbeatable. Students without a car, looking for cheap taxi's and transport into town need to keep 1Way Taxi Cab's number in their phone: 073 027 4664
To give you an idea of our taxi fares:
From UCT to Long street R70
From UCT to Waterfrant R120
From UCT to Camps bay R180
UCT to century city R120
If it's Touring you are looking for, use us too for your budget transport to Cape Point and more:
From city central to cape point return R1500
From cape town to ostrich return R550
All the prices are negotiable with 1Way Taxi Cab
Enjoy the ride