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C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (TNa) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (Qo2), TNa, fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent Qo2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (−24%), stop-flow pressure (−8%), and filtration fraction (−17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline TNa (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline Qo2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.
- diabetes mellitus
- oxygen consumption
- sodium excretion
there are several hypotheses for the mechanisms leading to the onset and progression of diabetes-induced renal dysfunction. The Diabetes Control and Complication Trial concluded that the degree of hyperglycemia is an important predictor of long-term renal complications in diabetes (7). The early augmented glomerular filtration may play a crucial role in the development of diabetic nephropathy, and inhibition of the diabetes-induced hyperfiltration has been shown to have beneficial effects, delaying the progression of kidney damage (33).
C-peptide, the 31-residue cleavage product of insulin synthesis, is secreted from the islets of Langerhans together with insulin. Since impaired insulin synthesis will affect C-peptide release to the same extent, C-peptide was initially used as a biomarker for estimation of insulin production. However, in the early 1980s, it was suggested that C-peptide may influence biological functions (59). Several recent studies have reported renoprotective effects of C-peptide when it is administered to patients with type 1 diabetes (13, 19, 20) and animal models of experimental insulinopenic diabetes (16, 36, 47–49, 51). The studies show that administration of physiologically relevant doses of C-peptide reduces diabetes-induced glomerular hyperfiltration, decreases albuminuria, reduces renal hypertrophy, and normalizes glomerular volume. Therefore, the lack of C-peptide has emerged as a possible mechanism for the development of diabetes-induced complications in diabetic patients. Peptides with the same amino acid composition as C-peptide, but in randomized sequences, have no interfering specificity (2, 35, 51).
The exact mechanism resulting in the diabetes-induced glomerular hyperfiltration is not fully understood (46). However, altered vascular tone of the afferent and efferent arterioles and increased proximal tubular Na+ reabsorption, all potential regulators of the glomerular filtration pressure and, thus, glomerular filtration rate (GFR), may contribute (46, 54). Nevertheless, glomerular hyperfiltration increases tubular electrolyte load, resulting in increased tubular Na+ reabsorption to maintain homeostasis. This will undoubtedly increase the O2 demand and, thereby, O2 consumption (Qo2) (27). A wide range of different techniques and animal models have been used to show that the increased O2 utilization eventually results in decreased tissue O2 availability in the diabetic kidney (9, 18, 23, 39, 40, 44, 45).
Na+-K+-ATPase is located in the basolateral membrane of tubular cells and creates the main driving force for tubular electrolyte reabsorption (24). Approximately 80% of total kidney Qo2 is related to tubular electrolyte transport (4). Numerous studies have reported increased renal Na+-K+-ATPase activity and increased Qo2 during the early hyperfiltration phase in streptozotocin (STZ)-induced diabetes (5, 27, 28, 58) and in other models of experimental diabetes (50). It has even been suggested that alterations in renal proximal Na+-K+-ATPase activity may regulate GFR (30). Thus regulation of GFR, tubular electrolyte handling, and renal blood flow (RBF) are interconnected via several mechanisms that must be investigated separately for a full understanding of how C-peptide might influence kidney function.
The present study aimed to provide mechanistic insights into the effect of C-peptide on GFR. We therefore tested the hypothesis that C-peptide reduces the diabetes-induced glomerular hyperfiltration via alteration of vascular tone of the afferent and/or efferent arterioles (measured as blood flow and tubular pressures) or proximal tubular Na+ reabsorption (measured as fractional urinary Na+ and Li+ excretions and inhibition of cellular Qo2 related to electrolyte transport), or a combination thereof.
Animals and induction of diabetes.
Age-matched male Sprague-Dawley rats (250–330 g body wt) were purchased from M & B (Ry, Denmark). Animals had free access to water and standard rat chow (0.3% Na, 0.8% K, 21% protein; R3, Ewos, Södertälje, Sweden) throughout the study. All experiments were performed in accordance with the National Institutes of Health guidelines for use and care of laboratory animals and approved by the Animal Care and Use Committee of Uppsala University. Diabetes was induced by an injection of STZ (50 mg/kg body wt; Sigma-Aldrich, St. Louis, MO) into the tail vein. Animals were considered diabetic if blood glucose concentrations increased to >18 mM within 24 h after STZ injection and remained elevated. Test reagent strips (MediSense, Bedford, MA) were used to determine blood glucose concentrations from blood samples obtained from the cut tip of the tail in all animals.
Surgical procedures.
At 2 wk after allocation to the study, the animals were anesthetized with thiobutabarbital (120 mg/kg body wt ip; Inactin, Sigma-Aldrich), placed on a thermocontrolled operating table at 37°C, and tracheotomized. Polyethylene catheters were placed in the right femoral vein for infusion of Ringer solution (5 and 10 ml·kg body wt−1·h−1 for normoglycemic controls and diabetic animals, respectively), the right femoral artery for blood pressure measurements (model P23dB, Statham Laboratories, Los Angeles, CA), and the left renal vein for blood sampling. The left ureter was catheterized for collection of urine for subsequent analysis, and the urinary bladder was catheterized to allow urinary drainage. The left kidney was exposed by a left subcostal flank incision, immobilized in a plastic cup, and embedded in pieces of saline-soaked cotton wool, and the surface was covered with paraffin oil (Apoteksbolaget, Gothenburg, Sweden).
Simultaneous measurements of GFR, total and cortical RBF, and total Qo2.
GFR was estimated by measurements of [3H]inulin clearance. 3H (American Radiolabeled, St. Louis, MO) was initially administered as a 185-kBq bolus and then continuously infused in Ringer solution (185 kBq·kg body wt−1·h−1). 3H activities in urine and plasma were measured using a standard liquid scintillation technique, and GFR was calculated as follows: GFR = U*V̇/P, where U and P denote the activity of [3H]inulin in the urine and plasma, respectively, and V̇ denotes the urine flow rate (in ml/min). After a 45-min recovery period, baseline measurements were obtained for 30 min. A single bolus dose of rat C-peptide (5 nmol/kg body wt; Sigma-Genosys, Cambridge, UK; >95% purity as measured by HPLC) was followed by a 40-min continuous infusion of C-peptide (50 pmol·kg body wt−1·min−1), which should result in plasma C-peptide concentrations within the physiological range (51). Thereafter, all parameters were measured during a second 30-min experimental period. Additional control and diabetic animals were given only saline vehicle and served as time controls, since the scrambled C-peptide has previously been shown to have no physiological effects (2, 35, 51).
Total RBF was measured using an ultrasound probe (Transonic Systems, Ithaca, NY) placed around the left renal artery, and cortical RBF was measured with laser-Doppler flowmetry (model PF 4001-2, Perimed, Stockholm, Sweden) (10+ concentrations were determined by flame spectrophotometry (model IL543, Instrumentation Lab, Milan, Italy).
Estimations of proximal tubular reabsorption using Li+ clearance.
In a separate set of control and diabetic rats (n = 7–8/group), Li+ clearance was measured according to a previously published procedure (32). Briefly, the animals were subjected to the surgical protocol described above (see Surgical procedures), except only the bladder was catheterized for urine collection, and the subcostal flank incision and the immobilization of the kidney with the plastic cup were not performed. Li+ was administered as a 4-mg ip bolus of LiCl at the onset of anesthesia followed by a continuous intravenous infusion (2.1 mg·h−1·rat−1), resulting in plasma concentration of 0.2–0.4 mM. After surgery, the experimental protocol described above was performed for measurements of Li+ and inulin clearance in these animals. Since C-peptide reduces GFR and, therefore, tubular Li+ load via the same mechanism, estimations of proximal tubular reabsorption were calculated as fractional urinary Li+ excretion.
The filtration fraction (FF) was estimated as follows: FF = GFR/RBF*(1 − Hct). Renal vascular resistance (RVR) was calculated as mean arterial pressure (MAP) divided by RBF. In vivo renal Qo2 (μmol/min) was estimated from the arteriovenous difference in O2 content (O2ct = [Hb]*oxygen saturation*1.34 + Po2*0.22) * total RBF.
Tubular Na+ transport (TNa, μmol/min) was calculated as follows: TNa = [PNa]*GFR, where [PNa] is plasma Na+ concentration. TNa per Qo2 was calculated as TNa/Qo2. Fractional Na+ excretion was estimated from [UNa]*[Pinulin]/[PNa]*[Uinulin], and fractional Li+ excretion was calculated according to [ULi]*[Pinulin]/[PLi]*[Uinulin], where [UNa] is urinary Na+ concentration, [Pinulin] and [Uinulin] represent plasma and urinary inulin concentration, and [PLi] is plasma Li+ concentration.
Measurements of tubular pressures.
