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Increased levels of O-linked attachment of N-acetylglucosamine (O-GlcNAc) on nucleocytoplasmic proteins are implicated in the development of diabetic cardiomyopathy and are regulated by O-GlcNAc transferase (OGT) expression and its substrate UDP-GlcNAc. Therefore, the goal of this study was to determine whether the development of diabetes in the Zucker diabetic fatty (ZDF) rat, a model of Type 2 diabetes, results in defects in cardiomyocyte mechanical function and, if so, whether this is associated with increased levels of O-GlcNAc and increased OGT expression. Six-week-old ZDF rats were hyperinsulinemic but normoglycemic, and there were no differences in cardiomyocyte mechanical function, UDP-GlcNAc, O-GlcNAc, or OGT compared with age-matched lean control rats. Cardiomyocytes isolated from 22-wk-old hyperglycemic ZDF rats exhibited significantly impaired relaxation, compared with both age-matched lean control and 6-wk-old ZDF groups. There was also a significant increase in O-GlcNAc levels in high-molecular-mass proteins in the 22-wk-old ZDF group compared with age-matched lean control and 6-wk-old ZDF groups; this was associated with increased UDP-GlcNAc levels but not increased OGT expression. Surprisingly, there was a significant decrease in overall O-GlcNAc levels between 6 and 22 wk of age in lean, ZDF, and Sprague-Dawley rats that was associated with decreased OGT expression. These results support the notion that an increase in O-GlcNAc on specific proteins may contribute to impaired cardiomyocyte function in diabetes. However, this study also indicates that in the heart the level of O-GlcNAc on proteins appears to be differentially regulated by age and diabetes.
- hexosamine biosynthesis
- protein O-glycosylation
- O-linked N-acetylglucosamine transferase
it is well established that diabetes leads to a markedly increased risk for cardiovascular disease including heart failure (12). Although much of the increased risk can be attributed to an increase in atherosclerosis, there is clear clinical (11) and experimental (2, 5, 28, 32) evidence demonstrating that diabetes leads to changes at the level of the myocardium consistent with the development of a diabetic cardiomyopathy. The mechanisms underlying the development of diabetic cardiomyopathy are not well understood; however, it has been proposed that the adverse effects of hyperglycemia on cardiomyocyte function may be mediated via a number of different pathways including increased flux through the polyol pathway (2); increased advanced glycation end products (2, 26); and protein kinase activity and increased levels of O-linked N-acetylglucosamine (O-GlcNAc) on proteins (2, 7, 14, 24).
There is increasing recognition that the O-GlcNAc modification of serine and threonine residues on cytosolic and nuclear proteins is an important regulatory mechanism involved in signal transduction (20, 34). Unlike other glycosylation events, this reaction occurs in the cytosol and the nucleus rather than in the Golgi or the endoplasmic reticulum and is regulated by the activities of two key enzymes, O-GlcNAc transferase (OGT) and N-acetylglucosaminidase (O-GlcNAcase) (20, 34). The activity of OGT is sensitive to the intracellular concentration of UDP-GlcNAc (20, 34), which is formed by the metabolism of glucose via the hexosamine biosynthesis pathway (HBP). We recently showed (24) that a brief period of streptozotocin (STZ)-induced diabetes blunted the inotropic response of the isolated, perfused heart to phenylephrine, which was reversed by inhibition of the HBP. We also found (24) that acute stimulation of the HBP with glucosamine in normal hearts also blunted the response to phenylephrine and that there was a strong negative correlation between the level of UDP-GlcNAc in the heart and the inotropic response. Previously, Ren et al. (27, 28) showed that incubation of isolated adult cardiomyocytes under hyperglycemic conditions resulted in defects in excitation-contraction (E-C) coupling that were very similar to those seen after STZ-induced diabetes and that this could also be mimicked by incubation with glucosamine. Clark et al. (7) also demonstrated in neonatal cardiomyocytes that increasing protein O-GlcNAc levels either by hyperglycemia or glucosamine treatment resulted in impaired sarcoplasmic reticulum (SR) function. Importantly, they demonstrated that the hyperglycemic effect could be blocked by increasing the expression of O-GlcNAcase and that increased expression of OGT under normal glucose conditions had effects similar to those of hyperglycemia treatment (7). Subsequently, Hu et al. (14) showed that increased O-GlcNAcase expression improved whole heart function in diabetic mice.
Together these studies support the notion that excessive levels of O-GlcNAc may contribute to cardiac dysfunction in diabetes. However, the majority of studies examining the impact of diabetes on E-C coupling have focused on uncontrolled insulin-deficient STZ-induced diabetes, rather than models of Type 2 diabetes. Despite the fact that >90% of patients with diabetes have Type 2 diabetes, relatively little is known about the effect of Type 2 diabetes on cardiomyocyte E-C coupling, and there is no information about the impact of Type 2 diabetes on either O-GlcNAc levels or the expression of OGT, which plays a critical role in regulating O-GlcNAc levels. Therefore, the goal of this study was to determine whether the development of diabetes in the Zucker diabetic fatty (ZDF) rat, a model of Type 2 diabetes, is associated with defects in E-C coupling in adult cardiomyocytes and, if so, whether this is associated with increased levels of O-GlcNAc and increased OGT expression.
All chemicals were purchased from Sigma-Aldrich unless otherwise stated. OGT antibody was purchased from Sigma, calsequestrin antibody was purchased from Abcam, and the anti-O-GlcNAc antibody (CTD110.6) was a kind gift from Mary Ann Accavitti (Div. of Genetic and Translational Medicine, Dept. of Medicine, Univ. of Alabama at Birmingham).
Animal experiments were approved by the Institutional Animal Care and Use Committees of the University of Alabama and the University of New England and conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Pub. No. 85-23, 1996). As a model of Type 2 diabetes, nonfasted male ZDF rats (Gmi-fa/fa) were used with age-matched lean littermates as controls. Animals were maintained on Purina 5008 diet as recommended by the supplier and killed at 6 wk of age or between 21 and 22 wk of age (described as the 22-wk group for clarity). Additional experiments were performed on nonfasted male Sprague-Dawley rats (Charles River Laboratories). In one study, untreated animals were killed at 6 and 22 wk of age. In another study acute insulin-deficient diabetes was induced with intravenous STZ injection (50 mg/kg) in 8-wk-old male Sprague-Dawley rats as previously described (24); vehicle-injected age-matched animals were used as controls. Animals were killed 5 days after treatment.
Analysis of serum metabolites.
Blood samples were collected immediately after decapitation from all animals. Serum glucose, insulin, and leptin levels were measured as previously described (35).
Ventricular myocyte isolation, myocyte mechanics, and intracellular Ca2+ transients.
Ventricular myocytes were isolated by collagenase digestion as previously described (10). Myocytes were allowed to attach on laminin (10 μg/ml)-coated glass coverslips, maintained in a Tyrode buffer (see below) at 37°C in an incubator, and used within 6 h of isolation. Mechanical properties and intracellular Ca2+ transients of ventricular myocytes were assessed simultaneously with a video-based detection system designed to measure dynamic changes in sarcomere lengths coupled to a fluorescent system (IonOptix, Milton, MA) as described previously (38). Briefly, myocytes were electrically stimulated at 0.5 Hz, and mechanical properties were recorded at a sampling rate of 240 Hz. Ca2+ transients were recorded with fluo-4 AM (Molecular Probes, Eugene, OR) while sampling at 1,000 Hz.
