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Bradykinin (BK), a proinflammatory factor and vasodilator, causes functional change of the small artery. However, it is not clear whether any of these changes induced by BK are mediated byN-acetyl-d-sphingosine (ceramide). Therefore, we investigated whether BK affects the hydrolysis of sphingomyelin and generation of ceramide in the intact rat small artery. Our results suggest that BK induces sphingomyelin hydrolysis and increases ceramide production in a time- and dose-dependent manner. Relative to controls, BK causes a 50% decrease in sphingomyelin levels. Ceramide levels increase in response to BK with the highest level being obtained with 10−8 M BK as well as similar amounts of ceramide are generated when exogenous sphingomyelinase (SMase) is added. We then determined which of the two BK receptors (BK-B1 antagonist Lys-Des-Arg9-Leu8-BK or the BK-B2antagonist HOE-140) are implicated in the BK-induced generation of ceramide. The BK-B2 antagonist did not alter the effect of BK on ceramide generation, whereas the BK-B1 antagonist blocked the BK-induced production of ceramide. Although ceramide had no effect on KCl-induced constrictions, ceramide dilated preconstricted (phenylephrine) small pressurized rat mesenteric arteries by ∼40%. These results suggest that the activation of the BK-B1receptor mediates the BK-induced activation of SMase and of the production of ceramide. In conclusion, BK-mediated effects on vascular tone may be due, at least in part, to the increased production of ceramide.
- phenylephrine
- receptor antagonists
- sphingomyelin
- vascular tone
the field of sphingolipid and N-acetyl-d-sphingosine (ceramide) signal transduction has recently advanced rapidly. Experimental results (18, 19) suggest that ceramide has important roles in many cell types. Sphingomyelin (SM) is composed of long chain saturated or monounsaturated fatty acid, a sphingosine base backbone, and a phosphocholine head group (3, 5, 37). Hydrolysis and synthesis of the sphingolipids that form the SM pool together form a dynamic balanced pathway called the "sphingomyelin pathway." SM turnover involves removal of the head group and amide-linked fatty acid by sphingomyelinases (SMases) and ceramidases, respectively. SMase action is the only known mechanism for SM hydrolysis in mammalian cells. Most, if not all, mammalian cells appear capable of signaling through the SM pathway (29). SM that is present either on the outer or on the inner layer of the plasma membrane can be used to generate ceramide that is involved in signal transduction pathways (11). Exogenous SMases are mainly of bacterial origin and have become important tools for investigating ceramide signal transduction, in particular because few antagonists for endogenous SMases are available. In general, exogenous SMase mimics the effect of ceramide-generating signals and is effective in hydrolyzing endogenous SM (6, 8,41). It has access to the bulk of cellular SM, which is located on the external portion of the lipid bilayer (36).
Ceramide has been proposed as a novel second messenger that mediates a variety of biological processes (18, 19). Specific stimuli induce SMase activity, which results in SM hydrolysis and ceramide production. Ceramide may activate or inhibit a variety of signals, for example: protein kinases, phosphatases, or phospholipases, which affect multiple downstream targets, including activation of nuclear transcription factors, leading to a variety of distinct cellular effects (19). A large variety of stimuli induce SM hydrolysis and ceramide formation (18, 19). There is evidence for extensive tissue specificity as indicated by the fact that for any given SMase activating stimulus, not all cells or tissues respond to that agent by hydrolyzing sphingomyelin; furthermore, different final effects can be obtained in different cell types in response to the same SMase activating agent (1, 12, 13).
As a novel lipid second messenger, ceramide derived from sphingolipids plays a central role in signal transduction and cell regulation. We (18) have previously shown that the effects of BK, a proinflammatory factor and vasodilator, were mediated by ceramide and by phospholipase D in cultured rabbit cortical collecting duct (RCCD) cells. In RCCD cells, BK increased SM levels and decreased ceramide levels. The BK-B1 receptor antagonist did not affect ceramide but the BK-B2 antagonist blocked the effect of BK on SMase, suggesting that the BK-B2 receptor mediates BK-induced inhibition of ceramide generation in RCCD cells. There is evidence in smooth muscle cells that sphingolipids are involved in regulating cell proliferation. For instance, in mesangial cells and A7R5 smooth muscle cells, platelet-derived growth factor increases sphingosine levels (19) by stimulating SMase and ceramidase activities (7). We do not have much information with regard to contractile responses. Cell-permeable ceramides and SMase treatment caused relaxation of phenylephrine (PE)-contracted endothelium-denuded rat thoracic aortic rings (16). In contrast, cell-permeable ceramide induced contraction of isolated rabbit rectosigmoid smooth muscle cells (35). However, in vascular smooth muscle, one effect of ceramide that may have particular relevance for smooth muscle contraction is the activation of the serine-threonine kinase Raf (15, 42), an upstream regulator of extracellular signal-regulated kinase (ERK) (34). Sphingosine induced vasoconstriction in coronary arteries, an effect that appeared to be mediated by the release of cyclooxygenase-sensitive vasoconstrictor prostanoids from the endothelium (24). Thus the SM pathway may be an important regulator of vascular function.
However, most studies to date have examined the role of ceramide in the context of cytokine signaling from cells in culture, whereas few studies have been done using intact tissues. No studies have been performed exploring the potential role of BK with regard to ceramide and SMase signaling by using intact tissues. Of interest, it is not known whether the effects of BK involve ceramide and SMase signaling nor whether the BK-induced increase in ceramide production may influence vascular tone in the intact pressurized rat mesenteric small artery. Therefore, we studied the effect of BK on ceramide and SMase in rat small artery.
Lipid Measurements
BK, Staphylococcus aureus, SMase, and all other standards, drugs, and salts were purchased from Sigma (St. Louis, MO). Medium 199 (M-199) was obtained from GIBCO-BRL. [Methyl-14C]choline chloride (specific activity 55.0 mCi/mmol) was supplied by Amersham. [14C]myristic acid (specific activity 40–60 mCi/mmol) was obtained from DuPont-New England Nuclear. Thin-layer chromatography (TLC) plates (0.25 mm thick) were purchased from Whatman. All solvents, acids used for lipid extraction such as chloroform and methanol, and high-perfomance liquid chromatography grade solvents were supplied by BDH.
Animals and Tissue Preparation
Adult male Sprague-Dawley rats, body wt ∼225–275 g, were anesthetized using Pentothal Sodium (Somnotol, MTC Pharmaceuticals). The mesentery was immediately excised and kept in ice-cold physiological salt solution composed of (in mM) 119 NaCl, 4.7 KCl, 25 NaHCO3, 1.17 MgSO4 · 7 H2O, 1.18 KH2PO4, 0.026 K2 EDTA, 5.5 glucose, and 2.5 CaCl2 · 2H2O, pH 7.2, until dissection. Adjoining fat and connective tissues were removed from the vessels with the use of a dissection microscope. Rat mesenteric arteries of ∼280–300 μm internal diameter were used for all of the experiments. A collection of five small arteries, each of which was ∼2 cm long, was used for each point; each sample contains ∼40 μg of protein.
Radiolabeling of small arteries.
An appropriate aliquot of radioactive material was dried down under a stream of nitrogen, placed in 200 ml of M-199 solution and redissolved by bath sonication for 5 min. Vessels were incubated in M-199 solution for 3 h at 37°C, washed in 3 ml of M-199 for 15 min, and then transferred to 3 ml of fresh M-199 solution.
Solvent extraction of small artery lipids.
The lipid extraction method was based on that of Bligh and Dyer (4) as described by Liu et al. (18). After BK or SMase stimulation, the reaction was terminated by transferring the vessels to an ice-cold ground glass homogenizer containing 0.5 ml chloroform-methanol-HCl (20:40:1, vol/vol/vol), homogenized, and left on ice for 30 min. The mixture was transferred to a microcentrifuge tube and the homogenizer was rinsed with 1 ml of chloroform. These washings were added to the tube along with 0.3 ml 1 M NaCl, vortexed, and spun at 11,000 g for 5 min at 4°C. The upper aqueous layer was discarded, and the lower layer, containing the lipids, was transferred to a 1-ml glass Chrompack vial, dried under a stream of N2, and redissolved in 200 μl of chloroform. Samples were stored at −20°C until analyzed. The particulate protein interface was air dried, dissolved in 0.5 ml 2 M NaOH, and assayed for protein according to the method of Lowry et al. (20).
Measurement of sphingomyelin hydrolysis.
Because choline is a component of sphingolipids (10), small arteries were prelabeled with 1 μCi/ml [methyl-14C]choline chloride in M-199 solution for 3 h at 37°C to label the sphingomyelin pool. Small arteries were then stimulated with or without BK (10−8, 10−7, and 10−6 M) for 30 min. Lipids were extracted and internal standards were added to each sample: 20 μl (10 mg/ml in chloroform) of SM + phosphatidylcholine. The TLC plates were preheated to 80°C for 30 min. The samples (25 μl in chloroform) were spotted onto the plates along with external standards: SM + PC (20 μl of 10 mg/ml in chloroform). The plates were developed in chloroform-methanol-acetic acid-water (50:30:8:5, vol/vol/vol/vol), dried, and stained with I2 to mark the areas corresponding to SM and phosphorylcholine.
Measurement of [14C]ceramide production.
To investigate the time and concentration-response of ceramide production to BK, [14C]myristic acid-labeled small arteries were stimulated with BK for 1, 5, and 30 min with 10−10–10−6 M BK. Lipids were extracted from small arteries and the 14C-labeled ceramide was separated from other 14C-containing lipids by TLC using the ethyl acetate-acetic acid-trimethylpentane solvent (9:2:5 vol/vol/vol). To determine which BK receptor subtype mediates BK-induced ceramide production, [14C]myristic acid-labeled small arteries were stimulated with BK (10−8 M) for 30 min with or without the BK-B1 receptor antagonist (Lys-Des-Arg9-Leu8-BK, 1 μM) or the BK-B2 receptor antagonist (HOE-140, 1 μM). Lipids were then extracted from arteries, and the 14C-labeled ceramide was separated from other 14C-containing lipids on TLC plates. These experiments were repeated three times.
Measurement of radioactivity.
[14C]SM and [14C]ceramide were measured using the Molecular Dynamics System with ImageQuaNT computer software. The developed TLC plates were exposed to phosphor screens for 72 h in exposure cassettes and were scanned with the phosphorimager. Results, obtained as volume per spot, are expressed as volume per milligram of protein. Volume calculations include the area and density of the radioactivity-generated spots. Results are expressed as a percentage of control.
To determine the statistical significance of differences between more than two groups, analysis of variance and Bonferroni multiple comparison tests were used (18). Differences ofP < 0.05 were considered statistically significant. Results are presented as means ± SE of 3–4 independent experiments.
Functional Assays
Tissue preparation.
Functional assays on intact pressurized rat mesenteric arteries were carried out as previously described (31) except that the endothelium was not removed. In brief, third-branch small arteries of ∼7.5 mm in length (mean lumen diameter in the absence of transmural pressure was 158 ± 7 μm, n = 13) were carefully dissected from the vascular bed, mounted on borosilicate cannulas in a perfusion chamber, and attached using silk suture threads. Criteria for viability and suitability of the artery included constriction to boluses of 1 M KCl and 10 mM PE, respectively, followed by evidence for a significant endothelium-dependent dilation by exposing the preparation to a bolus of 1 mM acetylcholine, and no pressure leak between the proximal and distal ends of the vessel. Suitable arteries were then allowed to equilibrate at 60 mmHg for 30–60 min at 36 ± 0.5°C before the experimental protocols were initiated.
Diameter measurements.
An image of the arteriole was projected onto a video monitor via a microscope-mounted charge-coupled device camera (model KP-113, Hitachi) at a final magnification of ×4. Lumen diameter of the vessel was monitored continuously by edge detection. Pressure transducers were attached at both the proximal and distal ends of the artery. Throughout all experiments, mesenteric vessels were pressurized at 60 mmHg. This pressure was monitored online from the proximal end of the vessel with the use of a pressure monitor (model PM-4, Living Systems Instrumentation; Burlington, VT). Video (diameter) and pressure were recorded simultaneously on a conventional videotape recorder (Vetter; Rebersburg, PA) and on a Pentium-based personal computer using Axoscope software (version 8, Axon Instruments; Foster City, CA) at a sampling rate of 20 Hz/channel. Final analysis was performed using Axoscope and Origin software (version 4.1, Microcal Software; Northampton, MA).
The solution used to dissect the arteries contained (in mM) 120 NaCl, 25 NaHCO3, 4.2 KCl, 0.6 KH2PO4, 1.2 MgCl2, 11 glucose, and 1.8 CaCl2. The normal bathing (control) solution was identical to the dissecting solution. Passive diameter changes to pressure were obtained by exposing the arteriole to a Ca2+-free solution of similar composition to the dissecting solution except for the omission of CaCl2and addition of 2 mM EGTA. The high-K+ (45 mM) solution was obtained by equiosmolar replacement of NaCl by KCl in the control solution. Test solutions were prepared by adding agents to the final concentrations into the control solution. PE and acetylcholine were prepared as 10 mM and 1 mM stock solutions, respectively, in control solutions. A stock solution of ceramide was prepared in dimethyl sulfoxide (DMSO) at concentrations of 50 mM; the final concentration of DMSO never exceeded 0.1%, which by itself produced no effect on PE-induced tone. All drugs were obtained from Sigma. Solutions were bubbled throughout with 5% CO2-12% O2-83% N2 (pH 7.4).
Equation used and statistical analysis.
Percent relaxation at 60 mmHg (%dilation) due to ceramide (Fig.1 B) was calculated using the following equation where Diam(ceramide), Diam(PE), and Diam(0Ca-EGTA) are the diameters measured in the presence of 50 μM ceramide + 1 μM PE, PE alone, or Ca2+-free EGTA (passive dilation) solutions, respectively. Results are presented as means ± SE of three or four independent experiments, with n referring to the number of experiments. With the use of Statistica for Windows 98 (version 5.5), statistical significance between individual means was determined using an unpaired Student's t-test or a one-way analysis of variance test with Tukey's honestly significant difference post hoc multiple-range test for repeated measure. P < 0.05 was considered to be statistically significant.
BK Stimulates Sphingomyelin Hydrolysis