The net glomerular filtration pressure (Pnet) was estimated by stop-flow technique at baseline and after 40 min of infusion of rat C-peptide (5 nmol/kg body wt bolus + continuous infusion of 50 pmol·kg body wt−1·min−1 in 5 control and 6 diabetic animals). Early proximal tubular segments (≥5/rat) were randomly chosen on the kidney surface before and after C-peptide administration. A pipette, filled with 1 M NaCl and Lissamine green and connected to a servo-null pressure system (World Precision Instruments, New Haven, CT), was used to determine proximal tubular free-flow pressure (Pff) and stop-flow pressure (Psf), the latter after tubular flow was interrupted with a wax blockade distal to the pressure pipette. Pnet was calculated as Psf − Pff.
Measurements of Qo2 in vitro.
Proximal tubular cells were isolated from normoglycemic controls (n = 9) and STZ-diabetic rats (n = 12) as previously described (27, 39, 40). Briefly, the renal cortical tissue was minced through a metallic mesh strainer and immediately placed in an ice-cooled buffer solution and incubated in collagenase (0.05% wt/vol; Sigma-Aldrich) at 37°C for 60 min while the buffer was equilibrated with 95% O2-5% CO2. Thereafter, the cell suspension was cooled to 4°C and filtered through graded filters with pore sizes of 180, 75, 53, and 38 μm, respectively. The cells were pelleted by a slow centrifugation (100 g, 4 min) and resuspended in a collagenase-free buffer, a procedure that was repeated three times. The suspension was kept on ice until Qo2 was measured according to a previously described procedure (19). Briefly, a custom-made thermostatically controlled (37°C) gas-tight Plexiglas chamber with a total volume of 1.10 ml was used. The chamber was filled with buffer solution (113.0 mM NaCl, 4.0 mM KCl, 27.2 mM NaHCO3, 1.0 mM KH2PO4, 1.2 mM MgCl2, 1.0 mM CaCl2, 10.0 mM HEPES, 0.5 mM Ca lactate, 2.0 mM glutamine, and 50 U/ml streptomycin, 298 ± 2 mosM, pH 7.40) and continuously stirred with an air-driven magnetic stirrer. Glucose concentration in the medium was 5.8 mM for cells from normoglycemic controls and 23.2 mM for cells from diabetic animals. O2 content was measured by a modified O2 sensor (model 500, Unisense, Aarhus, Denmark) calibrated with the air-equilibrated buffer solution as 228 μM O2 and Na2S2O5-saturated buffer as zero. Cell suspension (100 μl) was then injected into the chamber, and the rate of O2 disappearance was measured. At the end of each experiment, a 100-μl sample was taken for determination of the protein concentration using DC protein assay (Bio-Rad Laboratories, Hercules, CA). Qo2 was calculated as the rate of O2 disappearance adjusted for protein concentration. Qo2 was measured during baseline and after incubation with rat C-peptide (1 nM), ouabain (1 mM), Nω-nitro-l-arginine methyl ester (l-NAME, 37 μM), or a combination of C-peptide and either ouabain or l-NAME.
Statistical evaluation.
All statistical analyses were performed using GraphPad Prism software (San Diego, CA). Multiple comparisons between different groups were performed using ANOVA followed by Fisher's protected least significant difference test. Multiple comparisons within the same group were performed using repeated-measures ANOVA followed by Dunnett's post hoc test for paired comparisons. For comparison before and after a treatment within the same animals, paired Student's t-test was used. Descriptive statistics are presented as means ± SE. For all comparisons, P < 0.05 was considered statistically significant.
All diabetic animals were hyperglycemic compared with normoglycemic controls (22.3 ± 1.4 vs. 5.8 ± 0.2 mM). Diabetic animals gained less weight than the age-matched normoglycemic controls (281 ± 5 vs. 330 ± 6 g). Left kidney weight increased in diabetic animals compared with normoglycemic controls (1.71 ± 0.03 vs. 1.24 ± 0.03 g).
Diabetic rats displayed increased GFR (Fig. 1), which was reduced by C-peptide. FF was elevated in diabetic rats (Fig. 2) compared with controls. C-peptide selectively reduced FF by 17% in diabetic animals. MAP was similar at baseline in all groups (Table 1) and decreased in vehicle- and C-peptide-treated controls. However, MAP only decreased after C-peptide administration in the diabetic animals. Baseline TNa was 70% higher in diabetic animals than in controls (Fig. 3) and was only reduced by C-peptide in the diabetic group. Baseline fractional Na+ excretion was similar in all groups (Fig. 4), but C-peptide increased fractional Na+ excretion by 77% selectively in the diabetic group. Furthermore, fractional Li+ excretion increased only in the diabetic animals treated with C-peptide (Fig. 5).
There was no difference in total or cortical RBF in the diabetic animals compared with the normoglycemic controls (Table 1). C-peptide did not alter RBF in any of the groups. Total in vivo Qo2 was ∼50% higher in the diabetic animals (Table 1), although Qo2 did not differ between diabetic and normoglycemic control rats during baseline conditions (Table 1). C-peptide did not affect total Qo2 or TNa/Qo2 (Table 1).
Infusion of vehicle did not alter any of the parameters in controls or diabetic animals, except for RVR, which decreased in all groups as a function of time, and TNa/Qo2, which decreased in the normoglycemic controls (Table 1).
C-peptide reduced Pff by 5.2% (11.6 ± 0.2 vs. 11.0 ± 0.2 mmHg), Psf by 8.4% (41.9 ± 0.3 vs. 38.4 ± 0.3 mmHg), and calculated Pnet by 9.6% (30.3 ± 0.4 vs. 27.4 ± 0.3 mmHg) in the diabetic animals, whereas it had no effect in controls (Fig. 6).
Baseline Qo2 was increased in isolated proximal tubular cells from diabetic animals compared with controls (39 ± 3 vs. 28 ± 2 nmol·mg protein−1·min−1; Fig. 7). C-peptide reduced Qo2 in diabetic cells (28 ± 3 nmol·mg protein−1·min−1) but had no effect on cells from normoglycemic controls (26 ± 5 nmol·mg protein−1·min−1). C-peptide had no effect on ouabain-pretreated cells (17 ± 6 vs. 18 ± 2 nmol·mg protein−1·min−1; Fig. 7). Pretreatment with l-NAME had no effect in any of the groups and did not alter the effect of C-peptide in the diabetic cells (Fig. 7).
The main new finding from the present study was that acute administration of C-peptide reduced GFR in diabetic rats via two seemingly different mechanisms. 1) C-peptide caused a net dilation of the efferent arteriole in the diabetic rats, as evident from decreased FF and Psf in the absence of altered RBF. 2) C-peptide inhibited tubular Na+ reabsorption in diabetic rats, as evident from increased fractional Na+ and Li+ excretions and reduced transport-dependent Qo2 in isolated proximal tubule cells from diabetic rats.
Acute alterations in GFR are determined by the glomerular capillary hydrostatic pressure (Pcap), the hydrostatic pressure in Bowman's space, and the oncotic pressure (ΔΠonc). Changes in Pcap are a result of alterations in the interplay of afferent and efferent arteriolar diameter, which alter the pressure transmitted to the glomerular capillaries (41, 43). Constriction of the afferent arteriole or dilation of the efferent arteriole will reduce Pcap and lower Pnet, which reduces GFR. Intratubular hydrostatic pressure is mainly determined by early proximal tubular reabsorption and, under certain conditions, by the hydraulic resistance in the distal nephron segments, e.g., obstruction of the tubules (22). ΔΠonc is determined by differences in the protein concentration between the blood in the glomerular capillaries and the fluid in Bowman's space. The main intrarenal factor influencing acute changes in ΔΠonc is the FF (3, 38), which reflects the balance between the afferent and efferent arterioles during normal conditions. Reduced FF will decrease the concentration of proteins in the blood that leaves the glomerulus through the afferent arteriole and, thus, reduce the driving force for reabsorption along the proximal part of the nephron into the peritubular capillaries, commonly referred to as the glomerulotubular balance.
Diabetes-induced glomerular hyperfiltration is reduced by C-peptide in patients with type 1 diabetes (19, 20) and in animal models of insulinopenic diabetes (16, 36, 48, 49, 51), with concomitant reduction of diabetes-induced renal damage (14, 16, 48). The glomerular arterioles exert critical actions to control Pcap, thereby influencing the GFR. We previously reported that C-peptide constricts isolated afferent glomerular arterioles from diabetic mice in vitro (35). A similarly pronounced constriction of the afferent arterioles in vivo with no effect on efferent arterioles would undoubtedly reduce GFR and RBF and increase RVR. However, C-peptide reduced the elevated GFR and FF in the diabetic rats in the present study, but did not affect RBF, which is consistent with previous reports (20, 49). None of these parameters were altered in the animals treated with vehicle only. Furthermore, RVR was not increased in the diabetic animals treated with C-peptide but, rather, decreased as a function of time in all groups. Taken together with our finding of reduced Psf after C-peptide administration, this can only be attributed to a balancing dilation of the efferent arteriole. Similar dual actions have been reported for nitric oxide (NO) synthase inhibitors, Ca2+ channel blockers, atrial natriuretic peptide, and adenosine (1, 11, 15, 31). However, given the lowering of Pnet, this mechanism could have a significant effect on the outcome for diabetic patients, since it lowers GFR and, thus, the tubular Na+ load while maintaining RBF.