As previously reported (10), the indexes used to describe isotonic shortening and relengthening include peak fractional shortening (PS; peak shortening amplitude normalized to resting sarcomere length), time to peak twitch (TPT; measured between 10% and 90% above baseline), and area under the shortening (contraction) phase normalized to peak shortening amplitude (AC/PK) (Fig. 1A). The indexes for isotonic relengthening were time to relengthening (TR; measured between 10% and 90% below peak) and area under the relengthening (relaxation) phase normalized to peak amplitude (AR/PK). The indexes used to describe Ca2+ transients are summarized in Fig. 2A. The total area under the Ca2+ transient normalized to peak fluorescence (AT/PK) was used instead of separating systole and diastole. The ratio of peak fluorescence (F) to basal fluorescence (F0) was used as an index of the change in cytosolic Ca2+ during contraction, since this is independent of the intracellular concentration of the fluoroprobe (38).
All indexes of shortening/relengthening and Ca2+ transients were determined in the same myocyte after averaging ∼10 steady-state twitches for each myocyte. Myocytes were chosen randomly from those meeting the inclusion criteria of sharp, regular striations with visible F0 and the ability to achieve steady-state twitches and Ca2+ transients during electrical stimulation. Steady state was defined as consistent peak amplitudes during the recording period for each cell.
Western blots.
Hearts were either perfused (6- and 22-wk ZDF and Sprague-Dawley groups) or freshly isolated (Control and STZ groups) and were freeze clamped. As previously described (17, 21), tissue was homogenized in T-PER (Pierce) containing 5% protease inhibitor cocktail, 40 μmol/l PUGNAc (Carbogen), 1 mmol/l sodium orthovanadate, and 20 mmol/l sodium fluoride on ice. Lysates were separated on 7% SDS-PAGE and transferred to polyvinylidene difluoride membrane (Millipore), and equal loading of protein was initially confirmed by Sypro Ruby staining (Bio-Rad) on the membranes. Blots were probed with the appropriate antibody in casein blocking buffer and were visualized with an enhanced chemiluminescence assay (Pierce). The signal was detected with the UVP BioChemi System (UVP) and densitometry quantified with Labworks analysis software (UVP).
HPLC analysis of UDP-GlcNAc levels.
UDP-GlcNAc levels were determined as previously described by HPLC analysis of perchloric acid extracts (21, 24) with a Partisil 10 SAX column (Whatman) and a gradient from 5 to 750 mmol/l (NH4)H2PO4 and from pH 2.8 to 3.7 (31). Because this method cannot separate UDP-GlcNAc from UDP-N-acetylgalactosamine (UDP-GalNAc), the results are presented as the sum of UDP-GlcNAc and UDP-GalNAc; however, in cardiomyocytes the ratio of UDP-GlcNAc to UDP-GalNAc is ∼3:1 (7).
Data analysis.
Data are presented as means ± SE. Differences between experimental groups were evaluated with unpaired Student's t-test for comparisons between two groups or one-way ANOVA with Bonferroni's multiple comparison test. Statistically significant differences between groups were defined as P values <0.05.
Animal characteristics.
Body weight and serum glucose, insulin, and leptin levels in 6- and 22-wk-old Lean and ZDF rats are summarized in Table 1. Consistent with our earlier studies (35, 36) the 6-wk-old ZDF group was both insulin- and leptin resistant but normoglycemic, whereas by 22 wk of age insulin levels were lower and they had become markedly hyperglycemic. Although leptin levels increased significantly in the 22-wk Lean group compared with the 6-wk group, they were still markedly lower than the levels in the 22-wk-old ZDF group.
Cardiomyocyte mechanics and Ca2+ transients.
Cardiomyocyte mechanics are summarized in Fig. 1, B–D, and Table 2. At 6 wk of age, myocyte contraction [i.e., PS, AC/PK, TPT, and maximum positive length change (Max +dL/dt)] was not significantly different between the ZDF and Lean control groups. Myocyte relengthening [AR/PK, TR, and maximum negative length change (Max −dL/dt)] was also similar in the ZDF and Lean control groups. The lack of impaired contraction and relaxation in the 6-wk ZDF group was somewhat surprising since insulin resistance (duration ≥7 wk) has been shown to adversely affect cardiomyocyte E-C coupling (29, 33). However, at 22 wk of age both contraction and relaxation were significantly impaired in the hyperglycemic ZDF group compared with controls. The time courses of the Ca2+ transients (Fig. 2; Table 3) were consistent with the mechanical indexes; for example, at 6 wk of age, there were no differences between ZDF and Lean controls in peak Ca2+ (Fig. 2B), AT/PK (Fig. 2C), TPT, or TR (Table 3). However, at 22 wk, peak Ca2+ was attenuated (Fig. 2B) and cytosolic Ca2+ clearing was slowed (Fig. 2B) in the diabetic ZDF group compared with the normoglycemic Lean group. The attenuation in peak Ca2+ did not result in predictable changes in sarcomere shortening (Fig. 1B, Table 2).
To assess the effects of hyperglycemia, independent of the effects of leptin, we also compared cardiomyocyte contraction and relaxation between 6- and 22-wk-old ZDF groups. We found significantly impaired contraction and relaxation (Fig. 1D, Table 2) and slower cytosolic Ca2+ clearing in the 22-wk ZDF group (Fig. 2C, Table 3) compared with the 6-wk ZDF group. This was consistent with the differences between the 22-wk Lean and ZDF groups. However, peak Ca2+ (F/F0) was significantly increased in 22-wk animals compared with 6-wk groups (i.e., both Lean and ZDF), with a reduction in peak Ca2+ in the 22-wk ZDF group compared with the age-matched Lean group. It should be noted that there were also age-related changes involving contraction in myocytes from the control group (AC/PK and TPT); however, the impact of diabetes in the ZDF group exceeded these age-dependent effects.
Effect of Type 2 diabetes on cardiac levels of UDP-GlcNAc, O-GlcNAc, and OGT.
There was no significant difference in UDP-GlcNAc levels between 6-wk-old Lean and ZDF groups (86 ± 6 and 87 ± 5 nmol/g wet wt, respectively). However, at 22 wk of age UDP-GlcNAc levels were significantly increased in the ZDF group compared with the age-matched Lean group (103 ± 6 vs. 88 ± 3 nmol/g wet wt; P < 0.05). UDP-GlcNAc levels were also higher in the 22-wk ZDF group compared with the 6-wk ZDF group (P < 0.05).