SM is hydrolyzed by SMase to produce ceramide and phosphorylcholine. The arteries were prelabeled with [14C]choline chloride; thus a decrease in the radioactivity associated with sphingomyelin represents hydrolysis of sphingomyelin by SMase. To determine the SMase response to BK, arteries were stimulated with 10−8–10−6 M BK for 30 min (Fig. 1). At all of these concentrations of BK, [14C]SM levels decrease by ∼50%, which is significantly different from the control levels (P < 0.01, n = 3). Higher concentrations of BK did not cause a further decrease in the levels of SM.
Concentration-Dependent Increase in Ceramide Production by BK
To confirm that BK activates SMase and to investigate the concentration response of ceramide production to BK, rat small arteries were labeled with [14C]myristic acid, and the [14C]ceramide produced was measured after stimulation of rat small arteries with different concentrations of BK (10−10–10−6 M for 30 min). The data in Fig. 2 demonstrate a concentration-dependent increment in ceramide as BK is increased from 10−10 M (n = 3, P < 0.05) to 10−8 M (n = 3, P < 0.01). At 10−8 M BK, the production of [14C]ceramide reached a level that is threefold higher than control levels. The production of ceramide then reached a plateau and remained at that level as the concentration of BK was increased to 10−6 M.
Time-Dependent Increase of Ceramide Production Induced by BK
To further determine whether BK increases SMase activity, ceramide production was measured at different times after treatment. Small arteries labeled with [14C]myristic acid were then treated with 10−8 M BK for various times. Figure3 shows that ceramide production increased gradually with time, reaching a threefold increase at 30 min (n = 3, P < 0.01). No further increase was observed if the treatment was continued past 30 min. The exogenous standard ceramide and [32P]ceramide phosphate produced by exogenous SMase confirmed that the [32P]ceramide phosphate induced by BK was coming from the SM pool.
Exogenous SMase Induces Ceramide Production
Exogenous SMase is generally used as a tool to study ceramide signal transduction and is often used as a positive control to demonstrate the hydrolysis of SM. Exogenous S. aureus SMase (0.1 U/ml) catalyses the hydrolysis of endogenous SM to form ceramide. The effect of exogenous SMase or BK on ceramide production is shown in Fig. 4. Either exogenous SMase or BK (10−8 M) catalyzed the hydrolysis of endogenous SM to form ceramide. The [14C]ceramide production induced by exogenous SMase or BK was significantly higher (more than twofold) than the levels in the untreated controls (P < 0.01,n = 3).
BK-B1 Receptor Mediates Effect of BK on SMase
It is known that BK signals through two receptor subtypes, BK-B1 or BK-B2 (38, 49). To determine which receptor subtype is responsible for ceramide signal transduction, [14C]myristic acid-labeled rat small arteries were stimulated with 10−8 M BK for 30 min ±10−6 M BK-B1 receptor antagonist or ±10−6 M BK-B2 receptor antagonist. Figure5 demonstrates that BK increased ceramide levels and the presence of the BK-B2 receptor antagonist did not block the increase in ceramide levels induced by BK. In contrast, in Fig. 6, the BK-B1 receptor antagonist completely inhibited the effect of BK on ceramide production, indicating that the BK-B1receptor subtype mediated the effect of BK on ceramide production in the rat small artery.
Ceramide Effects on Vasomotor Tone
Functional experiments were performed to test the hypothesis that ceramide can influence vasomotor tone in rat mesenteric arteries of similar caliber to those used in biochemical experiments. Figure7 A illustrates a sample experiment where we tested the effects of ceramide on the lumen diameter of a preconstricted mesenteric artery pressurized to 60 mmHg. In the absence of an agonist, lumen diameter was 412 μm. These small arteries exhibited very little (<10% on average) myogenic active tone (in the absence of an agonist), which can be measured by subtracting the lumen diameter versus pressure relationship obtained in normal medium from the one registered in Ca2+-free medium (passive diameter). As shown, application of 1 μM PE, a α1-adrenergic receptor agonist, constricted the artery to a diameter of ∼170 μm. Application of 50 μM ceramide in the continued presence of PE slowly dilated the vessel, which eventually reached a diameter ∼270 μm after 62 min. Exposure of the preparation to a bolus of ACh (1 mM) led to a rapid transient vasorelaxation of which maximum level approached that measured in control and Ca2+-free conditions, suggesting that the endothelium was still functional in the presence of ceramide. Figure 7 B shows mean data from two separate series of experiments. The graph plots the time course of changes in lumen diameter expressed as a percentage of dilation relative to the passive diameter (100% level) estimated in Ca2+-free EGTA medium and maximum constriction induced by 1 μM PE (0% level). Similar to Fig. 7 A, 50 μM ceramide induced an ∼35% dilation, which took ∼10 min to reach a steady state (n = 6). The relaxation mediated by ceramide was not due to a desensitization of the α1-adrenergic receptor because the magnitude of the PE-induced constriction remained stable for >60 min as determined in parallel time control experiments carried out in the absence of ceramide (n = 3, open circles).
We also examined the possible effects of 50 μM ceramide on high-K+-induced constriction. As shown in Fig.7 C, increasing the concentration of K+ in the bathing medium from 5.4 to 45 mM, 15-min exposure, reduced lumen diameter by 57% on average. A 60-min exposure to ceramide produced no effect on the K+-induced constriction (n = 4). Our data indicate that while ceramide had no influence on the KCl-induced constriction, this compound partially dilated vessels, which were preconstricted with the α1-adrenoceptor agonist PE. These results suggest that BK-induced increased ceramide production also influence vascular tone in resistance arteries.
Many physiological functions have been ascribed to BK, including the promotion of contraction and relaxation of vascular and nonvascular smooth muscles, renal hemodynamics, cell proliferation, inflammation, edema, and pain (9, 10, 22, 28). BK has been shown to induce relaxation of many types of arteries, for example, in coronary arteries (2, 14, 30, 32, 33), pancreaticoduodenal artery (28), and rat mesenteric arteries (3, 5, 37). Contraction has also been observed, for example, in rat tail arteries (45) and in human umbilical and rabbit jugular veins (19, 30); this contraction is sometimes transient and followed and/or preceded by relaxation (30, 32, 33).
Few reports (18, 19, 21) have investigated the effect of BK on ceramide signaling. In human fibroblasts, BK activated sphingolipid metabolism and resulted in a rapid rise in ceramide. We also recently reported (18) that BK acts in part by modifying sphingolipid signal transduction. In contrast to the results obtained with human fibroblasts, BK inhibited the production of ceramide in RCCD cells. We speculated that BK could possibly be involved in counteracting the effects of agents that cause the generation of ceramide and thus have a regulating role in vasoconstriction and vasodilatation. The present study indicates that BK stimulates the rapid hydrolysis of sphingomyelin in rat mesenteric small arteries. The amount of 14C-labeled sphingomyelin obtained from arteries prelabeled with [methyl-14C]choline chloride decreases rapidly after treatment with BK. The effect is significant within 5 min of treatment and is maximal at 30 min. As expected, the decrease in sphingomyelin is accompanied quite closely by an increase in ceramide. The generation of ceramide, as measured by the generation of14C-labeled ceramide produced after stimulation of [14C]myristic acid-labeled cells with BK, is concentration dependent with the maximal amount being produced in response to 10−8 M BK. These results resemble those obtained in human fibroblasts in response to BK treatment but differ from the effect seen in RCCD cells (18). These results can probably be attributed to differences in cell specificity. We used exogenous SMase as a positive control to demonstrate the generation of ceramide. This treatment resulted in a rapid generation of ceramide. Exogenous SMase is widely used as a tool to investigate ceramide signal transduction. It is used to mimic the effect of ceramide generating signals (18, 19). Although it is not clear how exogenous SMase functions to generate an intracellular signal, some of the ceramide, which is generated on the cell surface, enters into the cell. That exogenously added SMase is very effective in hydrolyzing endogenous SM has been clearly demonstrated (18, 19, 27). Our results show that 10−8 M BK generate a ceramide signal comparable with that of 0.1 U/ml exogenous SMase.
BK receptors are generally divided into two major subtypes, BK-B1 and BK-B2 (18, 30, 32, 33). BK acts primarily by binding to the BK-B2 receptor, which is responsible for most of the following effects of BK: arterial vasodilatation, plasma extravasation, venoconstriction, activation of sensory fibers (pain), release of prostaglandins, and relaxing factors from the endothelium (19, 30, 32, 33). BK binds to the BK-B1 receptor; however, the receptor has a much higher affinity for the metabolite des-[Arg9]-BK. To determine which BK receptor subtype affects ceramide signal transduction, [14C]myristic acid-labeled small arteries were stimulated with BK in the presence of BK receptor B1 or B2antagonists. The BK-B2 antagonist HOE-140 did not block the effect of BK on ceramide generation. In contrast, the BK-B1antagonist Lys-Des-Arg9-Leu8-BK, which had no effect of background levels of ceramide, blocked very efficiently the generation of ceramide induced by BK. These results suggest that the BK-B1 receptor, and not the BK-B2 receptor, mediates the ceramide-generating effect of BK.
These results are in contrast to RCCD cells where we demonstrated that the BK-B2 receptor mediates the effect of BK on the inhibition of ceramide generation. In general, it is the BK-B2 receptor that is responsible for the contraction-inducing effect of BK on vessels such as the human umbilical vein (33), the rabbit jugular vein (33), and rat tail arteries (38) or for the BK-induced relaxation of pig coronary arteries (14, 32) and pancreatic arteries (28). More importantly, the relaxation that is induced by BK in rat mesenteric arteries is also mediated by the BK-B2 receptor (33, 37). It has been demonstrated that both types of BK receptors are present on rabbit superior mesenteric artery smooth muscle cells. Stimulation of the BK-B2 receptor by BK or the BK-B1 receptor by des-[Arg9]-BK results in intracellular Ca2+ signals that are transient or sustained, respectively. We have not measured Ca2+ signals; however, it is known that ceramide and other sphingolipid metabolites are implicated in generating these signals including in smooth muscle cells (19,26, 27).
It seems that the BK-B2 receptor mediates the effect of BK on inhibition of SMase in RCCD cells, whereas activation of the BK-B1 receptor leads to activation of SMase in rat mesenteric small arteries. Whether this is true of the two receptor subtypes in other cell types remains to be determined. Also unknown at the present time are the signaling pathways involved downstream of the BK-B1 or BK-B2 receptors and upstream of sphingomyelinase (Fig.8). There are presently many potential candidates that could be implicated: the ERK1, ERK2 mitogen-activated protein kinase pathway, the stress-activated protein kinase/c-jun NH2-terminal kinase or p38 pathways, various protein phosphatases, phospholipase A2, phosphatidylinositol or phosphatidylcholine phospholipase C, phospholipase D, protein kinase C, Ca2+, or nitric oxide (19). Also unknown at the present time is the involvement of other sphingolipid metabolites (sphingosine, sphingosine-1-phosphate, and ceramide-1-phosphate) in this model.
Our functional studies in intact rat mesenteric arteries show that a permeable form of ceramide, at a concentration estimated to be similar to that produced by a dose of BK eliciting maximum production of this second messenger, significantly dilated preconstricted intact rat mesenteric small arteries studied under isobaric condition. At the concentration of 1 μM, the α1-agonist PE is known to produce a contraction in this preparation that is near maximal and is entirely dependent on Ca2+ influx through voltage-gated L-type Ca2+ channels (40). In the presence of PE, ceramide did not attenuate contractility by suppressing smooth muscle Ca2+ channels because it had no effect on the constriction mediated by high-K+-induced membrane depolarization, which is abolished by dihydropyridines (40). The lack of effect of ceramide on high-K+-mediated constriction also rules out a nonspecific effect of this compound on the calmodulin and myosin light chain kinase pathway leading to actomyosin interaction.
Several possibilities could explain the effects of ceramide on PE-induced tone: 1) hyperpolarization of the smooth muscle cells by either enhancement of K+ channel activity (25) or block of Ca2+-activated Cl− (31) or nonselective cation (39) channels would result in reduced Ca2+influx through voltage-gated l-type Ca2+channels; 2) alterations in ion channel activity or the signaling pathways controlling the release of endothelium-derived relaxing (nitric oxide, prostaglandin I2, and endothelial-derived hyperpolarizing factor) or constricting (endothelin) factors; 3) modulation of the α1-adrenoceptor signaling pathway in the smooth muscle cells leading to a reduced sensitivity of the contractile machinery to intracellular Ca2+ levels. In contrast with our study, ceramide has been reported (17) to constrict bovine coronary arteries, possibly by inhibiting Ca2+-dependent K+ channels through a redox mechanism.
Interestingly, Ca2+-dependent K+ channels channels appear to play, at most, a minor role in the response of rabbit mesenteric arterial smooth muscle cells to PE (23). Recently, Zhang et al. (43) showed that ceramide constricts bovine small coronary arteries by impairing nitric oxide-mediated vasorelaxation, which would appear to involve an increased production of superoxide anion. Our results demonstrate in rat mesenteric small arteries: 1) the presence of SMase,2) SM hydrolysis is induced by BK, 3) SMase is activated by BK, 4) ceramide is generated in a time- and concentration-dependent manner, 5) the BK-B1receptor subtype is implicated in mediating the effect of BK on activation of SMase, and 6) ceramide induces a vasodilatation in mesenteric arteries, suggesting that ceramide bear differential effects on vascular tone in different vascular beds.
The authors thank Marie-Andrée Lupien for excellent technical and analytical assistance in the functional studies. The BK-B1 and BK-B2 receptor antagonists were a generous gift from Dr. Domenico Regoli, Department of Pharmacology, Faculty of Medicine, University of Sherbrooke.
↵* L. Kleine and G. Liu contributed equally to this work.
This study was supported by the Kidney Foundation of Canada, Canadian Institutes of Health Research Grant MT-14103 (to R. L. Hébert), by the Heart and Stroke Foundation of Québec, the Canadian Institutes of Health Research, and by the Montréal Heart Institute (to N. Leblanc). N. Leblanc holds a Fonds de la Recherche en Santé du Québec scholarship.
Address for reprint requests and other correspondence: R. L. Hébert, Dept. of Cellular and Molecular Medicine, Univ. of Ottawa, 451 Smyth Rd., Rm. 1337, Ottawa, Ontario K1H 8M5, Canada (E-mail: rlhebert{at}uottawa.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published September 27, 2001; 10.1152/ajpheart.00379.2001
- Copyright © 2002 the American Physiological Society