C-peptide may also decrease diabetic hyperfiltration through inhibition of Na+-K+-ATPase activity, as evident from the increase in fractional urinary Na+ and Li+ excretions and decreased transport-independent Qo2 in isolated proximal tubular cells from diabetic rats. It has previously been postulated that diabetic hyperfiltration occurs as a result of primary hyperreabsorption upstream of the macula densa and the normal physiology of tubuloglomerular feedback (53, 54). However, it has been suggested that diabetes-induced glomerular hyperfiltration is caused by TGF-independent mechanisms (10, 46), although conflicting results have been reported (55). These studies utilize adenosine A1 receptor-deficient mice, which have been shown to lack the TGF mechanism, but additional TGF-independent effects of adenosine A1 receptors on afferent arteriolar tone complicate the interpretation of these findings. Also, the degree of hyperglycemia must be considered in a discussion of the potential role of TGF in diabetes-induced glomerular hyperfiltration (55). The diabetic rats displayed reduced proximal tubular Na+ reabsorption after C-peptide administration, and it is possible that the reduced GFR in these animals is caused by a TGF activation. Furthermore, earlier work demonstrated that tubular reabsorption directly influences hydraulic resistance in the proximal tubule and, therefore, affects GFR (30). It has been shown that sustained hyperglycemia in patients (56), as well as experimental animal models (27, 54), results in increased proximal tubular Na+ reabsorption secondary to increased Na+-linked glucose reabsorption. It has also been shown that early distal tubular Na+ concentrations are decreased during hyperglycemia, together with increased cortical Na+-K+-ATPase activity (27, 50). Conversely, decreased Na+ reabsorption in the early proximal tubule will increase hydraulic resistance, which in turn lowers Pnet and, therefore, reduces GFR. This hypothesis is consistent with reports of a linear correlation between GFR and Na+-K+-ATPase activity in the kidney cortex during experimental diabetes (27, 50). Therefore, a reduced or normalized Na+ reabsorption in the early proximal tubule is likely to reduce GFR in the diabetic kidney. The differences in the reduction of Psf (−8.4%) and Pff (−5.2%) in this study are not definite proof but indicate that proximal tubular reabsorption is involved in the decrease in GFR. No reduction was seen in total Na+ excretion after C-peptide, a finding that is consistent with previous studies (42). However, the reduction in tubular Na+ load, due to reduced GFR after C-peptide, will conceal the inhibitory effect on total urinary Na+ excretion. The calculated fractional Na+ and Li+ excretions increased in the diabetic animals after C-peptide administration, which shows that C-peptide directly inhibits Na+ reabsorption exclusively in the diabetic rats.
Electrolyte transport via Na+-K+-ATPase activity accounts for ∼80% of total Qo2 in the kidney (52). Therefore, diabetes-induced increase in Na+-K+-ATPase activity is likely to influence total Qo2 and, therefore, possibly limit renal O2 availability. The finding of increased cellular Qo2 in diabetic rats in the present study is consistent with previous reports (27, 39). However, the present study shows that C-peptide directly inhibits Qo2 in isolated proximal tubular cells but that the in vivo total kidney Qo2 was not altered by C-peptide administration, even though TNa decreased by ∼17%. A possible explanation can be a shift of the Na+ reabsorption site along the nephron after inhibition of proximal tubular Na+-K+-ATPase activity. Qo2/TNa is significantly less in the proximal tubule than in more distal parts of the nephron, since a notable part of the Na reabsorption in the proximal tubule is achieved via paracellular transport (29). This explanation would account for lack of reduced Qo2 in the diabetic rats in vivo after C-peptide administration.
Na+-K+-ATPase is inhibited by ouabain, although complete inhibition cannot be achieved in rats (12, 34). Ouabain treatment reduced cellular Qo2 in both groups. C-peptide had no further effect on ouabain-treated cells, which indicates that C-peptide reduces Na+-K+-ATPase activity.
C-peptide reduced blood pressure in the present study, similar to previously reported findings (36), although most studies show no such effect. However, it is predicted that increased NaCl load to the macula densa will decrease renin release and, therefore, angiotensin II production (25), and it is possible that reduced tubular Na+-K+-ATPase activity may reduce long-term arterial blood pressure, which should further add to the renoprotective effects of C-peptide. However, the effect of long-term C-peptide administration on arterial blood pressure control in diabetic patients is beyond the scope of this study.
The beneficial effects of C-peptide on diabetes mellitus have been observed in various tissues (14, 17). However, on the molecular level, the data may seem contradictory. In the present study, C-peptide decreased the ouabain-sensitive Qo2 of cells from diabetic rats but did not elicit an effect in cells isolated from normoglycemic rats. The inhibitory effect of C-peptide on isolated diabetic proximal tubular cells persisted also when the cells where pretreated with a nonselective NO synthase blocker, indicating that the mechanism does not involve a stimulated NO release with concomitant inhibition of mitochondrial respiration. Several previous studies report stimulatory effects of C-peptide on Na+-K+-ATPase, but these studies were performed under normoglycemic conditions (37, 60). Furthermore, Na+-K+-ATPase activities in neurons and erythrocytes are reduced during diabetes, and C-peptide normalizes these impairments (8, 13, 17). However, Na+-K+-ATPase activity in the kidney is elevated during the early onset of diabetes, probably due to the increased tubular electrolyte load resulting from the elevated GFR (6, 27, 57, 58). We report increased fractional urinary Na+ excretion and decreased transport-related cellular Qo2 after C-peptide administration, which demonstrates an inhibitory effect of C-peptide on Na+-K+-ATPase in the kidney. Indeed, the effects of C-peptide on endothelial NO synthase under normoglycemic conditions are different from those under hyperglycemic conditions (21, 26).
In conclusion, these results indicate that C-peptide reduces the diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of Pnet. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.
This study was supported by the Swedish Medical Research Council, the Swedish Society for Medical Research, the Fredrik and Ingrid Thuring Foundation, the Marcus and Amalia Wallenberg Foundation, the Magnus Bergvall Foundation, and National Institute of Diabetes and Digestive and Kidney Diseases Grant K99/R00 DK-077858.
- Copyright © 2009 American Physiological Society


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|Home > Music Genre > Country Music > Country > Track Summary >
Track Summary
Music Track Title: Dawn's Delight
Catalog ID: 427143 ISRC: US5UL1046521
Description: Easy on the ears electric and fingerpicked acoustic guitar duet brings to mind images of a mellow country morning or a lazy afternoon. Good for hayrides, hayseeds, and hey you should check out this tune.
Social Media Link: https://www.audiosparx.com/sa/archive/Country/Country-General/Dawns-Delight/427143
Artist or Group: Wilton Vought
Keywords: Adventure Airy Americana Atmospheric Authentic Background Backpack Backwoods Beautiful Beauty Bonfire Buoyant Bouncy Bittersweet Bluegrass Camp Carefree Joyous
Music Genre > Sub-genre
Country Music
Country / general (categorization pending)
Extended Properties
Duration: 0:30 Tempo: Medium BPM: 120
Arrangement: Duo / Duet
Instruments: Guitar, Electric Guitar
Vocal Mix: Instrumental
Use Restrictions: Use in pornographic, x-rated, sexually stimulating or similar productions prohibited
Use in products or productions advocating racial, sexual or similar discrimination or bias prohibited
Moods: Atmospheric, Beautiful, Bouncy, Delicate, Delighted, Dreamy, Earthy, Easy, Elegant, Happy, Heartwarming, Innocent, Light, Mellow, Peaceful, Relaxing, Sensitive, Shimmering, Summery, Wholesome
Styles: Backwoods / Folksy, Ballad, Documentary, Family / Children, Film Instrumental, Nature, Rural / Country, Soundscape, Travel Channel, Western
Cross-Reference Genres:
Extended Keywords: celebration celebrating charming children chill chillout cinematic commercial communal countryside courtship cowboy credits delightful dialogue documentary dreamy elegance elegant emotional environment family farm feelgood feelings festive film finale flying folk folky folksy fondness freedom friendly fun gentle groove happiness happy heartening heartwarming hitchhiking hobbies hopeful indie innocent intimate intro joy joyous joyful kids kind kite laidback lakes life light listening lively longing love loving mature melodic melody memories moonshine mountains movie music natural nostalgia nostalgic old outdoors outro park passion playful picking playing peace poignant porch positive production pulsing ranch reflective refreshing relax relaxing remembering reminiscing rhythmic rivers romance romantic rural score sentimental serene sincere soothing soundscape soundtrack spacious summer sun sunrise sunshine sweet sweetness syncopated tender

subset: commoncrawl


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The name says it all. The Gamo Match Pellet was designed primarily for target and match shooting, when extreme accuracy and tight shot grouping is critical. This reliable and accurate pellet won't break the bank, and at the price is great for backyard plinking and target shooting as well, a precision pellet. A relatively light weight and flat head that cuts targets cleanly. Great for shooters wanting tight groups!