Consistent with the UDP-GlcNAc levels, there was no difference in O-GlcNAc levels between 6-wk-old Lean and ZDF groups, whereas there was a significant increase in O-GlcNAc at 22 wk of age between the ZDF and Lean control groups (Fig. 3, A and B). The difference in O-GlcNAc levels between the 22-wk ZDF and Lean groups was significant also when normalized to calsequestrin as a protein loading control. In all groups the anti-O-GlcNAc antibody, CTD110.6, identified 11 separate bands, all of them >57 kDa. Densitometric analysis of the individual bands in the O-GlcNAc immunoblots from 22-wk Lean and ZDF groups (Fig. 3C) revealed that the overall increase in O-GlcNAc levels was primarily due to increased O-GlcNAc on proteins in only three bands. There was no difference in OGT expression between ZDF and Lean groups at either age (Fig. 3D).
Since we saw similar functional alterations when comparing 22-wk Lean and ZDF groups and 6- and 22-wk ZDF groups, we also compared the O-GlcNAc levels in the 6- and 22-wk groups. Surprisingly, we found that O-GlcNAc levels were significantly lower in both 22-wk Lean and ZDF groups compared with their respective 6-wk groups (Fig. 3B), which was associated with a significant reduction in OGT expression in both Lean and ZDF 22-wk groups (Fig. 3D).
To determine whether the age differences in O-GlcNAc and OGT expression levels were strain specific, we also examined hearts from 6- and 22-wk-old Sprague-Dawley rats. Similar to the Lean and ZDF groups, there was a significant age-related decrease in both O-GlcNAc and OGT levels (Fig. 4). Again consistent with the Lean and ZDF groups, there was no difference in UDP-GlcNAc levels between the 6- and 22-wk groups (82.3 ± 4.3 vs. 83.6 ± 5.0 nmol/g tissue wet wt, respectively).
STZ-induced diabetes and the HBP.
ZDF rats develop diabetes between 10 and 12 wk of age; consequently, the increase in O-GlcNAc levels seen in these animals was observed after almost 3 mo of diabetes. Impaired cardiomyocyte function has been well documented after only a few days of STZ-induced Type 1 diabetes (24, 27, 28). Therefore, we also examined the effect of a brief period of STZ-induced diabetes (5 days) on cardiac levels of UDP-GlcNAc, O-GlcNAc, and OGT. Consistent with our previous studies (24), STZ treatment increased blood glucose levels (26.7 ± 3.3 vs. 7.9 ± 0.3 mM; P < 0.05). Surprisingly, UDP-GlcNAc levels were not significantly different between STZ and Control groups (192.9 ± 15.0 vs. 188.6 ± 14.6 nmol/g tissue wet wt); however, O-GlcNAc levels were increased ∼40% in the STZ group, but there was no difference in OGT expression levels between groups (Fig. 5).
Age affects different O-GlcNAc protein bands in Lean and ZDF groups.
To better understand the combination of age and diabetes on protein O-GlcNAc levels, we evaluated the change in intensity of specific protein bands with age in Lean and ZDF groups (Fig. 6). The area densities of all 11 bands were measured and normalized to calsequestrin levels. In the Lean control group all of the bands except band 1 showed significant decreases with age (Fig. 6A); the magnitude of this decrease ranged from 43% to 68% (Fig. 6A). In contrast, in the ZDF group the majority of the bands were unchanged between 6 and 22 wk (Fig. 6B); however, bands 5, 6, and 11 were significantly lower in the 22-wk group. Interestingly, the intensity of band 1 was significantly increased by approximately threefold in the 22-wk ZDF group compared with the 6-wk ZDF group. It is noteworthy that this same band was markedly increased in the 22-wk ZDF compared with the 22-wk Lean group (Fig. 3C). Thus the O-GlcNAc levels of band 1 appear to be consistently increased in response to diabetes independent of age differences or leptin levels.
There is increasing evidence linking elevated levels of O-GlcNAc on cytoplasmic and nuclear proteins to the contractile abnormalities in the heart seen in animal models of Type 1 diabetes (7, 14, 24, 27). Previous studies have demonstrated a link between increased O-GlcNAc levels and contractile dysfunction following a prolonged period of insulin-deficient diabetes (7, 14). However, to our knowledge no studies have examined the relationship between E-C coupling and O-GlcNAc levels in a model of Type 2 diabetes. We show here for the first time that there are no differences in any of the indexes of contraction or relaxation between 6-wk-old insulin-resistant ZDF rats and Lean controls; however, by 22 wk of age cardiomyocytes from ZDF rats exhibited significantly impaired relaxation and slowed cytosolic Ca2+ removal compared with both age-matched Lean control and 6-wk-old normoglycemic ZDF groups. Furthermore, in the 22-wk groups the impaired relaxation was associated with a significant increase in overall O-GlcNAc levels in the ZDF group compared with the Lean group. This increase in O-GlcNAc was associated with elevated UDP-GlcNAc levels with no change in OGT expression, suggesting that increased HBP flux is a primary mediator of the increased O-GlcNAc levels. These results are entirely consistent with the notion that elevated levels of O-GlcNAc contribute to E-C coupling abnormalities in diabetes.
Although we observed similar impaired relaxation and increased UDP-GlcNAc levels in the diabetic 22-wk-old ZDF group compared with the 6-wk-old normoglycemic ZDF group, paradoxically we saw a significant decrease in overall O-GlcNAc levels as well as a decrease in OGT expression. However, when comparing either 22-wk ZDF and Lean groups or 6- and 22-wk ZDF groups, we found that, independent of age and leptin levels, hyperglycemia was associated with increased O-GlcNAc levels in proteins in the very high molecular mass range (i.e., ≥205 kDa). This suggests that increased O-GlcNAc levels in this group of proteins may contribute to the impaired cardiomyocyte function associated with diabetes. These data suggest, therefore, that a global increase in O-GlcNAc levels is not a requirement for impaired cardiomyocyte relaxation seen with diabetes, but rather that increased O-GlcNAc on specific proteins may be responsible. This is consistent with a recent study in neonatal cardiomyocytes in which acute hyperglycemic incubation did not significantly increase overall O-GlcNAc levels but did increase O-GlcNAc levels in specific bands (4). Nevertheless, the observation that age and hyperglycemia lead to differential effects on O-GlcNAc levels on different groups of proteins is noteworthy and in need of further investigation.
Hu et al. reported that after 2–3 wk of STZ-induced diabetes there was a 20–30% increase in both OGT mRNA and protein (14), and they previously reported impaired cardiomyocyte relaxation in the same model (7), consistent with our earlier work (27). They also reported an increase in O-GlcNAc in hearts from a Type 2 model of polygenic diabetic mice, although they did not determine whether this was associated with changes in OGT expression and there were no reports of cardiomyocyte function from this Type 2 diabetic model (14). However, impaired E-C coupling has been previously reported in cardiomyocytes isolated from both ob/ob (16) and db/db (25) Type 2 diabetic mice. Consistent with the report by Hu et al., we saw an increase in overall O-GlcNAc levels in hearts from diabetic rats; however, we found no increase in OGT expression. It is not known whether insulin regulates OGT expression; thus the higher insulin levels in ZDF rats compared with the longer-term STZ model (14) could, in principle, account for the differences between our results in ZDF rats and those previously reported (14). However, we also found that in the short-term STZ model O-GlcNAc levels were increased, in the absence of any change in OGT expression levels, suggesting that increased OGT expression is not required for an increase in O-GlcNAc levels. In the 22-wk-old diabetic ZDF group, UDP-GlcNAc levels were significantly increased compared with their age-matched lean counterparts, which would suggest that increased flux through the HBP is a contributing factor in the increase in O-GlcNAc levels in this model.