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Hampton Inn Chester3
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Just when you thought it was safe to experiment with a few frills, flounces and patterned tights in seasonal red, cheery orange and winter white, so the fickle wheel of fashion turns, and black is back.
The celebs are choosing black over any other colour at the moment, and every party, premiere and VIP room looks like a particularly star-studded funeral (only with better canapes and less weeping).
But why the return to basics, we wonder? Is it a statement about the world economy? Are the stars wearing black because they want to express their disgust at the situation in Iraq? Is it a diatribe against the hidden forces of terrorism? A scathing indictment of the rise of global capitalism and its inevitably repressive effect on free choice?
Or did they just put on weight at Christmas and want to hide the flab in flattering black? Hey, you decide...


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All CRN Blogs
Opportunities to be included in CRN's 2017 directories, rankings and awards programs.
Beating Up On Market Development FundsWith the pace of change in the market and the need to cut costs and drive revenue, MDF scrutiny is going to increase.
IoT Is Taking Off: But You Must Make The Big Investments To ScoreAll of the recent paradigm shifts in IT pale in comparison to the Internet of Things, a transformation that requires solution providers to make significant investments in order to reap the rewards.
Sponsored Blog Post
Security: The Conversation You Need To Have NowDrive your cybersecurity infrastructure to win confidence and build business
The Art Of Being Brief: 10 Tips For SuccessMES invited The Brief Lab's Lead Instructor Charley Thornton to speak at the MES Fall conference to help senior IT leaders improve their communications skills.
Is Marketing A Make Or Buy Decision?The business of selling technology is evolving so rapidly that SSPs have to invest in how they convey their brand in the market. But that proposes a legitimate question: Are you better off buying your marketing from experts or assembling an in-house team?
Small Business-Minded: Linksys Arms Its Partners With Enterprise Tech At SMB Price PointsLinksys has long been known has a company capable of delivering enterprise-class products at SMB prices, but since being acquired by Belkin, it has significantly upped its investments in technology innovation and partner program improvement.
K12 - This Is U.S. History, I See The Globe Right There.It's that time of year again; school instruction is coming to a close and Jeff Spicoli is about to get a visit from Mr. Hand to go over the history lessons he ignored (reference: Fast Times at Ridgemont High).
What Is High-Tech's Obligation In The War On Terror?With the acceleration in terrorist attacks around the world, it can't be long before the debate escalates and pressure rises on those companies whose products and services are being used to plan, communicate and execute these horrendous crimes against innocent people.
The Digital Marketing Era: Why It's Do-Or-Die Time For The ChannelSolution providers that are not arming themselves with digital marketing demand generation expertise are at a serious risk of losing customers, and they might not even realize it until it's too late.
I Wouldn't Do That if I Were You – The Surveillance MarketPhysical security and cybersecurity go hand-in-hand with protecting corporate assets; and while news of cybercrime has recently dominated the headlines.
All-Flash Arrays Experience 72% Revenue Growth in Past YearNot many categories can boast that they grew 72% in U.S. sales in the span of a single year.
Using Marketing To Get To The 'As A Service' End GameStrategic service providers can't afford to be viewed as old-school on-premise infrastructure players. Rebuilding the legacy brand to present a leadership player capable of bringing the customer to the new compute model is the key first step to the 'as a service' end game.
Welcome To The Rise Of The Strategic Service Provider BusinessThe strategic service provider shift is forcing cloud services companies, including Google, to step up to the plate with new channel models.
Why It's Time For Tim Cook To Step DownWhile no one expected Tim Cook to be Steve Jobs, the expectation was that he would surround himself with people who would make up for his weaknesses in the visionary areas that Jobs excelled at.