Read More
- ManufacturerGamo
- Caliber0.177 cal
- ConditionNew
- Ammo TypePellets
- Ammo Weight7.56 gr
- Pellet ShapeWadcutter
- Pellet Quantity500
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Felix lemuel
5 Stars
I would recommend this item to a friend.
Consistent group shot.
February 8, 2017
Very good airgun pellet fir hunting ang plinking.
Palos Heights, IL
3 Stars
Good, not great
December 9, 2016
I have used this pellet in three separate pistols. Walther CP88Comp, CP99 and Beeman P3. The CP99 misfires quite a bit using this pellet. The other two handle it ok. The pellets are very inconsistent diameter. Some load with little to no force, others require significant force to put into place. The price is great, but I think other pellets at this price offer better value. Beeman Wadcutter Coated and Excite Econ both perform better than this pellet.
Pros:- Cost - Tin with screw-on lid
Cons:- Inconsistent diameter - Misfires in my CP99
South Glamorgan
5 Stars
I would recommend this item to a friend.
Very good quality at low price
December 8, 2016
I am using those with my Gamo PT85 and those are pellets which works best with this gun Consistent in size, but sometimes the are little amount of too big pellets in the box. With those I have been able to quite easily break the wine bottles from 10 meters using my Gamo PT85 Tactical.
Pros:Average weight make it capable do various jobs Quite consistent in size Good for targeting small competition especially if you use a selected pellets. Spectacular for breaking a duralex (IT'S EXPLODE UPON AN IMPACT) and the glass bottles using common cheap low power airguns. Available in the affordable cartoon boxes in a set of 250 pellets per box.
Cons:Occasionally you can found slightly oversized pellet in the box
2 Stars
I would recommend this item to a friend.
Inconsistant size
December 3, 2016
These are very affordable and make great target ammo, but they weren't sized consistantly. Another reviewer mentioned the distorted skirts. This also may make some of them fit tighter. About 1 out of 10 fit too tight. I am afraid this could nullify the savings. The accuracy is good enough.
Pros:value and accuracy
Cons:inconsistantly sized
Grayslake, IL
5 Stars
I would recommend this item to a friend.
Nothing wrong with these pellets
September 6, 2016
I ordered these after reading mixed reviews. I started shooting R10's in a new 747 and they were fine. I find these pellets to be just as accurate. In the past few weeks I find I am using these pellets more than the others that I have purchased. So, I guess they've become my favorite.
3 Stars
I would recommend this item to a friend.
November 26, 2015
When I first gotthese pellets there we alot of deformed skirts. It dosent seem like they put al that much efert into the pellets. But it came to may suprisetha their accuratsy was better than I pictured. But not that great, I was shooting at 20 yards and I am a nice shot but I was getting 4-5 inch groupings. Where as other pellets I get 2-3 inch groupings.
Pros:Cheap Decent groupings for the visuals
Cons:For a big name brand I would expect better precsion.
opglabbeek, Limburg
5 Stars
I would recommend this item to a friend.
June 21, 2014
Pretty accurate
Cape Coral, FL
5 Stars
Surprisingly Accurate
April 28, 2014
These pellets have been surprisingly accurate out of my CZ MP-53M pistol. Extremely affordable as well.
Pros:Great pellets at low cost.
Big Spring, TX
5 Stars
I would recommend this item to a friend.
March 16, 2014
For my money, I buy cheap pellets, stock up on them by the thousands and shoot all the time. I can't justify buying expensive pellets for my style of shooting. These pellets are great in every way, if you ask me.
Steve C.
hilliard, OH
5 Stars
I would recommend this item to a friend.
most accurate/best grouping
October 24, 2013
I have about 30 different kind of pellets and i have found that these provide the most consistent and accurate shots. Very tight grouping and never stray far from the center. great for target shooting.
Pros:accurate consistent low price
Cons:dont really do any damage to your target, so it wouldnt be good for small game/varmint hunting (just target shooting).
Indianapolis, IN
5 Stars
I would recommend this item to a friend.
Great pellets
August 28, 2013
These are great for target shooting, I've got about ten thousand stocked and it's cost me well under a hundred bucks. I'll be getting more for sure.
5 Stars
I would recommend this item to a friend.
GAMO .177 cal Match Pellet 500 Ct.
May 19, 2013
These are the best pellets I have every used. Far better quality than any other pellets and really cheap. Don't waste your time, just buy these. I will only buy gamo pellets from now on.
Pros:great quality great price
Loci, CA
4 Stars
I would recommend this item to a friend.
Drop Quickly
May 13, 2013
These pellets are cheap and pretty consistent, but they drop much quicker than any other brand I have tried. Compared to regular Crosman pellets these drop about four feet lower at 100 yards.
Pros:Good Price and consistent shooters.
Falls Church, VA
5 Stars
I would recommend this item to a friend.
Gamo Match Pellets
March 24, 2013
Gamo Match pellets are easily handled and loaded into most any type of pellet chamber or clip. The pellet design is reliably propelled down the barrel of most any .177 caliber pistol or rifle into which it is fired.
Ludington, mi
4 Stars
I would recommend this item to a friend.
pest control
July 11, 2012
Good target shooting pellet, not the best option for pest control. Good value.
Pros:Very accurate at close range and good for target shooting.
Cons:Not the best option for pest control. Not good at long range
cross lanes, wv
3 Stars
Indoor target trap shooting pellets...pistol
March 9, 2012
Having previously been shooting RWS R 10 Match pellets, I made the mistake of trying a less expensive Gamo "Match" pellet cause it sounded comparable. There is no comparison between the RWS and Gamo ! From a kneeling, with support, position (Barretta PX-$ Storm replica pistol) from 25 ft, I could shoot 8 or even both ends of clip (16) within a nickel sized Shoot-N-C self stick dot. With the Gamo Match I struggled to keep 8 within 2 inches....very disappointed. I guess you get what you pay for so my fault for gambling.
Pros:Nothing, since my only real fun with my pistol is precise target shooting. (Below i answered no to "Would you recommend this item to a friend', but it would be fine for plinking cans outdoors from a reasonable distance I guess...but then again, these were kinda all over the place.)
Cons:Lack of accuracy you would expect from a "Match" pellet.
New Braunfels, TX
5 Stars
I would recommend this item to a friend.
One of the best pellet values
January 17, 2012
when I was looking for a great deal on good pellets for target shooting and plinking, these appeared to be one of the best values. They have performed flawlessly so far and I have no complaints. I will likely look to repurchase.
Coarsegold, CA
4 Stars
I would recommend this item to a friend.
Not bad for the price
January 16, 2012
What can I say, good price for the tin and using this to break in my blackhawk.
Pros:Cheap Seems to be accurate in my blackhawk
Henderson, NV
5 Stars
I would recommend this item to a friend.
Beastly accurate
January 7, 2012
They are not good for hunting but they are good for target shooting. I have put so many of these down my chamber and love them. Love Gamo so of course I'll use their target pellets. They fly so nicely I have never missed when they are in the chamber
Cons:Def not for hunting
Forest Weston
3 Stars
GAMO .177 Match Pellets
September 1, 2010
Decent but not outstanding accuracy in my Crosman 1377. Great for plinking as they chamber easily, probably a bit too loose. I can manage 1" groups @ 33' if I do my part and use a padded rest.
5 Stars
Not Gamo's
June 13, 2010
I was substituted Daisy Precision Max instead and they work very good. + they refunded the cost of the Gamo's very nice company.
New User
5 Stars
April 14, 2009
Very accurate, one quarter inch at twenty-yards with Crosman 2100.
5 Stars
great pellet
February 18, 2009
this pellet offers awsome accuracy out of my ruger airhawk. i shot groups at less than half inch. this pellet is fairly light so you do get higher velocties and still have incredible accuracy
4 Stars
good accuracy
August 18, 2008
i am using these pellets as well as some others through my older style 1377c crosman. the pellets seem very consistent and yield decent groups. any bad groups are due to my gun im sure! nice pellet and affordable.
5 Stars
June 18, 2008
these pellets are so reliable they are always smooth and accurate not only are they reliable they are cool looking. I would reccomend this to anybody
Chuck V.
5 Stars
Accurate plat pellets
June 16, 2008
Besides being good for tight shot groups they also had really good results for squirrel and crows.My bigcat fitted w/ a cenerpoint 3x9x40 made kills up to 75 yards through oaktree thickets
5 Stars
Very good quality
August 13, 2007
These are very good quality pellets, better than the Corsman Silver Eagles. My Crosman 357W and Walther Lever-action rifle seem to like them alot. They give consistent grouping. Give them a try!
Lester E. Foreman
5 Stars
Gamo .177 cal pellets
July 28, 2007
These pellets are very consistent in their performance and quality. Very satisfied with this product.