An increase in HBP flux seen with diabetes may be a result not only of elevated plasma glucose levels but also of the redirection of the glucose fluxes due to increased circulating lipids and decreased activity of pyruvate dehydrogenase, both hallmarks of diabetes. It has been shown in skeletal muscle cells that increased fatty acid concentrations are associated with increased UDP-GlcNAc concentrations and expression of glucose fructose-6-phosphate amidotransferase (GFAT) (37). The latter regulates the entry of glucose into the HBP. Unfortunately, there is no information about the effect of diabetes on GFAT activity or expression in the heart; however, in skeletal muscle of non-insulin-dependent diabetes mellitus patients (41) and ob/ob mice (3) GFAT activity was increased. The lack of commercially available antibodies against GFAT precluded measurements of GFAT expression in this study; however, in the short-term STZ-treated rats no increase in UDP-GlcNAc was observed and yet O-GlcNAc levels were elevated. Thus other factors, such as increased enzyme activity, may also contribute to the increase in O-GlcNAc seen in these models. In addition, O-GlcNAc frequently competes for the same Ser/Thr residues as O-phosphorylation; thus another contributing factor to the increased O-GlcNAc levels could be a reduction in protein phosphorylation, thereby increasing the available sites for O-GlcNAc. Conversely, it is also conceivable that decreased phosphorylation may be a result of increased O-GlcNAc levels. An increase in O-GlcNAc may also occur in response to decreased O-GlcNAcase expression or activity. However, an increase in O-GlcNAcase mRNA in the heart has been reported in STZ-induced diabetes (14). The lack of a readily available source (commercial or otherwise) for an O-GlcNAcase antibody precluded the measurement of O-GlcNAcase protein expression in this study.
The fact that we did not see an increase in OGT expression in the STZ group is in contrast to the finding by Hu et al. (14). This discrepancy could be a consequence of different durations of STZ-induced diabetes (3 wk compared with 5 days here) or different species (mouse vs. rat). However, as noted above we also found no change in OGT expression between 22-wk ZDF and Lean control groups, even though the ZDF animals had been diabetic for ∼3 mo. To control for differences in protein loading we used calsequestrin, which exhibited no change in expression levels between Lean and ZDF groups of either age or between control and STZ-diabetic groups. Since we found no change in OGT expression in age-matched diabetic groups, regardless of whether or not the data were normalized to calsequestrin, we have a high degree of confidence in concluding that, after either a brief period of STZ-induced diabetes in Sprague-Dawley rats or a longer period of Type 2 diabetes in ZDF rats, there is no increase in OGT expression. Thus, in contrast to earlier reports (14), the increase in O-GlcNAc levels in both models of diabetes examined here cannot be attributed to altered OGT expression.
The development of obesity and diabetes in the ZDF group is due to a specific leptin receptor defect, which leads to elevated serum leptin levels. Since leptin itself has been shown to impair cardiomyocyte function (22), it is possible that the differences seen between the 22-wk-old Lean and ZDF groups could be a consequence of increased leptin levels in the ZDF group rather than the development of diabetes. However, E-C coupling was normal in the normoglycemic 6-wk ZDF group even though leptin levels were elevated at this age. Thus in ZDF rats impaired cardiomyocyte function is clearly associated with the development of hyperglycemia and is likely independent of serum leptin levels. To our knowledge, the effects on E-C coupling have not been previously described in 22-wk-old ZDF rats, and the cellular mechanisms contributing to impaired myocyte function remain to be delineated. On the basis of previous studies, it might be expected that increased O-GlcNAc levels would result in decreased sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) protein expression (7, 14), thus contributing to slowed relaxation (Fig. 1D). However, we previously showed (9, 10) that diet-induced insulin resistance (9–10 wk) leads to slower cardiomyocyte relaxation and impaired SERCA function without changes in SERCA protein expression. Although we did not determine SERCA expression in this study, Golfman et al. (13) reported that there was no difference in SERCA mRNA levels between 12-wk-old ZDF rats and age-matched lean littermates. This is also consistent with studies by Belke et al. (1) and Li et al. (16), who reported that despite impaired SR function there was no difference in SERCA protein levels in hearts from db/db diabetic mice compared with nondiabetic controls. Whether SERCA function is dynamically regulated by posttranslational modification by O-GlcNAc remains to be determined.
Shifts in myosin isozyme distribution have also been implicated in diabetic cardiomyopathy, and a recent report suggests that the levels of O-GlcNAc is greater in slow skeletal muscle fibers than in fast fibers (6). In rodents, Type 1 diabetes induces a shift in myosin heavy chain (MHC) isoform distributions (i.e., reducing the fast α-MHC and increasing the slow β-MHC), which is consistent with myocardial contractile dysfunction (8). In the ZDF model of Type 2 diabetes there was no change in α-MHC expression, although there was a significant increase in expression of β-MHC (13). In db/db mice there was also an increase in β-MHC, concomitant with a decrease in α-MHC expression (16). It is intriguing to speculate that MHC isoform expression (or function) may be regulated by O-GlcNAc, but this remains to be determined.
Surprisingly, despite the marked hyperglycemia in the 22-wk group and increased cardiac UDP-GlcNAc concentrations, there was a significant decrease in total O-GlcNAc compared with the 6-wk group, which was associated with reduced OGT expression. Even though there was an overall decrease in O-GlcNAc levels between 6- and 22-wk ZDF groups, there was a significant increase in O-GlcNAc levels in proteins in the high molecular mass range (i.e., >205 kDa) (Fig. 6B). Proteins in the same molecular mass range also showed increased O-GlcNAc levels in the 22-wk ZDF group compared with the age-matched Lean group (Fig. 3C). It is tempting to suggest, therefore, that increased O-GlcNAc levels in this group of proteins may play a role in the development of impaired cardiomyocyte function associated with diabetes. Cardiomyocytes contain many high-molecular-mass proteins including cytoskeletal and contractile proteins such as titin, dystrophin, myosin (mentioned above), as well as proteins that may play a critical role in regulating the changes in metabolism seen in response to diabetes, such as acetyl-CoA carboxylase 2. However, standard SDS-PAGE is not well suited for separation of proteins in excess of ∼200 kDa; furthermore, some large proteins such as myosin tend to form aggregates under the typical conditions used for gel electrophoresis (23). To identify these proteins, further studies using protein separation techniques specifically developed for high-molecular-mass proteins (23) are needed.