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Stock Graphic >> Illustration - Steampunk mechanism 276741 by alena.sipilova @ CreativeMarket
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The set contains 3 posters, pictures, calendars 3 2016, 2 objects on a white background, ready to print in the style of steampunk with relevant elements and colors
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Steampunk mechanism
by alena.sipilova
Keywords: steampunk, technology, gear, steam, watch, industrial, measuring, mechanic, mechanical, mechanism, metal, metallic, punk, wheel bolt, clockwork, device, engineering, machine.


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Bonny brunette teen gets her asshole completely destroyed by big cock of her BF
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10.9 e vertical roller mill
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Vertical roller mill machines are widely used in the concrete and mining fields, and are also used to process gypsum. ... B Series Deep Rotor Vertical Shaft Impact Crusher; Grinding Equipment. MTM Medium Speed Mill; MTM130XUltrafine Mill; Cement Mill; LM Grinding Mill;Read More
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Vera Melendez
- 31 years old
- Date of birth: Jan 27, 1983
- Place of birth:
Chicago, Illinois, United States
- Date of passing: Jan 16, 2015
- Place of passing:
Chicago, Illinois, United States
|Let the memory of Vera be with us forever
This memorial website was created in memory of our loved one, Vera Melendez, 31, born on January 27, 1983 and passed away on January 16, 2015. We will remember her forever.
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Over 1.8 million nonprofits and charities for donors, volunteers and funders
Mission: To produce innovative professional shakespeare productions that are both free and accessible to a diverse audience, whether set on the green or in the classroom. Our vision is to broaden the cultural environment of our community with high quality professional theater.
Programs: Shakespeare on the green- each summer season runs for about three weeks and generally includes two plays- typically one tragedy and one comedy. Through this cultural experience, parents can introduce their children to the power and beauty of classical theatre, produced by a professional company of artists from across the country. People who ordinarily either would not or could not attend a shakespeare play are able to discover the unique and life-affirming qualities that live theater provides. In addition to the main performance are educational preshow seminars and a green show entertainment featuring a juggler and local musicians, and a "shakespeare" interactive educational tent utilizing donated materials and manned by volunteers with educational expertise.
the touring theater company has been able to provide live performances of shakespeare's works to many rural communities and schools where access to educational performing arts is limited. The tour includes public and community performances in addition to private performances for middle and high school students.
educational workshops and a two-week camp for students ages 8-18 compliment the tour and summer performance programs. Our one-hour workshops include "through the language of shakespeare", "shakespeare unplugged", "words. Words. Words", "thinking makes it so", "thus we play", "i bite my thumb", "speak the speech", and "light in spirit" all with individual themes and learning objectives.


text: Steve Schmidt A Celebration of Ella Fitzgerald at Miami University By Lee Hay • Nov 8, 2017 Miami University Department of Music and the William E. Schmidt Foundation present Grand Night: Love Letters to Ella Celebrating 100 years of Ella Fitzgerald at Miami University Salute To Musician Larry Goshorn 8 p.m. Saturday By John Kiesewetter • Jul 29, 2016 Lee Hay This sounds like fun: Gary Burbank, Katie Laur Marcos Sastre, former Pure Prairie League drummer Billy Hinds and others join Brian O'Donnell for a two-hour tribute to longtime Cincinnati guitarist Larry Goshorn at 8 p.m. Saturday on WVXU-FM and WMUB-FM. Remembering Jazz Expert Oscar Treadwell, Who Died In 2006 By John Kiesewetter • Mar 30, 2016 WVXU You just know that jazz expert Oscar Treadwell is smiling on Cincinnati. Ten years after his death, his adopted hometown provides the background for a major motion picture about jazz icon Miles Davis, Don Cheadle's new "Miles Ahead." Treadwell, who died on April 1, 2006, at age 79, was the jazz voice and conscience for Cincinnati for 46 years. If a Miles Davis tune was heard on radio here, most likely it was on Treadwell's shows on WVXU-FM, WNOP-AM, WGUC-FM, WVAE-FM or WZIP-AM. In fact, "O.T." is such an institution that his shows are still on the air here at WVXU-FM 10 p.m.-midnight Sunday. Meet The Royal Bopsters Project, Including Singer Amy London By Lee Hay • Sep 4, 2015 Listen Listening... / 13:14 The Royal Bopsters Project is a new jazz vocal quartet featuring singer Amy London who, along with one of the guests on their new CD, local piano great Steve Schmidt, join our Lee Hay to talk about this group and some of the guests on the album including jazz legend Mark Murphy. Jazz singer Amy London talks about her exciting new CD, "Bridges" By Lee Hay • Jun 26, 2015 Listen Listening... / 12:54 Acclaimed jazz singer Amy London stopped by our studio recently to talk with Lee Hay about her newest musical project, a CD called Bridges that features a variety of guest performers including local jazz pianist Steve Schmidt. Upcoming jazz concert featuring Jackie Allen and Steve Schmidt By Robyn Carey-Allgeyer • Jul 11, 2014 Listen Listening... / 4:18 Robyn Carey-Allgeyer has information about an upcoming concert by jazz singer Jackie Allen, happening at The Greenwich on Saturday, July 26. Joining Jackie Allen that night will be local jazz legend, pianist Steve Schmidt.