Read More
are these pellets good to use in the Gamo SOCOM Tactical - .177 Caliber - 1200 FPS Whisper Quiet w/Adjustable Cheek Rest, 3-9x40 Scope, Laser & Flashlight? because thats the one im ordering, and i want the max performance with my gamo because i will only use gamo, and is this type of pellet good for small game hunting such as squirrels and birds? because they are all over the place and they make my dog bark like crazy n it drives me nuts so i need to get rid of them especially since my neighboors are complaining about my dog barking all the time.... plz help me i want this taken care of as quickly and easily as possible while still having my fun with it.
By Kyler from Eddyville, KY on February 12, 2012
By Staff on February 22, 2012
Answer:Yes they would great to use for that rifle, though I would recommend getting a hunting pellet for you rifle if you are looking to take out small game, like the Red Fire or the Blue Flame pellets.
Read More


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It's time for a digital detox. Open your mind, pack lightly, and leave the iPad at home (or at least in your hotel room). Seem impossible? We have 10 tips for successfully (and safely!) going off the grid for a little while. Trust us, the world looks a lot better when it's not pixelated.
1. Unplug Your Expectations
Getting off the grid also means leaving the safety nets behind and, in my experience, usually means you run into more hiccups than following a more established plan. Be ready for anything.
2. Traveler, Know Thyself…
Do you really want to leave Wi-Fi behind? There's no shame in a yoga retreat that is just meant for Instagram, or in wanting to send those irresistible Viber fox stickers to your boo.
3. …And Challenge Thyself
At the very least, try a one-day digital detox and see how you feel. You might even extend it to two days. Or twelve.
4. Research, Research, Research
Do your homework to make the trip as seamless as possible. Before traveling to Yelapa last year, I discovered that I would spend an hour in a tiny boat, then need to hike 15 minutes (over cobblestones) to get to my treehouse hotel—so I skipped the suitcase and brought a backpack.
5. Be Safe
Use the buddy system whenever possible and keep your passport, money, and phone on you. Traveling solo? Use Kitestring to keep people looped into your travel plans.
6. Get (Rosetta) Stoned
Getting off the grid also means you may stay in small towns where they may not speak your first language, of course. But try to nail down those basic travel phrases before you arrive so you can whip them out on the fly.
7. Catch New Zzzzs
Part of the fun of getting off the grid is trying out new accommodations. Skip the hotel and explore homestays, book a room on Airbnb, WWOOF it up. But build in at least one pampering night at a hotel at the end of your trip (one of these might do the trick).
8. Go Hands-On
Take a Balinese dance class in Ubud, try a singing lesson Vienna, or tour a shoemaker's workshop in Mallorca—it's age-old advice, but taking a class in the local culture is often the best way to understand a new place. And to pick up a new skill or two along the way.
9. Live Local
There are so many fun ways to connect with people in a new city these days. Prefer to eat your way to the heart of a culture? Try EatWith, which allows home cooks around the world to invite you in for dinner. Want a truly local guide? Vayable and even the new Airbnb Experiences pair travelers with locals who have similar interests.
10. Be Mindful
Philippe Brown, founder of bespoke travel company Brown + Hudson, always builds in down time for his travelers. After touring that temple in Cambodia, don't immediately rush to the next activity, he says. Find the best possible view of it and spend an hour sketching it—even if you're not an artist. It gives your brain time to rest and absorb the experience. From personal experience, I know that writing letters by hand while traveling has seared memories into my brain in a way that tweeting never has.
Want more ideas for getting off the grid? Check out our guide!
Photo by Brian Adams


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Palmer PEPAMPMKII Pocket Amp MKII
Palmer PEPAMPMKII Pocket Amp MKIIDetails
The Palmer PEPAMP Pocket Amp MkII is an entire guitar rig in a single pocket-sized device. It features a wide range of high quality amp tones, both clean and dirty, along with speaker cabinet emulation for extra authenticity. The PEPAMP is equipped with a headphone output for quiet solo practice, while the XLR output can be connected to a PA mixer or recording console for use during band rehearsals, recording sessions or even live performances.
Product Ref: 59848View Full Description
Full DescriptionView Full Description
Comments from customers who bought this item:
The Palmer PEPAMP features a number of controls to help you find your ideal sound. It features switchable amp selection with Clean, Crunch and Heavy modes, along with variable loudspeaker/mic position simulations and Drive, Level, Treble and Bass controls. Able to run on either a standard 9V battery or a Palmer 9V DC power supply (sold separately), this convenient device allows you to rock out anywhere you go!
- Inputs: 1
- Input Connector: 6.3 mm Jack
- Input Impedance: 1 M Ohm(s)
- Outputs: 3
- Output Connectors: XLR, 6.3 mm Jack, 3.5 mm TRS
- Output Impedance: 510 Ohm(s)
- Channels: 1
- Indicators: on/off
- Controls: Treble, mic position, mode, level, ground lift, Drive, Bass, amp select
- Power Supply: 9 V battery, 9 V DC power supply
- Cabinet Material: die-cast aluminium
- Width: 100 mm
- Depth: 100 mm
- Height: 55 mm
- Weight: 0.36 kg
The product price includes 6 years' warranty and 180 day money back guarantee.
However, the Gear4music extended warranty scheme provides an enhanced service, and is designed to offer a higher level of protection than many 'free' warranties offered by some retailers and manufacturers.
The highlights of this enhanced warranty service are:
- Warranty is extended to 6 years from the date of delivery.
- Our Money Back guarantee is extended from 30 days to 180 days (terms apply after 30 days)
- Collection and delivery costs are included for the first 2 years
- Claim 50% cash back on the cost of the policy after 6 years if it has not been used!
- Warranty is transferable if the item is re-sold
- Loan or replacement equipment will be provided if the product isn't repaired within 30 days
- If an item can not be repaired, a similar alternative product or cash discount (as defined in this policy) will be offered
- The policy can be cancelled within 30 days, and at any time after that for a pro-rata discount
Please note that this extended warranty is currently only available on products sold within the EU or EEA, and is subject to the terms and conditions as detailed on the extended warranty certificate provided.
For customers in outlying areas of the country, the price of the Extended Warranty may be marginally higher, due to the potential for higher collection and redelivery transport costs.
This enhanced warranty is in addition to the standard Gear4music and manufacturer warranty policies, and the Gear4music terms and conditions of trade. No statement or condition of sale contained within these terms affects or restricts your statutory rights as defined under the Consumer Contracts Regulation 2014.
Once the product is delivered, you have 180 days to decide that you definitely want to keep it. If you decide it is not suitable for any reason, you can return it back to us for replacement or full refund, including standard delivery charges.
All Products are new unless stated, and include a minimum of 2 years warranty.
Some items are only eligible for money back guarantee if they are returned to us unused and sealed in the original packaging, and in the case of software, unregistered. These items include:
- Software
- CDs & DVDs
- In-ear Monitors
- Earplugs and Ear Protection
- Mouthpieces, Reeds etc… for Woodwind and Brass instruments
- Mouth / Lip Care Products
We are unable to accept returns of any custom made items designed to work together as a unique package, such as computer system built to a customer's personal specifications. Exceptions may only be possible with prior agreement of the vendor, and may be subject to a cancellation fee.
If you also purchase items that do not qualify for free delivery, some delivery charges may be applied to your order which will be shown in your shopping basket.


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Awakening in America® author Robert Taub is a uniquely gifted spiritual healer and teacher who resides in Chicago Illinois. He provides clients with an inspirational guidebook, workshops, seminars and sessions.
He has presented his work to audiences for over 15 years and conducted several thousand group and individual transformational healing and guidance sessions.
His clients:
- Awaken and progress spiritually, discover a greater sense of self-awareness, find their life's purpose, free creative flow, enhance intuitive abilities and achieve higher consciousness.
- Obtain clarity, receive useful information, experience energetic healing sensations, reduction of symptoms and even spontaneous remissions of health challenges during sessions or in the days following.


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Obituary & Guest Book Preview for PHILLIP NUCCI
PHILLIP NUCCI Obituary
Published in Staten Island Advance from Apr. 5 to Apr. 6, 2014
First 25 of 36 words
: NUCCI Phillip Nucci of Stapleton on April 3, 2014. Dear brother of Edward and Mario Nucci. Funeral from Casey Funeral Home, 350 Slosson Ave, Castleton...
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"I'm so sorry. I just saw this. He's in our prayer. May he rest in peace. He's with our Lord now. Rosie" -
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"With fond memories and laughs, I remember Phil as the "comic" sidekick at Ira's auctions. My sympathies. I am living now in Florida." -
Kevin Caye
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Wessex FM News
Roadworks Back In Bridport On Monday
10:18am 28th September 2012
A £400,000 project to upgrade the local gas supply network in Bridport will be completed as quickly as possible say Southern Gas Networks.
Work will resume on Monday (1st October), meaning more roadworks for the town.
SGN had to stop work in November 2011 to secure listed building consent for some of the gas service pipe installations.
Seever engineering difficulties with the pipe work meant that only a third of phase one was completed before Christmas. Phase one was finally finished March this year.
From next week Gundry Lane will be closed westward from its junction with South Street with an alternative route and temporary traffic lights for ten days.
The following seven weeks from October 15th South Street will be closed between its junction with Gundry Lane to its junction with West/East Street.