It is noteworthy that a decrease in overall O-GlcNAc levels was also evident in the 6- and 22-wk-old Lean groups as well as 6- and 22-wk-old Sprague-Dawley rats, suggesting that this difference was not strain specific or dependent on the development of diabetes. Furthermore, since calsequestrin levels did not change between 6 and 22 wk of age, the reduced OGT expression that occurred between 6 and 22 wk of age cannot be attributed to a nonspecific decline in protein content over this age range. To our knowledge this is the first report of an effect of age on OGT and O-GlcNAc levels in the heart. Others have shown age-dependent changes in O-GlcNAc levels in the brain, showing an increase between 3- and 5-mo-old animals followed by a decrease over the following 2 mo (30). In the brain a reduction in O-GlcNAc levels has been associated with neurodegenerative diseases and loss of key proteins (15, 39, 40), which is consistent with suggestions that O-GlcNAc levels play a role in regulation of the ubiquitin-proteasome system (18, 42). However, it is premature to conclude that the reduction of O-GlcNAc levels in the heart seen here is necessarily detrimental given that these changes may simply reflect maturation. Clearly, further studies are warranted to determine whether cardiac O-GlcNAc levels are further reduced in older rats, which have been reported to be more susceptible to ischemic injury (19).
In conclusion, we have demonstrated for the first time that in ZDF rats the development of impaired E-C coupling is associated with the development of frank diabetes (i.e., hyperglycemia) and appears to be independent of leptin levels. Furthermore, impaired cardiomyocyte function was also associated with an increase in O-GlcNAc levels in high-molecular-mass proteins. In contrast with earlier studies (14), this increase in O-GlcNAc was associated with an increase in UDP-GlcNAc but with no concomitant increase in OGT expression. Surprisingly, there was a marked decrease in total O-GlcNAc levels between 6 and 22 wk of age in Lean, ZDF, and Sprague-Dawley rats that was associated with decreased OGT expression. Thus the regulation of O-GlcNAc levels in the heart is clearly complex, since changes in overall O-GlcNAcylation can occur with or without changes in either OGT expression or UDP-GlcNAc levels. This complexity is further emphasized by the fact that O-GlcNAc levels on proteins in a specific molecular mass range can change in the opposite direction to overall O-GlcNAc levels.
This work was supported by National Heart, Lung and Blood Institute Grants P50 HL-077100, R01 HL-67464 (to J. C. Chatham) and R01 HL-66895 (to A. J. Davidoff) and American Diabetes Association Grant 7-04-RA-23 (to A. J. Davidoff).
We thank Charlye Brocks, Marybeth W. Carmody, and Karen Slocum for technical assistance.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2007 the American Physiological Society


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Indian Boxing Council inducted in World Boxing Organisation
The convention was also attended by Neerav Tomar, Managing Director and CEO of Infinity Optimal Solutions (IOS), which is the India promoter of star boxer Vijender Singh.
Ketan Desai, Indian doctor accused of crimes, becomes president of World Medical Association
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Medical Council of India ruining medical education: Satyendra Jain
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"The committee on MCI has finalised its report after several rounds of deliberation on the issue with stakeholders and experts," a source said.
Medical industry needs stable environment: US-India Business Council
Given the unmet medical need in India, there are "grand possibilities" for greater FDI into India in the medical device sector, USIBC said in a statement today.
GST council meeting brief by FM
GST council meeting brief by FM
Tata Capital sells stake in Indian dialysis service provider to Fresenius Medical Care
FMC's acquisition of Sandor marks the beginning of a series of investments the company intends for its expansion in the Indian dialysis market.
No breakthrough on second day of GST council meet
The Goods and Services Tax (GST) Council ended in New Delhi after the States failed to come to a consensus on the rates.
JuD medical team applies for Indian visa to travel to Kashmir
The applicants have taken a plea in the visa application that they want to go to Kashmir to treat the people injured in clashes with the Indian Army.
JuD medical team to apply for Indian visa to travel to Kashmir
Prof Dr Zafar Iqbal Chaudhry said if the Indian government does not allow its medical team to travel to Srinagar to treat the injured Kashmiris it would hold demonstrations against it.
Indians spent most on health and medical on overnight trips
As per the report titled "Key Indicators of Domestic Tourism in India" released by the National Sample Survey Office (NSSO) on Wednesday.
Why medical information of leaders is also confidential
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GST Council eyes 16% levy on gold jewellery and 4% on bullion
If implemented, a buyer of gold jewellery will end up paying around 6 percentage more by way of tax as at present the total tax comes to around 12.5%.
Latest draft of medical devices rules disappointing, says industry
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Solar / Wind Power Storage Battery -2v500ah
Posted at: Offers to Sell and Export | Posted on: Thu 06 May, 2010 7:22 am |
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Animasportiva ships immediately! Every order is handled with the utmost urgency. As soon as we receive the order, product retrieval occurs; then, when we receive the payment, we prepare the package and shipping follows.
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Is there someway to not send this infomation?
Your question is nonsensical unless you tell us WHAT information you don't want to send, specifically.

a number of HTTP headers are essential for HTTP communication, you see.

and btw, from server, or client?
A non-team player developer at work is blocking me from having a link to his site by using the below code. While I fight the politics I still want my link to work. Can I mask the name of my "MyPortal" so I can link to his site?

dim sTemp
sTemp = Request.ServerVariables("HTTP_REFERER")
If instr(LCase(sTemp),"MyPortal") > 0 Then
 Response.End
End If
If sLevel = "" Then
 sLevel = Session("Level")
End If
%>
use a proxy server which blocks it. Or use Mozilla, which IIRC can do this in 'privacy'.

this is NOT an ASP question. It's down to the client's configuration, and you can't do anything about that from your code.

and thirdly, if it's HIS site you're linking to, he has a right to block whoever he likes. He also has the right to block people with blank referers.

j
http://rtfm.atrax.co.uk/
We work for the same company and there is no reason for this kind of action. Thanks for the info but it seems like there is nothing I can do.......as far as code goes.
what, is this an intranet thing? why would a colleague of yours block referals from your site?

btw have you tried the javascript new window trick?

I think he wanted to design the portal and now someone else is (not me) but I never wanted to be the boss man. He is putting up a fight...he will lose in the end.

javascript new window trick? No what is that?
What is the code for that and what does IIRC mean?

Thanks for the help,
Dan
IIRC

see the javascript section of http://rtfm.atrax.co.uk/ for window manipulation stuff. What's your job title?
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Is this Australia's most expensive shed? Timber shack with rotting walls and floors sells for nearly $1 MILLION - and the proud new owner plans to demolish it
- A house on Edith St, Leichhardt has sold for $980,000
- The run-down shack has not been lived in for 20 years
- The walls, roof and floors are disintegrating and it is strewn with rubbish
A run-down shack in inner Sydney with a rotting deck, collapsing walls and disintegrating floorboards sold for almost a million dollars on Saturday.
The property on Edith Street, Leichhardt, was expected to sell for $850,000, but ended up going for $980,000 at auction.
The small cottage has been uninhabited for 20 years and is in a state of very poor repair – the walls that have not disintegrated are covered in graffiti and the house is littered with rubbish.
This house in Leichhardt in inner-Sydney sold for $980,000 on the weekend, despite the fact that it is an unlivable shack
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The Leichhardt home is in a quiet and desirable block, close to shops, cafes and a new light rail stop
The million-dollar property is going to be pulled down and a new house built on the block by the new owners
'It's a timber shack, it basically needs a bit of attention, it's not liveable at the moment, it's got holes in the walls, holes in the floors,' he said.
'I think it's an opportunity for people to build something they'd like,' said Mr Hassen who added that most people who were bidding for the home were keen to renovate and sell.