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PrimeFaces Cookbook - Second Edition by Mert Çaliskan
English | 29 May 2015 | ISBN: 1784393428 | 412 Pages | EPUB/MOBI/PDF (True) | 28.06 MB
This book is for everybody who would like to learn modern Java web development based on PrimeFaces and is looking for a quick introduction to this matter. Prerequisites for this book are basic JSF, jQuery, and CSS skills.Over 100 practical recipes to learn PrimeFaces 5.x – the most popular JSF component library on the planetAbout This BookThe updated second edition of the first PrimeFaces book ever released is brought to you straight from the horse's mouth, and focuses on practical implementations of the framework rather than theoretical onesWith this book, you will get everything you need to know about PrimeFaces first-hand and will learn how to easily integrate and use PrimeFaces successfully with your JSF projectsThis book is written in a clear, comprehensible style and addresses a wide audience who set their scope on Java EE development What You Will LearnUnderstand basic concepts such as AJAX processing and partial view submit so that you can work with PrimeFacesGo beyond the basics and discover more interesting features of PrimeFaces: PrimeFaces selectors, RequestContext, Dialog Framework, and moreDelve deep into over 100 rich UI components with all the required detailsGet practical solutions to complex problems that arise in a JSF ecosystemUse best practices, avoid pitfalls, and get performance tips when working with the component suiteIn DetailPrimeFaces is the most popular component library used in the JSF ecosystem. It is a lightweight library with one JAR, zero configuration, and no required dependencies.This book covers over 100 effective recipes for PrimeFaces 5.2, which is a leading component suite to boost JSF-based applications. The book starts with an introduction to PrimeFaces and its concepts, such as AJAX processing, the selector mechanism, partial view submit, and i18n support. Later chapters then focus on theming and the usage of over 100 input and output components, such as tables, charts, menus, and so on.This cookbook provides a solid foundation by covering all the knowledge needed to work with PrimeFaces components in the real world.
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Photo credit: zimmytws / Bigstock
19. Batesville High School, Batesville, IN
Batesville High School is a public school in Batesville, Indiana. It has 734 students in grades 9-12. The teachers are always there to help students do their best, but also be their friend when things get difficult. The vast classing options allows students to discover their passion, or what they might want to pursue in the future. Overall, Batesville High School is a wonderful school, with a very high success rate.
There are many options when it comes to scheduling, from Woodworking to Film Literature. There are many arts programs that students can choose from and many Math and English classes offered.
Every class is taught by a personable teacher who is there to teach and have fun. They honestly enjoy the company of students and will even allow them to hang out after school to just talk and work over homework lessons.
Workload is relatively easy and not too overwhelming. Along with offering many high school classes, this high school also offers free classes at the local Ivy Tech campus and dual credit high school/college classes. Almost 1/4 of students are enrolled in at least one AP or dual credit class.
There is a variety of extracurricular clubs and organizations at BHS. Some of the clubs have a pretty high commitment level, but most are laid back and meet and get things done when it's convenient for most. Teachers and administration do support clubs and organizations.
School coaches know how to really connect with their athletes. 90% of students participate in the athletics, and they love it. All of school equipment is fairly new and works great. All of games are well attended, students love to go to support a good win against the rivalry teams.
- Batesville High School graduation rate is 95.0%. National average is 82.2%.
- 92.0% students of Batesville High School scored at or above proficiency levels on their state math assessment test.
- 92.0% students of Batesville High School scored at or above proficiency levels on their state reading/language arts assessment test.


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The following information is only an estimate of . The webpage's visitors, value, income, position etc can vary heavily from day to day. Our estimation of visitors and income, is only based upon statistics from a specific moment on a specific day. You should visit the site frequently to see if the website increases or decreases in value. :-)
Ad revenue and visitors
|Daily pageviews
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|Yearly income
|3,060 £
|Info last updated:
What is Saxon Spanking Web: OTK Spanking BDSM Erotic Schoolgirl Discipline?
|Central (Reference) Section Spanking and BDSM Implements Advice Articles and advice on the various aspects of erotic discipline, BDSM, corporal punishment and schoolgirl fetish including use of common discipline implements and techniques, using a cane, a paddle, belt or strap, and making and using a birch rod.
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H2: Central (Reference) Section
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HTTP/1.1 200 OK Content-Type: text/html Server: Microsoft-IIS/8.5 X-Powered-By: ASP.NET X-Powered-By-Plesk: PleskWin Date: Wed, 15 Nov 2017 19:26:15 GMT Connection: close Content-Length: 17231
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Our Mission
To provide compassionate services to pets and people in crisis.
About Us
LOH is the only organization in the Valley dedicated to rescuing pets abandoned, or at risk of homelessness, due to foreclosure, eviction, or other financial hardship.
The most obvious recipients of our assistance are the pets we rescue, re-home, and feed; however, the mission of LOH is linked directly to the human-animal bond.Read more
A Trusted Charity
Lost Our Home is a top-rated charity by these charity watchdog groups.


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What is menopause?
Menopause is the time in a woman's life when her periods stop and she can't have children anymore. This happens because as a woman ages, her ovaries stop making enough of the female hormones estrogen and progesterone.
Some things you might have heard about menopause aren't true. For example, women don't lose interest in sex or have more mood changes because of menopause.
When does menopause occur?
The average age for women to have their last period is about 50. But it's normal for menopause to occur any time from age 41 to 59. A woman often goes through menopause at about the same age as her mother.
Women who have both ovaries removed will go through "surgical menopause" at the time of their surgery. If the uterus is taken out but the ovaries are left, a woman won't have periods but she will only go through menopause when her ovaries stop making estrogen.
If you stop having periods early–before age 40–your doctor can do a blood test to see if you're going through menopause.
Menopause is a gradual process that can take several years. You're not really through menopause until you haven't had a period for 6 to 12 months. (During this time, keep using birth control if you don't want to become pregnant.)
What are the common signs and symptoms of menopause?
Some women just stop having periods. Others experience symptoms, such as the following:
A change in your menstrual cycle. This is one of the first signs of menopause. You may skip periods or they may occur closer together. Your flow may be lighter or heavier than usual.
Hot flashes. Hot flashes are the most common symptom of menopause.
When you have a hot flash, you'll feel warm from your chest to your head, often in wave-like sensations. Your skin may turn red and you may sweat. You may feel sick to your stomach and dizzy. You may also have a headache and feel like your heart is beating very fast and hard.
Thinning of your vagina and vulva (the area around your vagina). The skin of your vagina and vulva becomes thinner with menopause. Your vagina also loses its ability to produce as much lubrication (wetness) during sexual arousal. These changes can lead to pain during sex.
An estrogen cream (put in and around your vagina) or a water-based lubricant (such as K-Y Jelly) to make sex less painful.
Urinary tract problems. You're more likely to have bladder and urinary tract infections during and after menopause. Talk to your doctor if you have to go to the bathroom often, feel an urgent need to urinate, feel a burning sensation when urinating or are not able to urinate.
Headaches, night sweats, trouble sleeping and tiredness are other symptoms. Trouble sleeping and feeling tired may be caused by hot flashes and night sweats.
Does menopause have emotional symptoms?
Many women experience emotional symptoms during menopause. These symptoms may include sadness, anxiety and loss of sleep. For some women, symptoms can be severe. If you find that you're having emotional problems, talk to your family doctor.
What is hormone replacement therapy?
Hormone replacement therapy (HRT) involves taking estrogen alone or estrogen combined with another hormone, progestin. Some women have found that HRT can relieve symptoms such as hot flashes, vaginal dryness and some urinary problems. However, HRT is not for everyone. Talk to your doctor about the risks and benefits of HRT.
Are other treatments available?
Yes. Medicines such as estrogen cream, antidepressants, soy products and certain herbal supplements may help ease some menopausal symptoms. Discuss these options with your doctor.


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Johnstown, NY (PressExposure) December 01, 2009 -- Lone Palm Gourmet Coffee is famous for the over 45 exciting varieties of tea and coffee that it provides. On these top quality products, they are providing a shipping offer with which you can easily have them on their way in one business day.
The owner of Lone Palm Gourmet Coffee said, âSince we've been in this business, we are refining our business processes. The customers have really appreciated our shipping policy and our orders have certainly increased. We ship our products to ensure they arrive safely, quickly, and with all the flavor and aroma youâd expect.â
Lone Palm Gourmet Coffee has been gaining its due recognition in the field of Organic gourmet coffee and tea products. The coffee products are selected and produced with a priority on being eco-friendly and minimizing harm to the environment. In the shipping process it is made sure that the products don't lose out the aroma and original flavors, therefore, they are packed in air-tight bags.
The revenue earned from fair trade coffeeproducts is used to reach out to the children in need. Apart from making products that are completely environment-friendly, whatever the company is earning on the sale of these products, they are divesting some part of the funds to child welfare organizations as well(http://www.lonepalmcoffee.com/about-us).