During both road closures all on street parking will be suspended between the two zebra crossings wither side of Gundry Lane and Folly Mill Lane.
The road works are to replaced existing metal gas pipes with modern plastic polyethylene pipes to ensure the safety and reliability of Southern Gas Networks' services.
The third and final phase is due to start in January 2013 and estimated to finish by Easter Bank Holiday.
Sign up for the latest local news direct to your inbox


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Q. I read that you could deduct home-office expenses based on the number of rooms in the home. Is that correct? J.R.M, Largo, Fla.
A. Yes. Typically, home-office deductions are based on the percentage of business use (square footage of the business portion of the home divided by the total square footage). But the IRS says in Publication 587, Business Use of Home, a taxpayer can base the percentage on the number of rooms or another reasonable method.
For instance, say you use one room of an eight-room house for business. The room is 300 square feet out of a total of 3,000 square feet. In this case, the "rooms method" (12.5%) yields a bigger deduction than the square-footage method (10%).
Tip: Access Publication 587 at www.irs.gov/pub/irs-pdf/p587.pdf.
Related Articles...
- Small Business Tax Deduction Strategies No matches


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The Starting Out Guide details a lot about specific capsules and what you can do,
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Bay Area: Local blood banks NEED O-Negative blood donors. Please donate tomorrow morning, if you can. #SanBrunoFire
Demonstrators gathered in front of the Wells Fargo building at California & Montgomery, chanting "Let us in!" #wfa24 twitvid.com/BRAL2
San Bruno Residents: @americanapparel is offering you free clothing at their Burlingame location, if you're in need http://bit.ly/9638Cg
Oakland: Small group chanting at corner 'Justice for Oscar Grant'! Elder woman from 3rd floor apt yells "Go to YOUR OWN neighborhood!"
14th/Broadway intersection. AC Transit bus is 'stuck' here, despite pleas to let it thru http://twitpic.com/23lk7f
Google homepage is sick! Use the joystick on the right to adjust your 'view' from the submarine. #JulesVerne
Bay Area: This is my dear, dear friend's nephew. Pls share. RT @EastBayExpress East Bay Man Missing


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Go back in time and join the gold rush at Uptown Aces Casino by spinning the reels on the exciting Pay Dirt slot in their latest freeroll, the $1000 Challenge. Yes, that right, this generous RTG Casino is hosting a fabulous freeroll tournament, giving you a chance to win huge bonus prizes with no buy-in required. Take a minute to read our story and find out all the details. Just make sure you act quickly, for this huge freeroll will end on February 6th.
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Matlab Code
Budjetti ₹600-1500 INR
I need to implement paper on MATLAB. It's an IEEE paper
3 freelanceria on tarjonnut keskimäärin 12117 ₹ tähän työhön
Hello We are highly motivated young technocrats from IIT (ISM) Dhanbad, India. We are approachable, you can come to us if you have a struggle, we are happy to help. Team TiponTongue
I have 4 years of working experience in the field of machine learning and AI using python and matlab. Some notable projects done in python: 0. RAISR implementation: A fast low resolution to high resolution image conve Lisää


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Michael writes,
Is Advion Insect Granule Bait harmful to pets outdoors?
When used as directed on the product label, Advion Insect Granules should not pose any threat to pets. According to the MSDS if Advion Insect Granules are eaten: "No specific intervention is indicated as the compound is not likely to be hazardous."
Answer last updated on: 07/02/2011
7 of 8 people found this answer helpful. Was it helpful to you? Yes No


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Find amazing and healthy recipes at kulinarian.com
Yellow Cake With Chocolate Frosting
Created on
Favorited: 0
Your Rating
Prep Time: 00:25
Cook Time: 00:25
Main Ingredients
1 1/8 cup flour
1/2 tsp baking soda
1/4 tsp salt
1 ( stick) butter at room temperature
1 cup sugar
1 egg
1 tsp vanilla extract
1/4 sour cream
1/2 cup milk
1 cup butter ( stick) at room temperature
2 1/4 cups powdered sugar (more if needed)
1/2 cup unsweetened cocoa powder
1/4 cup milk
1 tsp vanilla extract
Dash of salt
1Preheat oven to 350 F. Grease AND FLOUR baking pans.
2Mix flour, baking soda, and salt in a bowl.
3In another bowl, cream butter on high until creamy and smooth. I use a hand mixer, but a stand mixer will work just as well.
4Add the sugar and beat into butter for a full 3 minutes on high until well combined.
5Reduce speed to medium-high and add the egg. Beat in until well combined.
6Put the speed back up to high and add the vanilla extract and sour cream.
7Reduce speed to LOW, add the dry ingredients in thirds alternating with the milk. Mix each time until just combined. Don't overmix! The batter will be pretty thick, but smooth and creamy.
8Spread batter into pans and bake for 20-25 minutes, or until the cake is slightly browned and a toothpick (or a knife since we never have toothpicks) comes out clean. Let cool COMPLETELY.
9For the frosting: cream that butter again, this time about 4 minutes.
10Mix the cocoa powder and powdered sugar together and gradually add to the butter, on low speed.
11Add the milk, vanilla, and salt. Beat for about 3 minutes on medium high speed. If the batter is too thin, add more powdered sugar.
12Frost the cake when it is completely cooled and out of the pan.
Additional Notes
*This recipe originally made a 12x17 inch cake, so feel free to double this recipe to make that much or visit the original recipe at Sally's Baking Addiction!
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Behind the buzz and beyond the hype:
Our Nanowerk-exclusive feature articles
Subscribe to our Nanotechnology Spotlight feed
Neural engineering is an emerging discipline that uses engineering techniques to investigate the function and manipulate the behavior of the central or peripheral nervous systems. Neural engineering is highly interdisciplinary and relies on expertise from computational neuroscience, experimental neuroscience, clinical neurology, electrical engineering and signal processing of living neural tissue, and encompasses elements from robotics, computer engineering, neural tissue engineering, materials science, and nanotechnology. In order for neural prostheses to augment or restore damaged or lost functions of the nervous system they need to be able to perform two main functions: stimulate the nervous system and record its activity. To do that, neural engineers have to gain a full understanding of the fundamental mechanisms and subtleties of cell-to-cell signaling via synaptic transmission, and then develop the technologies to replicate these mechanisms with artificial devices and interface them to the neural system at the cellular level. A group of European researchers has now shown that carbon nanotubes may become the ideal material for repairing damaged brain tissue.Posted: Dec 29th, 2008
Miniaturizing traditional laboratory assays to automated lab-on-a-chip devices holds tremendous potential for enabling multiplex, efficient, cost-effective and accurate pathogen sensing systems for both security and medical applications. These sensors could be used to detect bacteria such as E. coli and Salmonella, but also other pathogens that could be used for bioterrorism. Traditional identification methods required time intensive cell culturing processes but novel pathogen sensors based on nanomaterials are promising vastly improved and speedy detection technologies. A recent example is a label-free sensor chip assembled from peptide nanotubes that enables the electrical detection of viruses with an extremely low detection limit. This could lead to compact super-sensitive pathogen detection chips for point of care applications that have a high tolerance against false-positive signals.Posted: Dec 2nd, 2008
Quantum dots are emerging as an important class of nanoparticles with applications ranging from medicine to energy. These nanocrystals possess size tunable optical and electronic properties resulting from quantum confinement which allow them to be suitable candidates for applications in solar cells and light emitting devices. For instance, quantum dots have been identified as important light harvesting material for building highly efficient solar cells - when exposed to light at certain wavelengths they can generate free electrons and create an electrical current. Having a high resistance to photobleaching, quantum dots (QDs) also are attractive materials for optoelectronics and in vivo biosensing. Researchers have now demonstrated that QDs, in addition to being excellent fluorescent probes, can be used as photoacoustic (which combines the advantages of optical absorption contrast with ultrasonic spatial resolution for deep imaging) and photothermal contrast agents and sensitizers, thereby providing an opportunity for multimodal high resolution photoacoustic/photothermal-fluorescent imaging as well as sensitizers in nanotherapeutic applications.Posted: Nov 12th, 2008
Developed originally for the surface finishing industry, diamond nanoparticles are now finding new and far-reaching applications in modern biomedical science and biotechnologies. Due to its excellent biocompatibility, diamond has been called the Biomaterial of the 21st Century and medical diamond coatings are already heavily researched for implants and prostheses. Nanoscale diamond is also being discussed as a promising cellular biomarker and a non-toxic alternative to heavy metal quantum dots. Further extending the nanomedical use of diamond, researchers now have demonstrated a nanodiamond-embedded device that could be used to deliver chemotherapy drugs locally to sites where cancerous tumors have been surgically removed.Posted: Nov 7th, 2008
Mesoporous materials, i.e. materials with pores that measure less than 50 nanometers in size, have been researched extensively for at least 20 years now. Especially mesoporous silicates, due to their large surface area, their uniform pore size, and the accessibility of these pores, have become very popular as catalyst materials and excellent dug delivery candidates. Despite of the long research history of mesoporous silica materials and their biomedical potential, there have been only few reports on actual in vivo applications. Although the theory looks good, there are several practical obstacles for mesoporous silica materials to be used as drug carriers or for instance as in vivo cancer targeting agents. Researchers who tried making small mesoporous silica particles with sizes of around 100 nm often ended up with much larger lumps of aggregated particles. These larger chunks cannot be used because, due to their size, they are easily trapped in the body's defense mechanism, the reticuloendothelial system (RES). Researchers in South Korea have now reported the fabrication of discrete, monodisperse, and precisely size-controllable core?shell nanoparticles that are smaller than 100 nm, by using single magnetite nanocrystals as core and a mesoporous silica shell.Posted: Nov 6th, 2008