He added that despite its condition, he is not surprised that people were so eager to purchase land in Leichhardt, where properties regularly sell for over a million dollars.
'It's in a great spot, the area is well-serviced in terms of shops, cafes, restaurants, now with the new light rail the public transport is great,' he said.
The ceiling, walls and floor are disintegrating and the backyard features the remains of an outhouse and weeds
Despite the condition of the house it sold for nearly one million dollars at auction on the weekend
The back end of the Edith Street house has seen better days
The site is strewn with rubbish and debris, collected over the years
The dilapidated house is located on a lovely Leichhardt street and is surrounded by houses in considerably better condition
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Carbon Shift
How Peak Oil and the Climate Crisis Will Change Canada (and our lives)
by Thomas Homer-Dixon
- #10690 in Nonfiction, Social & Cultural Studies, Social Science
- #279 in Nonfiction, Science & Nature, Science, Biological Sciences, Environmental Science
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"We are now so abusing the Earth that it may rise and move back to the hot state it was in fifty-five million years ago, and if it does, most of us, and our descendants, will die."
-James Lovelock, leading climate expert and author of The Revenge of Gaia
"I don't see why people are so worried about global warming destroying the planet - peak oil will take care of that."
-Matthew Simmons, energy investment banker and author of Twilight in the Desert: The Coming Saudi Oil Shock and the World Economy
The twin crises of climate change and peaking oil production are converging on us. If they are not to cook the planet and topple our civilization, we will need informed and decisive policies, clear-sighted innovation, and a lucid understanding of what is at stake. We will need to know where we stand, and which direction we should start out in. These are the questions Carbon Shift addresses.
Thomas Homer-Dixon, author of The Ingenuity Gap and The Upside of Down, argues that the two problems are really one: a carbon problem. We depend on carbon energy to fuel our complex economies and societies, and at the same time this very carbon is fatally contaminating our atmosphere. To solve one of these problems will require solving the other at the same time. In other words, we still have a chance to tackle two monumental challenges with one innovative solution: clean, low-carbon energy.
Carbon Shift brings together six of Canada's world-class experts to explore the question of where we stand now, and where we might be headed. It explores the economics, the geology, the politics, and the science of the predicament we find ourselves in. And it gives each expert the chance to address what they think are the most important facets of the complex problem before us.
There are no experts in Canada better positioned to explain the world that awaits us just beyond the horizon, and no better guide to that future than this collection of their thoughts. Densely packed with information, but accessibly written and powerfully timely, Carbon Shift will be an indispensable handbook to the difficult choices that lie ahead.
David Hughes is a former senior geoscientist with the Geological Survey of Canada
David Keith is Canada Research Chair in Energy and the Environment, University of Calgary
Jeff Rubin is Chief Economist, Chief Strategist and Managing Director, CIBC World Markets
Mark Jaccard is professor of environmental economics in the School of Resource and Environmental Management at Simon Fraser University and a member of the Intergovernmental Panel on Climate Change (IPCC)
William Marsden is an investigative reporter and author of Stupid to the Last Drop: How Alberta Is Bringing Environmental Armageddon to Canada (And Doesn't Seem to Care)
Jeffrey Simpson is a Globe and Mail national columnist and author, with Mark Jaccard, of Hot Air: Meeting Canada's Climate Change Challenge
With a foreword by Ronald Wright, author of A Short History of Progress and What is America?
From the Hardcover edition.
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by on October 23, 2016
eBook Details
- Random House of Canada, June 2011
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Home >> Accounting Basics
Data: Alpine, Inc., has been experiencing losses for some time, as shown by its most recent income statement:
All variable expenses in the company differ in terms of units sold, except for sales commissions, which are based on sales dollars. Variable manufacturing overhead is 50 cents per unit. The company's plant has a capacity of 70,000 units.
Management is specifically disappointed with 2011's operating results. Some possible courses of action are being studied to find out what should be done to make 2012 profitable.
1) Redo Alpine, Inc.'s 2011 Income Statement in the contribution format. Show both a total column and a per unit column on your statement.
2) In an effort to make 2012 profitable, Micah Patdu, the president is considering two proposals prepared by members of her staff:
a) Jon Michael, the sales manager would like to decrease the unit selling price by 25 %. He is certain that this would fill the plant to capacity.
b) Mary Wilkinson, the executive vice president would like to raise the unit selling price by 25 %, increase the sales commissions to 12 % of sales, and increase advertising by $90,000. Based on experience in another company, she is confident this would trigger a 50 % increase in unit sales.
Make two contribution income statements, one showing what profits would be under Jon Michael's proposal and one showing what profits would be under Mary Wilkinson's proposal. On each statement, comprise both total and per unit columns (don't show per unit data for fixed costs)
3) Refer to the original data. Micah Patdu, the president thinks it would be unwise to change the selling price. Rather, she wants to use less costly materials in manufacturing units of product, thus reducing costs by $1.73 per unit. How many units would have to be sold during 2012 to earn a target profit of $59,000 for the year?
4) Refer to the original data. Alpine, Inc.'s advertising agency thinks that the problem lies in insufficient promotion. By how much can advertising be increased and still allow the company to earn a target return of 4.5 % on sales of 60,000 units?
5) Refer to the original data. Suppose that the company was approached by an overseas distributor who wanted to purchase 15,000 units on a special price basis during June 2011. There would be no sales commission on these units. Though, shipping costs would increase by 80 % per unit, and variable administrative costs would be decreased by 50 % per unit on these "special order" units. In addition, Alpine, Inc., would have to pay a foreign import duty of $3,150 on behalf of the overseas distributor in order to get the goods into the country. Given these data, what unit price would have to be quoted on the 15,000 units by Alpine,
Inc., to permit the company to earn an 'overall' profit of $18,000 for the year ended June 30, 2011 on total operations? Regular business would not be disturbed by this special order.
Accounting Basics, Accounting
Management Accounting - Farnsworth's Fine Furniture Ltd Question 1 - (a) Prepare a new profit statement for Fred, using a variable costing approach (Also known as marginal costing, or the contribution margin approach). Y ...
While auditing the financial statements of Forble Corp. (which are to be included in a Securities Act registration statement), Ernie, a certified public accountant, fails to review any of Forble's journal entries, does n ...
Following is the current balance sheet for a local partnership of doctors: Cash and current assets $ 50,000Liabilities $ 90,000 Land 290,000 A, capital 70,000 Building and equipment (net) 220,000 B, capital 90,000 C, cap ...
Problem: You have decided to start a business selling widgets. You form a corporation, Widgets, Inc. You paid $10 per share for 1,000 shares of stock on January 1, 2016. Next the company borrowed $30,000 from your Aunt S ...
ACCOUNTING AND BUSINESS How does the business maintain its financial records? Who does the accounting for the business? What accounting or records is used? Who periodically reviews and analyzes the accounting records? Wh ...
In this assignment, complete Sections III and IV of the project. For this part of the assessment prepare a Word document that addresses the critical elements below. Make sure answer each question in a substantive way and ...
Question: Case Study Essay on Martin Shkreli Fraud Case. Case Study Criteria: Financial reporting and prevention of fraud through the application of significant internal policies and adherence to corporate governance ele ...