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Discussion in 'Nintendo Wii Chat' started by Glen W, Aug 4, 2007.
Somebody give me info on mario cart for the wii
its comin out in the begginin of 08 and it will have online play with 12 racers and comes with a free steering wheel to play with, very good game nuf said
Oh Thank you
Its also more back to roots (ie no dd two people in a kart shite)
See here
siiiiiiiiick moooit
Where was 12 confirmed? As far as I knew, we were still in the dark about the increased number of players.
I believe the E3 video showed 12 people racing, thats the only source we have...........
I'm so glad there wont be any double-driver crap this time around. MIGHT actually pick this one up.
DD wasn't that bad. It was actually quite fun. I think it was to include the whole LAN network 16 players, without having to overly stretch the game itself (not sure if the cube could handle 16 individual karters all at the same time).
I'm kinda glad that they made it single character Karts though. Hopefully it will mean more characters we can play as.
I still say they should make it an option to use double cars in Mario Kart Wii. That would be the best thing for the game. You can either have single kart races or double kart races.
I didn't think it was too bad an idea, I think it realistically did little to change the gameplay. However I could imagine much younger kids it making a big difference for, if only one had to drive and one could shoot. So I agree with sillyhat, it should be left as an option, but not the main style of play.
That whould mean that the wait system whould have to be brought back in and loads more messing around
It should be kept simple
Did you even play the older Mario karts ?
There was no aiming it was just fire foward or back ward
Like holding down A and pressing one other button is hard
If it is try going back to the Atari vcs/2600 with its one button
I think DD was an awesome game, it added a whole different strategy to the game. People need to stop wanting to play the same exact game over and over. Change is what makes game different and more fun. I definitely think it would be aweosme if they added maybe a DD cup, where maybe there is a set of races that are Two cart races. Just to leave that in there. I want to see 4 players (atleast!) being able to compete in the grand prix. I absolutely can't wait for this game, its one of the main reasons i bought a wii. And was the sole reason i bought a GC.
Okay think about a 5 year old child. Yes it was simple to shoot, but for a five year old child that might be the ONLY thing they can handle. It's not that wild a thought...kinda like what a lot of other games are already moving towards. One setup in the game for most gamers, one setup for non-gamers and children, like the new Madden
Also for anyone that actually played double dash...switching drivers was ridiculously simple and easy, people just didn't like the fact that it was different. It didn't add a whole lot, but it took away nothing from the game.
I can't wait for this game. The only MK I have played is on my wife's DS. And once played one on the GC at a friends house... I think it was that DD one.
I really am hoping for a GREAT online for this game.
I'm not saying I like the double karts better than the single karts, I'm just saying it would be nice to have an option like that. I definantly like the single karts way better.
Pumped for this one!
Dispite the fact that it was only announced the other week
Last time I checked 5 year old children wont care about haven others doing the driving.
Thed be to busy playin "Genaric Disney game 2007" or "Another colorfull game" to care
I did play/have it
I didnt like it
I have some info, it is Kart, not cart.
Everyone else covered everything else about the game pretty well :lol:


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The habits of highly effective community development practitioners
This paper is the result of a study aimed at answering the question: 'What makes effective community development practitioners effective?' In it, all the articles published over a 10-year period in the Community Development Journal, International Social Work, Journal of Community Practice and Social Work (South Africa) were subjected to a secondary analysis. This made it possible to identify eight 'habits of effectiveness'. This set of habits can form a credo to guide a practitioner's service delivery. It also provides a list of criteria to help identify ineffective habits and confirm effective ones.
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Volume (Year): 28 (2011)
Issue (Month): 1 ()
Pages: 87-98
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Separate names with a comma.
Posted By The Village Idiot,
Feb 4, 2013 at 9:03 PM
Sorry for your troubles. as far as the stove i am not familiar with it but you can check the gaskets with the dollar bill test to make sure you are getting a good seal all the way around. And as far as the electric Can you get your hands on a kerosene heater to supplement the stove ? I have 2 just incase of an emergency and the kerosene can be stored for years. Its a good back up plan just a thought good luck.


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Tarare - Salieri
Release Date: 31 January 2005 | Certificate: Exempt
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The Salieri opera peformed at the 1988 Schwetzinger Festspiele. Tarare tells the story of the Spirit Of Nature who creates new people in an attempt to cleanse the human race. The results bring love and jealousy. Sung in French.
Release Date: 31 January 2005
Certificate: E - Exempt from Certification
Region 0
Aspect Ratio: 4:3
Sound: PCM Stereo
Running Time: 184 minutes
Production Year: 1988
Main Language: French
Subtitles: Dutch\English\French\Spanish
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Catalogue No: 100557


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Spalding Square (Skilled Care)
Nazareth Home respects and understands that elders and their families are placing their trust in us to provide quality care and honor their choices. Our experienced team provides a full spectrum of compassionate care that is based on the individual needs and wants. Nazareth Home's person-centered philosophy creates an empowering environment where positive relationships are fostered between the elder and staff through consistent assignment, open communication and family engagement, and the goal to reinforce each elder's sense of purpose. This isn't your granparent's nursing home. Each elder's mind, body and spirit are treated with ultimate respect and consideration.
Spalding Square elder's and their families have earned the right to:
- private rooms
- Experienced and compassionate staff
- Individualized Care Plans
- Neighborhood setting
- Daily Activities including a full service beauty salon
- Spirituality and Daily Living programs
- Therapy and dietician services available
- Social Services
- Music and Memory Certified
- Namaste Care
- End-of-Life Care
Nursing Neighborhood Fees
- Room: $278 per day, $8,618 per month, $101,470 per year
- Large Room: $288 per day, $8,928 per month, $105,120 per year
Optionl Items:
- Cable: $20 per month
- Phone: $10 per month
- Laundry Services: $35 per month
One time move in fee: $2000
Companion Rates: $18.50 per hour
* Must provide own TV and Phone
All rates are subject to change. Daily rate does not include supplies or cost of medications


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Hi all
Long time no posting hey?
Been really busy here as usual with kids and scouts and hubby and well life in general.
Last post i chatted about taking the kids to disney on ice. It was wonderful. The costumes are beautiful and colourful and the story was great plus the skating was fantastic. The boys had a blast and cheered and clapped and pointed and screamed. Merchanise was so expensive so we didnt walk away with much but heaps of photos and some great memories.Thought i would share some pictures with you.
The boys enjoyed having their cousin Kurt around. He spoilt them rotten and played rough with them. Aunty Helen did a lot of spoiling too and the boys lapped up every moment of it.
Ashley starts joeys tonight. Should be interesting. He is taking some cup cakes with him as it was his birthday on the 21st. Might have to take the camera and get a couple of photos.
Bought some really cute patterned paper today from the reject shop so i am hoping and praying that i can make a card or two soon. Fingers crossed this is the inspiration i have been praying for.
Well i am off.


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odm+ DD99B Iron Man3 digital watch
odm+ is proud to announce the launch of cross-over pieces on odm's most wanted models featuring well-known heroes- Ironman. Numbers of odm well-received models are selected and re-design with Iron Man fabulous elements.
|case : PC case
|movement : o.d.m. digital module with time, date, personalized message function & EL backlight
|water resistant: 3 ATM
|strap / band : Silicone strap


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Portland's finest Chromatics appeared on last night's Twin Peaks season three premiere, performing their gorgeous 2015 track "Shadow" at the stage of Bang Bang Club. Now, Johnny Jewel and the band have shared a video for the new video of "Shadow", which pays tribute to David Lynch's 1986 film "Blue Velvet" and Julee Cruise. Welcome back to Twin Peaks.
Directed By Rene & Radka.
Chromatics: "Magazine"


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October 9, 2011 BY Brendan Dunne
As it turns out, the 'Hiker Pack' lineup for the Nike Sky Force '88 Mid runs a little deeper than we thought, with the clean white pair shown above set to hit shelves in the coming months as well. The choice of colors, or lack thereof, might not exactly exude that outerwear feel, but the d-ring lacing and metal eyelets are there all the same. Also the ankle material has been switched out, going for a warm fleece in place of the fuzzy wool that we saw on the other two 'Hiker Pack' models. Best of all may be pristine white soles, devoid of any pre-yellowing or faux vintage treatment. Check out the full pics of this Nike Sky Force '88 Mid after the jump and grab em now from France's SNKRS.
Filed under: Nike Force Nike Retro Upcoming Sneakers
Tags: Nike Sky Force '88 Mid


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Puzzler Brain Games
Release History
|Puzzler Brain Games
|Koch Media
|19th April 2013
|Puzzler Brain Games
|FuRyu Corporation
|North America
|23rd April 2013
Game Overview
Puzzler Brain Games is a series of different puzzle games developed by Ideas Pad for the iOS, Microsoft Windows, Nintendo DS. With daily workout programmes designed to keep your brain active, these exciting games and challenges contain four categories; Memory, Numerical, Word and Visual - all designed to enhance and exercise your mind.
Similar Games
- Professor Layton and the Mask of Miracle (1.85m)
- Professor Layton vs Phoenix Wright: Ace Attorney (0.82m)
- Professor Layton and the Azran Legacy (0.81m)
- Puzzle & Dragons Z + Super Mario Bros. Edition (0.56m)
- Tetris Axis (0.44m)
- Bust-A-Move Universe (0.31m)
- Layton's Mystery Journey: Katrielle and the Millionaire's Conspiracy (0.17m)
- Puyo Puyo!! 20th Anniversary (0.13m)
- Picross 3D 2 (0.12m)
- Puyo Puyo Tetris (0.11m)
- Scribblenauts Unmasked: A DC Comics Adventure (0.10m)
- Brain Age: Concentration Training (0.10m)
- Mahjong Cub3D (0.09m)
- Nikoli's Pencil Puzzle (0.09m)
- Puzzler Mind Gym 3D (0.08m)
- Mario vs. Donkey Kong: Tipping Stars (0.08m)
- Cut the Rope (0.07m)
- Sumikko Gurashi: Koko, Dokonan Desu? (0.06m)
- Paddington: Adventures in London (0.04m)
- Azada (0.03m)