Bone grafts are second only to blood transfusions on the list of transplanted materials. With bone grafts, a surgeon replaces missing bone with material from the patient's own body, or a synthetic or natural substitute. Traditional tissue repair techniques, especially with synthetic materials, may lead to poor integration with the existing bone or tissue structure, potentially transfers dangerous pathogens into the body, and sometimes lead to a complete rejection of the graft. To minimize these harmful side effects, researchers are developing sophisticated tissue engineering techniques based on the construction of three-dimensional scaffolds out of biomaterials to provide mechanical support and guide cell growth into new tissues or organs. In the quest to make bone, joint and tooth implants almost as good as nature's own version, scientists are turning to nanotechnology. They have found that the response of host organisms to nanomaterials is different than that observed with conventional materials. The surface nano-characteristics of biomaterials are increasingly recognized as crucial factors with regard to tissue acceptance and cell behaviors. While this new field of nanomedical implants is in its very early stage, it holds the promise of novel and improved implant materials.Posted: Nov 4th, 2008
The study of individual live cells is a hugely important scientific task and essential to the field of molecular biology and biomedical research. Among the most significant technical challenges for performing successful live-cell imaging experiments is to maintain the cells in a healthy state and functioning normally on the microscope stage while being illuminated. Especially if scientists want to look into cellular processes that occur inside cells in their natural state and that cannot be observed by traditional cytological methods. Quantum dots (QDs), also called nanocrystals, hold increasing potential for in vitro and in vivo cellular imaging. For instance, we have previously reported about how researchers have used QDs for in vivo imaging of embryonic stem cells in mice, a novel technique that has opened up the possibility of using QDs for fast and accurate imaging applications in stem cell therapy. The usefulness of quantum dots comes from their peak emission frequency's extreme sensitivity to both the dot's size and composition. QDs have been touted as possible replacements for organic dyes in the imaging of biological systems, due to their excellent fluorescent properties, good chemical stability, broad excitation ranges and high photobleaching thresholds.Posted: Oct 8th, 2008
Genomics and proteomics, the studies of genes and proteins, provide the underlying basis for many advances in drug development and effective treatments of diseases. These studies heavily rely on unveiling the behavior of a single DNA or protein in an investigative sample. You could compare this challenge to somehow finding, then catching and monitoring a particular fish in a vast ocean. The scientific term for 'catching the fish' is 'immobilization' - a powerful technique for the study of biochemical systems that allows for the continuous observation of dynamic behavior of a chosen target. Immobilization methods anchor the to be observed molecule onto a surface in order to restrict it from escaping the observation volume. Researchers have now developed a new platform which consists of a carbon nanotube nanoneedle for capturing, isolating and measuring the activity of miniscule amounts of proteins.Posted: Oct 3rd, 2008


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Best Paper Shredders Review – The paper shredder is generally found in homes and offices. It is used for shredding up the papers that are not of any use to anyone, or for shredding the secret documents that one would not like to reveal to anyone. Typically, all of the shredders are usually same in structure that is; having two blades that rotate within the machine-body, a paper comber and a motor that is the most important component of the entire shredding machine. Its working mechanism is based on a simple procedure. The user inserts the paper, document, bills or receipts that he wants to dispose off, into the machine which then cuts up the paper into small pieces. Some shredding machines cut the paper into strips while some into small pieces. Thus, you can buy a shredder that cuts the paper in a shape according to your choice or need.
Introduction To The Best Paper Shredders Review
The main job of a shredder is to assist a user to get rid of all the unnecessary papers or the personal writings that one may not like them to be seen by others. The members of an office or home can simply discard the un-wanted paper-documents to reduce the litter within a room. In the same way, the confidential files are also torn down to avoid unveiling of the secret information to others.
Till 1980's, these shredders were only used by the governmental offices and military staff to destroy the sensitive papers. However, their used was spread, after the Supreme Court's announcement, to the use by private offices and homes. Now, shredders are commonly used and have become popular to be seen in banks, organizations and homes that aid the users to cut the paper that needs to be disposed off, without showing any poor performance even after ages of time.
One can easily find a wide variety of shredders in market. Visiting online websites makes you become familiarize with the features of the best paper shredder and will help you in deciding buying a shredder that suits your needs. So, have a look at this article and you'll get to know all types of shredders available in different styles and designs. Some shredders work to cut only papers while new ones can also demolish cards and thick material chart-paper. Similarly, some shredders are best for being used in homes whereas; big size shredders are popular to be used for the commercial purpose. Shredders diminish the amount of waste being collected in a store room and clears off a wide area for you to consume it for placing any other furniture or thing.
Having a fine quality paper shredder offers you many advantages while being at home or in a working environment. You can minimize a huge amount of trash from your place and it helps you in hiding the secret content before somebody can get a hand on it. Hence, buying a best shredder will benefit you in fulfilling the needs of your home or office environment. You would have to be very careful during your research about the shredders, to find a one that has best of the features and to keep in mind the purpose of using it. You will surely be freed of the worry and duty to assemble and manage all the documents by simply shredding the papers into small pieces that are not of need anymore. Customers have been very pleased by using paper shredders as they have been very convenient in concealing their special papers to be accessed unlawfully by thieves.
|$ 67.47
|AmazonBasics (Micro-Cut)
|$ 99.99
|AmazonBasics (Cross-cut)
|$ 99.00
Top Ranked Paper Shredders Review
We have reviewed all the types of paper shredder and mentioned below the top ranked ones to help you in making decision for buying the best paper shredder, that have great features. There are number of paper shredders present in different colors, sizes and designs in market. Mostly, some shredders are ranked at top as compared to others on the basis of their durability and performance efficiency. These are considered ideal and safe to be used in both home and office environment. These top ranked models of paper shredder are basically reliable to provide you relation and peace of mind that your top secret papers would not be disclosed to anyone after being shredded in to little fragments. All the top graded shredders come along with the facility of warranties, so when you plan to buy one, do not forget to register for warranty. So, in case of any accident or damage to the shredder, you can easily show your warranty receipt which would prevent you from having to buy a new one of a high cost.
Following are the best three paper shredders that you may want to buy one for your use;
Fellowes W-11C 11 Power-shred Paper Shredder (Cross-cut)
Power-shred paper shredder is different from other typical paper shredders because it has a special feature of cutting the paper cross wise, making the paper cut down in smaller pieces at a security level of three (3). This type of shredder torn down the paper of size 8.5 x 11 into 400 minute pieces, that allows a user to destroy his important pages that could not be set back in to one single piece of paper. The security level (3) is a mid range level, good enough for using in business environment. The size of the Fellowes Power-shred paper shredder is suitable to be placed in home offices or in small private offices.
One can very easily shred things like credit-cards, receipts, invoices, old bills, school forms, letters, out-dates information etc by using this shredder to lessen the waste from your store. This shredder has a basket that has a capacity to gather 5 gallons of tattered paper so you would not have to empty the basket very often. The basket can be taken out and all the waste can be cleaned quite handily. One of the excellent feature it incorporates is the 'safety lock' feature which means if the shredding machine is in working mode and the covering lid is lifted off then the shredder automatically stops to avoid any damage or injury and this is the reason that this shredder is well famous as an outstanding safe shredder. Power-shred shredder can also very easily manage to shred papers with staples or other types of clips.
It has an automatic on and off button that provides assistance in operating this shredding machine. It also has a reverse button, to use for the purpose to clean out the jammed papers. Companies offer a warranty of 3 years on this product to the buyers.
|Paper Cutting Speed (ft per min)
|Cut Type
|Sheet Capacity
|Shred Size
|5/32 x 1/38 in
|Run Time
|20 min
|Waste Bin Capacity
|4.75 Gallon
|Paper Feed Length
|9 in
|Customer Rating
|4.0/5 By 2804 Customers
AmazonBasics High-Security 12-Sheet, CD, Card And Paper Shredder (Micro-cut)
This shredder has been ranked at the top because of the high quality features it offers. It has also been the Amazon's best selling model of the shredder. This shredder can easily shred 12 sheets of paper at a time. Even if clipped with the clipper, stapler or hard glue the shredder performs it function thoroughly. This high quality shredder can also cut down the CDs, credit cards or card-boards and have a special opening area for inserting these types of things. The cutting speed of this shredding machine is 6-feet per minute, making the work of disposing off huge amount of papers much easy, in less time. One of best feature it includes is, it has an exclusive entrance area designed for the paper entry that may not cause any injury to hand while placing the papers into the shredder.