Imagine you are a member of the project approval committee. An ambitious young manager in the marketing department is well connected with the top management team in your company. He catches you in the hall and mentions t ...
1. The rule that requires financial statements to reflect the assumption that the business will continue operating instead of being closed or sold, unless evidence shows that it will not continue, is the: Going-concern a ...
Assignment - Journals, Ledger and Trial Balance The following transactions relates to Merlin Bruce, a sole trader, during his first month of business: Date Transaction details 01-Jan Started business by investing $25,000 ...
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¡Explora estas ideas y mucho más!
This photograph was taken in Scotland, and has won the major Award Wedding of the United States, the Grand Imaging Award 2012, from Professional Photographer of America (PPA).
This wedding in the Scottish Highlands could not be any more romantic. #wedding #scotland #scottish
Portraits - Susan Stripling
Are you looking for a package wedding in Scotland? http://www.fuzeceremonies.co.uk/blog/2014/wedding-packages-in-scotland/
For a wedding in Scotland, nothing is quite as festive as a groom in a kilt, wouldn't you say? Visit Travel Connections on Facebook at www.Facebook.com/TravelConnectionsPeru!
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Sex-crazed Angelina Jolie lookalike 'forces taxi driver to have sex with her at knifepoint twice' - then stabs him when he refuses a third go around
- Luminita Perijoc, 30, had already forced cabbie at knifepoint to have intercourse and perform oral sex
- But she flew into a rage when he refused to satisfy her again
- Police say her behaviour may have been down to medication she was taking
Femme fatale: Angelina Jolie lookalike Luminita Perijoc, allegedly stabbed a taxi driver after he refused to have sex with her for a third time
A Romanian taxi driver claims a sex-crazed Angelina Jolie lookalike passenger stabbed him after he refused to satisfy her for a third time.
Nicolae Stan told police stunning Luminita Perijoc, 30, had already forced him at knifepoint to have intercourse and perform oral sex.
He claims Perijoc had asked him to help her with his bags but once inside her apartment she demanded sex.
When he refused she allegedly pulled out a knife and forced him to undress.
Police investigating his claims say the Perijoc's behaviour may have been down to the fact she was on medication at the time.
Mr Stan said that his life has been made a misery by pals ribbing him about the fact that he had turned down the beautiful double of the Hollywood star.
He said: 'It is terrible. I am now a local celebrity, every one is talking about me.
'They don't understand why I refused her, but they do not know what it is like to have a mad woman yelling at you at knife point.
Perijoc, 30, forced cabbie Nicolae Stan at knifepoint to have intercourse and perform oral sex on her but flew into a rage when he refused to satisfy her again, police were told
Mr Stan said his life has been made a misery by pals ribbing him about the fact that he turned down the beautiful double of the Hollywood star. Pictured: How the incident was reported on a Romanian website
The original: Perijoc is a huge fan of Angelina
'They look at her, then look at me an laugh. But I think anyone would find it impossible to perform with a knife at their throat even if they were with Miss Romania.'
'She asked me to help with her bag but when we were upstairs she got me in to her kitchen and told me she had to have sex with me,' claimed the married dad-of-three.
'I think she wasn't used to anyone saying no because she flew into a rage when I declined. She took out a knife and forced me to undress and have sex with her.
'But she wasn't satisfied and wanted sex again.
'When I refused she attacked me with a knife, and forced me to have oral sex with her but she still stabbed me,' he added.
Friends told local media that Perijoc is a huge fan of actress Jolie and models herself on the Tomb Raider star.
Mr Stan says he only escaped when he managed to barricade himself into a bedroom and dial 999 on his mobile phone.
Police say he was taken to hospital with more than half a dozen stab wounds.
'We are interviewing both parties to discover what could have happened,' said a police spokesman.
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Former Indians slugger Jim Thome joins SportsCenter to explain how watching Cleveland in the World Series brings back great postseason memories and what it would mean for the city to win two championships in one year.
Tim Kurkjian breaks down how the Indians' pitching staff was able to shut down the Blue Jays' offense to earn a berth in the World Series.
Jeff Goodman says that in order for the Bulls to be successful this season under coach Fred Hoiberg, he will need to better earn the trust of his players, especially from Dwyane Wade and Rajon Rondo.
Packers quarterback Aaron Rodgers reacts to a book excerpt claiming he called Brett Favre "Grandpa" upon their first meeting in 2005.
Josh Donaldson breaks down his fifth-inning stop that prevented Carlos Santana from a potential game-tying hit and looks ahead to Game 5 and how the Blue Jays will prepare.
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This all boils down to what knowledge, philosophy and beliefs mean to you.
I urge you to force yourself to believe in hedonism at least. If there is no purpose at least try and focus on doing things that bring you pleasure. Just do me a favor and don't hurt others while doing it mkay ?


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|By PR Newswire
Article Rating:
|January 17, 2013 07:00 AM EST
WINSTON-SALEM, N.C., Jan. 17, 2013 /PRNewswire/ -- At 6am, Tuesday, January 22, 2013, residents of Greenville, South Carolina and surrounding communities are invited to celebrate the opening of the new Krispy Kreme Doughnut Factory, located at 1215-B Woodruff Road, Greenville, SC 29607. The Hot Light goes on at 6am. The first 100 guests receive free doughnuts for a year, commemorative t-shirts and tasty prizes.
"Krispy Kreme has been a staple in the Greenville, South Carolina community for over 60 years," says Cindy Bay, SVP of US Franchises and Company Stores for Krispy Kreme. "We are extremely excited to bring this new shop and our delicious variety of one-of-a-kind sweet treats and complementary beverages to our fantastic Greenville, South Carolina doughnut fans."
The approximately 2,300 square foot location with a drive-thru will feature more than a dozen varieties of Krispy Kreme's one-of-a-kind doughnuts, including the signature hot Original Glazed® , as well as a complete menu of Krispy Kreme Chillers®, iced beverages and Krispy Kreme Signature Coffee Blends.
Hours of operation will be Monday through Sunday, 6:00 a.m. to 11:00 p.m.
Get there early on grand opening day for a chance to win one of these sweet prizes:
- One free dozen Original Glazed® doughnuts every week for a year to the FIRST customer in line;
- Customers 2 through 99 receive one free dozen Original Glazed® doughnuts every month for a year;
- AND, the first 100 customers in line will receive a commemorative Grand Opening t-shirt.
Krispy Kreme will also host a ribbon cutting ceremony at 11 a.m. on grand opening day featuring Krispy Kreme team members and local dignitaries.
Be among the first to see the Hot Light go on at the new Greenville, SC Shop. Download the Krispy Kreme Hot Light app www.hotlightapp.com to get Hot Light alerts and store directions from your smartphone.
Follow the grand opening activities on Facebook and live on Twitter #KrispyKremeLive.
About Krispy Kreme
Krispy Kreme is an international retailer of premium-quality sweet treats, including its signature Original Glazed(R) doughnut. Headquartered in Winston-Salem, N.C., the Company has offered the highest-quality doughnuts and great-tasting coffee since it was founded in 1937. Krispy Kreme is proud of its Fundraising program, which for decades has helped non-profit organizations raise millions of dollars in needed funds. Today, Krispy Kreme can be found in over 700 locations around the world and approximately 10,000 grocery, convenience and mass merchant stores in the U.S. Krispy Kreme Doughnuts, Inc. (NYSE: KKD) is listed on the New York Stock Exchange. Visit us at www.KrispyKreme.com.