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European Hospitality Awards 2013
Scott Brownrigg's design for the Park Plaza Histria, Pula has been shortlisted for Best Hotel Spa of the Year at the European Hospitality (EH) Awards. The EH Awards celebrate the finest in hospitality, with the judges looking for innovation approaches in all categories.
The hotel spa award recognises the best use of interior space and spa installation. How the spa has had an impact on the reputation and brand of the hotel, and how individual it is.
Scott Brownrigg completed the renovation of the Park Plaza Histria Pula in May 2011. Co-Owned by PPHE Hotel Group, owner and operator of upscale and lifestyle hotels; Park Plaza Histria Pula is now PPHE Hotel Group's flagship hotel in Croatia within the Istrian region. The hotel's Spa & Wellness Centre is also operated by PPHE Hotel Group and was designed in line with their operational requirements.
The refurbishment of the1980s hotel has allowed for the incorporation of the Spa & Wellness zone which cleverly uses space from an area previously used as a doctors' surgery and physiotherapy clinic. The Spa is located on the lower ground level of the hotel's main building.
As the hotel is nestled on a hillside slope overlooking the Adriatic Sea, direct access from the Spa to the outdoor swimming pool, stone covered terraces and the private beach has been achieved. The journey from the Spa to the beach is adorned with olive trees in elegant white Ming vases designed by Rodolfo Dordoni for Serralunga and a Mediterranean garden filled with lavender and rosemary, also used in essential oils for the Spa treatments.
At the Spa guests are directed into the waiting area for treatment consultations. Whilst this zone has been placed at the heart of the deep floor plate of the lower ground floor, ample light streams through via the full height glazing of the indoor swimming pool, creating a light, relaxing and refreshing atmosphere. From here guests go to the changing rooms that lead onto the individual treatment rooms or the wet spa. The wet spa boasts a sauna, steam room, cold plunge pool and a relaxation area. Restricted space has resulted in the relaxation area being located in the heart of the wet spa, with clever use of mosaic covered heated benches and solid teak lounge beds.
The route to the treatment rooms is via a windowless corridor, which the design team transformed into a light, tranquil zone with the use of back-lit Perspex and a Kerrock feature wall. Treatment rooms are named after the signs of earth, water, air and fire, depicted in the ancient letters of the Glagolica, Mediaeval language of Istrian ancestors.
Elements of Istrian nature are subtly translated and applied in abstracted timber motifs; from the bespoke design of the reception desk through to the carefully positioned sections of walls in the treatment and changing rooms.
Clever use of space and light create a very unique spa experience for the enjoyment of the hotel guests. The winners will be announced at the Awards Dinner which takes place on the 1 November.


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(763) 762-8071
Minnesota Exteriors, Inc.
70 years in business8600 Jefferson Hwy
Osseo, MN 55369-4504
Fax Numbers
- (763) 493-8980
Additional Phone Numbers
- (800) 359-1363
- (763) 391-5583
- (800) 359-1352
- (763) 493-5500
- (651) 760-7622
- (763) 762-8079
Additional Email Addresses
- firstname.lastname@example.com
- firstname.lastname@example.com
- email@example.com
Find a Location
BBB File Opened: 04/01/1987
Business Started: 01/01/1947
Business Started Locally: 01/01/1947
Business Incorporated: 01/01/1971 in MN
Type of EntityCorporation
Business Management
- Katie Andrews, Marketing Coordinator
- David Kapsner, President
- Bob Reiner, Sales Manager
Business Category
- Siding Contractors
- General Contractor
- Gutters
- Insulation Contractors
- Roofing Contractors
- Construction Services
- Window Installation
- Doors
- Storm Windows and Doors
- Windows
Products & ServicesMinnesota Exteriors offers home exterior products such as siding (vinyl, aluminum, steel, fiber cement, engineered wood), windows (vinyl, wood, fiberglass, composite), roofing (metal, asphalt) seamless gutters, soffit/fascia, insulation, and stone.
Service AreaWe service the following area(s): Albertville, MN, Andover, MN, Anoka, MN, Bayport, MN, Belgrade, MN, Bellechester, MN, Bethel, MN, Biscay, MN, Burns Township, MN, Burns Twnshp, MN, Cambridge, MN, Cedar E Bethl, MN, Cedar East Bethel, MN, Cedar, MN, Center City, MN, Centerville, MN, Circle Pines, MN, Clearwater, MN, Columbus, MN, Corcoran, MN, Crown College, MN, Crystal Bay, MN, Dayton, MN, Delano, MN, Dennison, MN, East Bethel, MN, Eden Prairie, MN, Elk River, MN, Elko New Market, MN, Elko New Mrkt, MN, Elko, MN, Excelsior, MN, Forest Lake, MN, Glencoe, MN, Goodhue, MN, Greenwood, MN, Hamel, MN, Hampton, MN, Heidelberg, MN, Hopkins, MN, Hugo, MN, Inver Grove Heights, MN, Inver Grove, MN, Lake Elmo, MN, Lake ST Croix Beach, MN, Lakeland Shores, MN, Lakeland Shrs, MN, Lakeland, MN, Lakeville, MN, Lino Lakes, MN, Little Canada, MN, Long Lake, MN, Loretto, MN, Maple Grove, MN, Maple Lake, MN, Maple Plain, MN, Marine On Saint Croix, MN, Marine St Crx, MN, Medina, MN, Mendota, MN, Minetonka Mls, MN, Minneapolis, MN, Minnetnka Mls, MN, Minnetonka Mills, MN, Minnetonka, MN, Minnetrista, MN, Monticello, MN, Mound, MN, New Prague, MN, New Trier, MN, North Oaks, MN, Norwood Young America, MN, Norwood, MN, Nowthen, MN, Nya, MN, Oak Grove, MN, Oak Park Heights, MN, Oak Park Hgts, MN, Oak Park Hts, MN, Orono, MN, Osseo, MN, Otsego, MN, Prior Lake, MN, Ramsey, MN, Regal, MN, Rockford, MN, Rogers, MN, Saint Augusta, MN, Saint Bonifacius, MN, Saint Cloud, MN, Saint Paul Park, MN, Saint Paul, MN, Sartell, MN, Sauk Centre, MN, Scandia, MN, Sentinel Butte, ND, Sentinl Butte, ND, Shakopee, MN, Silver Creek, MN, South Haven, MN, South Saint Paul, MN, South St Paul, MN, St Bonifacius, MN, St Croix Bch, MN, St Croix Beach, MN, St Marys Point, MN, St Marys Pt, MN, St Paul Park, MN, Stanchfield, MN, Stanton, MN, Stillwater, MN, Taconite, MN, Vadnais Heights, MN, Vadnais Hts, MN, W Lakeland, MN, Waconia, MN, Watertown, MN, Wayzata, MN, West Lakeland, MN, White Bear Lk, MN, Young America, MN
Alternate Business Names
- North Country Distributors Inc
Methods of Payment
- Cash, Check, Credit Card, Financing Programs available through Synchrony Bank.
Minnesota Exteriors is family-owned and operated. All of our projects are backed with a lifetime workmanship warranty in addition to the manufacturers' warranties.
BBB Reason for Ratings
Licensing information is provided in the BBB Business Profiles to inform the public about industries that may require professional licensing, bonding, or registration. Better Business Bureau encourages you to check with the appropriate agency to be certain any requirements are currently being met.
Advertising Review
BBB promotes truth in advertising by contacting advertisers whose claims conflict with the BBB Code of Advertising. These claims come to our attention from our internal review of advertising, consumer complaints and competitor challenges. BBB asks advertisers to substantiate their claims, change ads to make offers more clear to consumers, and remove misleading or deceptive statements.
Government Actions
BBB reports on known significant government actions involving the business's marketplace conduct.
Out of Business
BBB reports on a company that is out of business for one year from the date the company closes its doors or ceases to do business.
Misuse of Better Business Bureau Name/Logo
BBB reports on unauthorized use of the Better Business Bureau's name and/or logo for as long as the business continues to use it in any advertising, or for one year after the business ceases any repeated unauthorized uses.
BBB reports on a business's bankruptcy as long as the business remains in bankruptcy.
Mail Returned
BBB reports when mail sent to the business was returned by the Postal Service.


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Below is a great link which share some important numbers and how NBA teams and a proposed revenue sharing agreement with NBA players will not help small market teams survive. Its funny how most basketball fans think that owning an NBA team is a great way to make money. Those of us who study numbers for a living know that most of the NBA's teams make little or no money year in and year out while the players continue to make huge salaries.
Owners in the BSN face this same issue as players continue to demand large salaries while most teams lose money hand over fist. Look at Carolina Gigantes, one of the best run teams and most successful teams in the league is now decided to recess for a year or two and analyze if and how the franchise can come close to just breaking even.
As I tell my son, the numbers never lie!