It is named as High-security shredder because of its capability to shred a paper at four times of security; which means the private files and documents are chopped down into such fine tiny pieces that they could not be put back together even if tried hard. Normally, it's quite well known that using a motor machine would make much noise but this Amazon basic shredder is admired to be used in office settings, schools and homes as it does not make any noise at all. This special paper shredder does not occupy much space or area of the room and has a stylish design to be placed in a home or office environment.
Another latest feature it possesses is a 'pull-out' basket that can collect up to 6.7 gallons of shredded paper at one time. The basket can be easily drawn out with the rotating wheels attached underneath it for your convenience that enables a basket to slide out of the shredder.
If in case, paper or papers get stuck in the shredder, then simply switch on the manual mode and clear out the jammed papers to restart the machine automatically. It also has a safety feature of indicating the 'overloading' of the papers to decrease the pressure over the shredder at the entry area.
Customers have given extreme positive feedback's by availing the benefits of using this paper shredder in office place and even in home. The Amazon sellers also provide a 1 year warranty for buying Basic high quality paper shredder.
|Paper Cutting Speed (ft per min)
|Cut Type
|Sheet Capacity
|Shred Size
|0.125 x 0.47 in
|Run Time
|20 min
|Waste Bin Capacity
|8 Gallon
|Paper Feed Length
|9.1 in
|Customer Rating
|4.6/5 By 2342 Customers
AmazonBasics Cross-cut Cd, Paper, Credit Card Shredder
If you are in search of a simple cross cut paper shredder then Amazon Cross-cut shredder is the best option to go for that shows high quality performance. You would not have to remove the clips, stapler pins etc before placing the paper sheets in this shredder rather this shredder can easily shred CDs and DVDs as-well, and have a separate entry area for them. The attached waste-bin has a capacity to hold 4.8 gallons of tiny paper pieces. The paper is shredded at a level of 3 of security level that does make possible piecing back the shredded paper by anyone, especially if it was a personal manuscript.
Its popular features include automatic starting function, the reverse option for clearing out the jammed papers and a safety feature of automatically shutting-off the shredder if it exceeds a certain level of temperature while in working form. This Amazon cross-cut paper shredder can shred 8 to 9 pieces of paper very proficiently but it has capacity to shred 12 papers at a time too. The Basic cross-cut shredder is considered as a normal shredder with the ability to cut 600 sheets of paper in one day, which makes it a useful machine to be used in homes, small offices and institutes.
This Amazon cross-cut shredder is available in a reasonable range of price, making possible for you to do your shredding work quite efficiently. However, it does make some noise as compared to other shredding appliances but a motor does create some sound while in working position. This Amazon shredding product is available with a warranty of 1 year for the interested customers.
|Paper Cutting Speed (ft per min)
|Cut Type
|Sheet Capacity
|Shred Size
|7/32 x 1-27/32 in
|Run Time
|10 min
|Waste Bin Capacity
|4.8 Gallon
|Paper Feed Length
|8.7 in
|Customer Rating
|4.1/5 By 7327 Customers
What to look for in a Paper Shredder?
The market is filled with the availability of huge variety of paper shredders with different designs and sizes. The most important thing to know is what is the necessary element to look for in a best paper shredder? Thus, the significant feature is the security level that a paper shredder offers. Depending upon your choice about the shredding size of paper, a paper shredder typically uses any of the three cutters to shred paper into pieces;
- Strip-cut: Strip cutter provides the lowest degree of security. When the papers or documents are inserted in to the shredder, then the strip cutter shreds the paper in to Ribbon like strips that are approximately 1/12 to 1 wide. Whereas, generally, as much wider a strip is, that much less is the level of security a shredder proposes. It means that a paper can be pieced together and the information can be revealed, that was unwanted to be read by any other person. The strip-cut shredder is popular to be known as cutting a paper in unfinished form.
- Cross-cut: Cross-cutters are used for the safe disposing off of the papers that are of high privacy. The cross-cut shredders are typically used in commercial environment where piles of papers are needed to be thrown out after some time to clean an area filled with waste material. The cross cutters cut the paper in horizontal and vertical style, making 500 to 800 small pieces of a paper. This type of shredding offers a huge security in regard of anyone's attempt in putting back the pieces of paper to unveil the private information.
- Micro-cut: The micro cutter cuts the paper at the highest level of security. The micro-cut shredder is mostly used by the high officers and other governmental organizations in terms of keeping the private information hidden by shredding the paper collection. These micro cutters are capable of shredding a paper into hundreds of tiny pieces. Mainly, a micro-cut shredder cuts a paper in either of two states, i.e. in 6000 pieces or in 12,000 pieces. This type of shredding can turn a heap of paper in mini size pieces within minutes.
Each of the above cutters cut a paper for particular times in a specific shape, making paper either completely destroyed or being available in strips. Generally, more the cuts on a paper, more it is impossible to piece back the tattered paper. Thus, it depends upon your need and preference that which type of a paper shredder you would want to buy, with a specific cutter of your choice.
Safety measures for a Paper Shredder
A paper shredder provides a user a lot of features for the convenience at workplace or at home like the speed, waste-bin capacity and much more. A shredder that performs its work efficiently and provides security is the most important machine to be used in offices and is much valued among the users. More the features a paper shredder offers, more it is precious for the users. Thus, if a shredder can offer a person much assistance in his daily life then is not it's his duty to take much care of such machine? YES, it is very important for a user to watch out over the maintenance and other precautionary measures of the shredder to ensure its efficiency and work ability.
- Entry rate: It is the rate at which a shredder can handle a certain amount of papers and the speed at which it shreds those papers. The entry rate of the paper can be measured by the amount of papers you enter the shredder each day. If you need to shred a lot of papers in a day then it is recommended to buy a paper shredder that has a wide entrance and can shred a bundle of papers at once. If you have to use paper shredder quite often and for maintaining mass of papers then buy a one that is best in performing better high duty tasks. This type of safety measure will prevent you from the collapsing of the shredding machine. Thus, feed a shredding machine with a quantity of paper at a time, for whatever amount it has been made capable of shredding.
- Items to be shred: It is extremely important to be careful about what you are actually shredding because a typical shredder is made to cut only papers and its attached paper clips or the stapler pins. Some machines are also designed to shred crumpled paper much easily. While some shredders have cutting blades that can easily shred CDs. DVDs, credit cards and other computer disks also. However, it is crucial to know which type of a shredder is best for shredding soft papers and which one for shredding the hard material items to avoid any damage and break down to your shredding machine.
- Careful Handling: A paper shredder should be handled with much care as it works through the use of electricity and contains sharp cutting blades and has other moving parts. Always keep electric machines away from the water to avert any shattering of the machine. Be careful while plugging in the switch so you may not suffer from any electric shock. If you do not feed the shredder carefully with the papers then you may result in cutting your hand through the fast movement of the blades. This is the reason that many users have now shifted towards using an automatic paper shredder that has an auto shut off feature. This feature is best in keeping a user safe from any injuries; especially if he ever tries opening the covering lid during the working condition then the shredder automatically shuts off. Moreover, some shredders have a brilliant opening area for the paper entry due to which a person's hand remains safe from any cut.
- Cleaning: If you use your paper shredder most often, then it is important to clean the waste-bin of the shredder in time before it gets over flown and might become difficult for you to carry such a heavy basket to throw away the waste. Similarly, many users buy a paper shredder that has a feature of making no noise while in working state. However, after some period of time and due to frequent use of it, a paper shredder might begin to make some noises. And this is the time it requires to be cleaned i.e. a machine has a fan that becomes dusty. So, it is important to clean the fan of the shredder that starts to make noises because the dirt gets stick to it.
- Power save mode: Many shredders come with a feature of power save mode that puts the shredding machine in sleeping mode when it is not being used. This type of feature enables saving the electricity cost and ensuring the durability of the shredder as it is not being used continuously for drawing energy for shredding the paper.
- Waste basket: At the time of buying a paper shredder, keep in mind the type of waste basket you would be easy to handle. There are different types of shredders that offer the different styles of waste basket. Some can be detached; others can be pulled out while some contain a bag. So, each shredder has its own type of waste bin to hold a specific amount of shredded paper.
- Warranty time: A customer should always keep the warranty receipt safe to show it to the retailer in times of any accident occurrence to the paper shredder. In many cases, if the paper shredder does not breakdown but the warranty time is still present then companies offer replacement of the machine rather than offering repairing. You can prevent the breaking down of the shredding machine by following the manual instructions provided to the user.By following the safety measures you can ensure the long lastingness of the paper shredder and it would prove to work efficiently for years without breaking.


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Wow that was fast. And I know with as many people on the group it will take Brat awhile to get all the notificiations out. I will wait patiently.
When I was at Joann's yesterday, I found some really cute summer picnic fabric. I am waiting patiently for my partner.
No rush no worries here.