SOURCE Krispy Kreme Doughnut Corporation
In his session at Cloud Expo, Robert Cohen, an economist and senior fellow at the Economic Strategy Institute, will provide economic scenarios that describe how the rapid adoption of software-defined everything including cloud services, SDDC and open networking will change GDP, industry growth, productivity and jobs. This session will also include a drill down for several industries such as finance, social media, cloud service providers and pharmaceuticals.
Oct. 27, 2016 10:30 AM EDT Reads: 2,073
DevOps is speeding towards the IT world like a freight train and the hype around it is deafening. There is no reason to be afraid of this change as it is the natural reaction to the agile movement that revolutionized development just a few years ago. By definition, DevOps is the natural alignment of IT performance to business profitability. The relevance of this has yet to be quantified but it has been suggested that the route to the CEO's chair will come from the IT leaders that successfully ma...
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Ask someone to architect an Internet of Things (IoT) solution and you are guaranteed to see a reference to the cloud. This would lead you to believe that IoT requires the cloud to exist. However, there are many IoT use cases where the cloud is not feasible or desirable. In his session at @ThingsExpo, Dave McCarthy, Director of Products at Bsquare Corporation, will discuss the strategies that exist to extend intelligence directly to IoT devices and sensors, freeing them from the constraints of ...
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What happens when the different parts of a vehicle become smarter than the vehicle itself? As we move toward the era of smart everything, hundreds of entities in a vehicle that communicate with each other, the vehicle and external systems create a need for identity orchestration so that all entities work as a conglomerate. Much like an orchestra without a conductor, without the ability to secure, control, and connect the link between a vehicle's head unit, devices, and systems and to manage the ...
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Intelligent machines are here. Robots, self-driving cars, drones, bots and many IoT devices are becoming smarter with Machine Learning. In her session at @ThingsExpo, Sudha Jamthe, CEO of IoTDisruptions.com, will discuss the next wave of business disruption at the junction of IoT and AI, impacting many industries and set to change our lives, work and world as we know it.
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DevOps is being widely accepted (if not fully adopted) as essential in enterprise IT. But as Enterprise DevOps gains maturity, expands scope, and increases velocity, the need for data-driven decisions across teams becomes more acute. DevOps teams in any modern business must wrangle the 'digital exhaust' from the delivery toolchain, "pervasive" and "cognitive" computing, APIs and services, mobile devices and applications, the Internet of Things, and now even blockchain. In this power panel at @...
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By now most people have either created their configuration management solution or are just embarking on this journey. In his session at @DevOpsSummit at 19th Cloud Expo, Marco Ceppi, a DevOps Engineer working at Canonical, will discuss how to take configuration management to the next level with modelling and orchestration. He will also discuss how and why people are moving from a machine-centric view to a service/application-oriented view of deployments, and how you can leverage the knowledge a...
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Enterprises have been using both Big Data and virtualization for years. Until recently, however, most enterprises have not combined the two. Big Data's demands for higher levels of performance, the ability to control quality-of-service (QoS), and the ability to adhere to SLAs have kept it on bare metal, apart from the modern data center cloud. With recent technology innovations, we've seen the advantages of bare metal erode to such a degree that the enhanced flexibility and reduced costs that cl...
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Fact: storage performance problems have only gotten more complicated, as applications not only have become largely virtualized, but also have moved to cloud-based infrastructures. Storage performance in virtualized environments isn't just about IOPS anymore. Instead, you need to guarantee performance for individual VMs, helping applications maintain performance as the number of VMs continues to go up in real time. In his session at Cloud Expo, Dhiraj Sehgal, Product and Marketing at Tintri, wil...
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As software becomes more and more complex, we, as software developers, have been splitting up our code into smaller and smaller components. This is also true for the environment in which we run our code: going from bare metal, to VMs to the modern-day Cloud Native world of containers, schedulers and microservices. While we have figured out how to run containerized applications in the cloud using schedulers, we've yet to come up with a good solution to bridge the gap between getting your conta...
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19th Cloud Expo, taking place November 1-3, 2016, at the Santa Clara Convention Center in Santa Clara, CA, will feature technical sessions from a rock star conference faculty and the leading industry players in the world. Cloud computing is now being embraced by a majority of enterprises of all sizes. Yesterday's debate about public vs. private has transformed into the reality of hybrid cloud: a recent survey shows that 74% of enterprises have a hybrid cloud strategy. Meanwhile, 94% of enterpri...
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Amazon has gradually rolled out parts of its IoT offerings, but these are just the tip of the iceberg. In addition to optimizing their backend AWS offerings, Amazon is laying the ground work to be a major force in IoT - especially in the connected home and office. In his session at @ThingsExpo, Chris Kocher, founder and managing director of Grey Heron, explained how Amazon is extending its reach to become a major force in IoT by building on its dominant cloud IoT platform, its Dash Button strat...
Oct. 27, 2016 07:00 AM EDT Reads: 4,935


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text:
What we're eating this week:
Monday-Family Golf Night-so we grabbed something before our round of golf.
Tuesday-We had pizza at one of my favorite pizza places!
Wednesday-BBQ Chicken Tacos are up tonight!
Thursday-BBQ Chicken Rice Bowls-I'm making extra chicken tonight so dinner will be ready crazy quick tomorrow night.
Friday-On Fridays, Mama likes to keep the kitchen clean by going out.
What I'm Reminiscing About:
At this time last year I was binge watching my way through the entire series of Gilmore Girls. Oh my goodness! I LOVED that show! Apparently, it's what I do in October because as teeny bopper as it is...I'm doing the same with One Tree Hill right this second!
What I'm Loving:
THIS WEATHER! Our weather has been incredible! This week the highs are in the 80's, but the 80's are feeling like fall 80's and not middle of summer 80's...if that makes any sense. ha! We've officially busted out all the fall clothes!
What We've Been Up To:
ALL THE FALL activities!
What I'm Dreading:
Nothing at the moment.
What I'm Working On:
Light fixture hunt! The front sitting room is almost completely finished. I just have to find a new light fixture. Right now there's an ugly white fan. Ugh!
I was working on this last month...still working. :)
What I'm Excited About:
Taking these crazies to New York! THANK YOU SO MUCH for all your recommendations yesterday. I appreciate them SO much!
What I'm watching/reading:
I'm in the middle of Season 5 on One Tree Hill. I'm not even reading a book right now because I can't wait to get to the end of this show.
What I'm Listening To:
The same songs as usual...Kidz Bop, Disney, and Christian music.
What I'm Wearing:
Top: Exact here. (On super sale!)
Jeans: Similar here.
What I'm Doing This Weekend:
We have all kinds of Halloween fun planned for the weekend.
What I'm Looking Forward to Next Month:
Seeing all these faces in layers of fall clothes around a Thanksgiving table.
Hope you ladies have a great Wednesday! XOXO