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Fox Rage Illusion Fluorocarbon
It's important to fish a mono leader with braid and most anglers will use 3ft to 4ft of fast sinking fluorocarbon to reduce the visibility of their rig in gin-clear water. Fox's popular Illusion fluoro offers high knot strength, abrasion resistance, and high breaking strains for their diameters. Most anglers add a micro swivel between their braid and fluoro to reduce line twist.
RRP £10.49 for 50m spool


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There are more than 20 possible successors; carbon nanotubes, graphene and 3D devices are way down on the list.
Chipmakers continue to scale the CMOS transistor to finer geometries, but the question is for how much longer. The current thinking is that the CMOS transistor could scale at least to the 3nm node in the 2021 timeframe. And then, CMOS could run out of gas, prompting the need for a new switch technology.
So what's after the CMOS-based transistor? Carbon nanotubes and graphene get the most attention. Over time, the industry could migrate towards stacked-die or monolithic 3D devices. All told, there are nearly 20 viable next-generation transistor candidates on the table, although there is a possibility that CMOS may prevail over the long term.
Surprisingly, based on the latest performance benchmarks from Intel, carbon nanotubes, graphene or even 3D devices failed to make the cut. Conducted in the lab, Intel's benchmarks are based on throughput, power consumption and other criteria. In simple terms, the most promising devices on Intel's current list are narrowed down to five technologies—spin-majority gate; spin-wave devices; III-V tunnel field-effect transistors (TFETs); heterojunction TFETs; and graphene nanoribbon (GNR) TFETs.
TFETs are attractive because they are steep sub-threshold slope devices, and an evolutionary step from today's MOSFETs. The spin-based, or nano-magnetic, technologies are intriguing because they are nonvolatile logic devices.
Intel's list isn't set in stone and could easily change. Others may have different ideas. For example, on Imec's list for the ultimate next-generation switch, the R&D organization currently identifies two technologies right now—the heterojunction TFET and GNR TFET.
In any case, the benchmarks provide a clue where the industry is heading if or when CMOS hits the wall. "There are a lot of research projects in the industry," said Mark Bohr, a senior fellow and director of process architecture and integration at Intel. "The problem is that many of these projects are not applying rigorous benchmarks."
The idea behind Intel's benchmarks is to narrow down the potential choices based on known criteria, Bohr said. "As an industry, we just don't have enough money to fund all projects," he added.
Clearly, the development of a next-generation switch will require new materials and fab tools. But even with substantial funding and new breakthroughs, it's still unclear when the next-generation switch will appear. "They are not that far along to predict an insertion point," said Thomas Theis, executive director at the Nanoelectronics Research Initiative (NRI), a program at the Semiconductor Research Corp. (SRC). "And it's certainly too early to pick the winners. But optimistically, I can see some version of tunnel FETs in 10 years. But I am not ready to say that about the nano-magnetic devices."
Narrowing the choices
In 2005, the SRC launched the NRI, a group that is researching futuristic devices capable of replacing the CMOS transistor by 2020. The NRI include GlobalFoundries, IBM, Intel, Micron, TI and several universities.
Generally, today's MOSFETs are limited to 60-millivolt per decade swing, making them difficult to scale below 0.5 volts. Seeking a technology that will break this barrier, the NRI is exploring technologies in four basic categories—charged (CMOS, TFET); electric dipole (FeFET); magnetic (spin devices); and orbital state (BisFET). Researchers are also exploring carbon nanotubes, graphene and other technologies.
Most of the next-generation technologies share the same problems. "The principles don't need to be invented," said Theis, who is on assignment from IBM. "But none of these technologies actually exist right now in a laboratory as a voltage switch device. That will be a major breakthrough when somebody puts a voltage on one of these technologies and gets it to switch."
The challenges and costs, according to some experts, could push out the development of a next-generation switch at least for several decades. "Not every change is worth doing," said Chenming Hu, a professor at the University of California at Berkeley. "Regarding things that go beyond CMOS, we are really talking about 2030 or 2040 or so."
Considered the father of the finFET, Hu believes that CMOS will likely last much longer and for good reason. Chip-manufacturing and design costs are becoming astronomical. And to get a return, chipmakers could extend the CMOS nodes beyond the traditional two-year cycle. "A pattern is emerging at the 28nm node," Hu said. "The big difference is that the nodes will last longer. 28nm could be the sweet spot for a long time."
Some chipmakers have or will soon migrate from planar transistors to finFETs. Today's silicon-based finFETs will scale to 10nm. Then, at 7nm, finFETs may require new and costly III-V channel materials. "I don't think the industry will migrate from 14nm to 10nm and to 7nm so quickly," Hu said. "Once finFET costs come down, the 10nm node will be the sweet spot for a long, long time."
Regarding 2.5D/3D stacked-die, Hu said the technology is still too expensive for mainstream applications. "It helps with the performance and power, but let's not forget about cost," he added.
What's next?
Still others believe that the industry will require a next-generation switch sooner than later. The prevailing wisdom is that a futuristic technology must have many of the same characteristics as today's CMOS logic devices.
Based on this criteria alone, the industry has eliminated many of the more exotic candidates—domain wall ring; electron structure modulation FET; excitonic FET; and graphene thermal transistor. However, the industry is still taking a hard look at the following technologies—all spin logic; BisFET; graphene pn junction; spin FET; spin majority gate; spin torque triad; spin torque oscillators; spin wave devices; and the TFET.
Based on the benchmarks from Imec and Intel, the TFET is showing the most promise. Aimed for the 5nm node, the TFET is a gated-diode that makes use of an electron tunneling technology. TFETs can break the 60-millivolt per decade swing barrier at room temperature. "The problem with TFETs is that they have a smaller on-current than the MOSFET," said Dmitri Nikonov, a research scientist at Intel.
In its benchmarks, Intel lists three types of TFETs. The heterojunction TFET and III-V TFET are somewhat similar, as they use different materials for the PFET and NFET. Recently, Imec described a heterojunction vertical TFET using a germanium-source-on-silicon technology. "Going vertical gives us advantages," said Aaron Thean, director of the logic program at Imec. "We can selectively convert any of the silicon pillars and grow different types of devices using this method."
The third TFET, the GNR TFET, utilizes p-doped GNR as the source and n-doped GNR as the drain. The GNR TFET promises to achieve steep sub-threshold slopes, but the challenges include the fabrication of the GNR material.
"New materials like graphene and carbon nanotubes look attractive," said An Chen, senior member of the technical staff at GlobalFoundries. "But consider the integration challenges with CMOS. For real applications, we need to look at systems instead of just devices with interesting materials and structures. So, for that reason, I don't think we will see a CMOS replacement. The industry will be building a better system based on the CMOS platform. That means you still have CMOS, but you build more functionality on top of that."
Chen is more optimistic about a potential TFET technology described by Pennsylvania State University. In that work, Penn State described a 32-core structure that combines CMOS and TFET transistors in the same device. "I think that looks more likely," he said. "One core could be TFET-based. One core could be CMOS-based. CMOS is doing more of the high-performance things. The TFETs are doing low power things."
Like Intel, IBM, Imec and others, Chen is also bullish about spin-based logic, which falls into the broad categories of spintronics or nano-magnetics. The technology is associated with MRAM, but it can be extended to logic. "In spin, you don't need to move electrons. You just flip the spin. In this idea, spintronics would consume lower power, because you are not moving anything like electrons," Chen said.
Spin-based logic is also attractive because it combines the switching speeds of logic and the non-volatility of memory. "When you shut the power down, and you bring it back up, every device in the logic circuit is still in its state," NRI's Theis said. "That might also lead into new approaches in re-configurability. Right now, re-configurability means FPGAs. With spin-based devices, we can explore new ways to get the same kind of function."
There are also some challenges, however. "The switching speeds are limited by the dynamics of spin, which is pretty fundamental," Theis said. "I believe you have to re-invent these devices quite a bit."
There are several types of spin-based technologies, but the most promising one is the spin majority gate device. This technology consists of a gate based on magnetic materials. Vertical nano-pillars, which sit on top of the gate, switch the magnetism in the bottom layer.
"The idea is that you use a spin torque. All of the inputs come in. The magnetism is added together and then the majority wins. And that gives you a majority function," GlobalFoundries' Chen said. Spin majority gate provides a steep sub-threshold slope, but the problem is that it has a relatively small on-current performance.
A related technology, the spin wave device, uses a wave of spins within a ferroelectric material to transfer information. The AC current causes an input magnetization to oscillate, which propagates a spin wave. "It's nonvolatile, but we ready haven't explored what kind of circuit architectures and applications we need for that kind of logic," NRI's Theis said.
Another technology, all spin logic, is also the subject of interest. "All spin logic has gain," Theis said. "That means you have isolation between input and output. That means you design logic along the confines that a conventional logic circuit designer can understand."
Spin-based devices, TFETs and the other next-generation technologies are clearly fascinating. But based on the challenges, it's unclear if the industry will meet its stated goal of developing a viable next-generation switch by 2020. By then, it might be too expensive to design and make devices based on the new technologies, leaving many to believe that CMOS will rule the roost for the foreseeable future.