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An analytical approach for the determination of trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) and its glucuronide and sulfate conjugates in dog plasma by LC-MS/MS (without enzymatic hydrolysis of the conjugates) was validated to support pre-clinical toxicological and pharmacological studies. The approach required two independent sample extractions and consequent instrument runs. Samples for resveratrol determination were prepared by protein precipitation with acetonitrile; acetonitrile-methanol was used instead for resveratrol metabolites. Chromatographic separation was performed using a C18 column (30 × 2.0 mm) at a flow rate of 0.25 mL/min. For resveratrol the mobile phase consisted of A: 5 mM ammonium acetate in water-isopropanol (98:2, v/v) and B: methanol-isopropanol (98:2, v/v) and for metabolites the mobile phase was modified as follows: A: 0.1% (v/v) formic acid in water and B: 0.1% (v/v) formic acid in acetonitrile. Total run time was 12 min for each run with retention times of about 4-5 min for all analytes. A turbo ion spray source was used operating in negative mode for resveratrol and resveratrol sulfate and in positive mode for resveratrol glucuronide. Calibration curves were linear from 5 to 1000 ng/mL for resveratrol and its glucuronide, and 10 to 2000 ng/mL for resveratrol sulfate. Linearity was assessed using the internal standard method for resveratrol and the external standard method for the metabolites. Method accuracy was 90 to 112% of the true value for all analytes with precision of 9 %RSD or less for all validation experiments. The validated method was applied to a preclinical toxicology study in dogs after oral administration (200 to 1200 mg/kg) of the agent. Peak plasma resveratrol concentration (Cmax) for most animals was observed within 1 to 5 h of dosing, with group mean values in the 1.7 to 9.9 μg/mL (7.5 to 43 μM) range. Area under the plasma concentration-time curve (AUC) mean values for resveratrol ranged from 3.6 to 44 h*μg/mL for all study groups and were generally proportional to the dose, with no consistent statistically significant changes observed for gender or number of doses. Mean molecular-weight adjusted ratios of resveratrol metabolites to resveratrol for AUC ranged from 1 to 9 for resveratrol glucuronide and from 2 to 11 for resveratrol sulfate.
The polyphenolic natural product trans-resveratrol (5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol; Fig. 1; referred to hereafter as resveratrol), found in grapes, berries, peanuts and other foodstuffs, continues to be the subject of numerous studies probing into its diverse properties and potential health benefits. Literature about its varied biological activity derived from in-vivo and in-vitro studies and about its potential as a disease-preventing agent is extensive and includes cancer prevention, cardioprotection and life span prolongation [1-7]. However, in spite of the large volume of published research, complete understanding of resveratrol's fundamental properties as a therapeutic remains elusive [8-10]. For example, resveratrol's health benefits when ingested in the diet; the efficacy of supplementation for disease prevention; and its therapeutic window and toxicity at the high doses proposed as necessary for beneficial effects have yet to be fully researched. Resveratrol's low oral bioavailability and fast first-pass metabolism have been reported in species including human, mouse, rat, rabbit and pig [11-16]. Specifically, oral bioavailability was reported as 1.5% in rabbit [15] and up to 30% in rat [13]. In human studies, resveratrol plasma levels have been reported at below the limit of quantitation or low levels after oral administration of the agent [17]. Although metabolic profiles may differ, all species have in common an acceptable absorption after oral administration followed by fast conversion of the agent to glucuronide and sulfate metabolites, with plasma levels of the metabolites larger than those of the parent compound. Whether the prevalent metabolites are biologically active [8,18-19] or serve as a systemic repository of the agent through, for example, enterohepatic recirculation [14] is not completely understood. It is therefore apparent that the complete assessment of resveratrol's potential as a therapeutic should include not only the agent's pharmacokinetics but that of its prevalent conjugate metabolites as well.
A number of references are available with validated methods for the determination of resveratrol in plasma from multiple species [14,20-25]. Additionally, resveratrol metabolite identification following oral administration of the agent has been performed for multiple species, with results consistently identifying mono-glucuronides and mono-sulfates as two of the prevalent metabolites [13-14,20,26-27]. Published methodologies for the determination of resveratrol metabolites in plasma and tissues include HPLC with UV detection [11,20-21,28-29] and tandem mass spectrometry [14,30]. With few exceptions [28-29], in these earlier methods enzymatic hydrolysis of the conjugates and indirect determination from the increases observed in the concentration of resveratrol were necessary to estimate the degree of Phase II metabolism. HPLC methods are long, approximately 25 min per run, and sample preparation is demanding, often requiring solid phase extraction (SPE) to purify the extracts and remove interferences. The indirect approach using LC-MS/MS with selective hydrolysis requires three separate extractions and its accuracy depends heavily on the selectivity of the enzymatic hydrolysis and the extent to which the reaction is carried out. A direct determination approach for resveratrol mono-sulfate by LC-MS/MS was published earlier; however, resveratrol mono-glucuronide concentrations were estimated using the parent compound calibration curve and method validation results were not provided [26].
In this work, we present a fully validated LC-MS/MS analytical approach for the determination of resveratrol and of resveratrol glucuronide and resveratrol sulfate without previous enzymatic hydrolysis to free resveratrol. The chromatographic separation of resveratrol is based on an HPLC method published earlier [20] and optimized here for throughput and performance using tandem mass spectrometry detection. This modified approach was first validated for resveratrol and later validated for the direct determination of resveratrol mono-glucuronide and mono-sulfate metabolites after additional modifications using a separate protein precipitation sample preparation and instrumental analysis. The approach was applied to examine the pharmacokinetics of resveratrol, resveratrol glucuronide and resveratrol sulfate in dogs after a 13 week oral administration of resveratrol, a study that was performed as part of the preclinical investigation of resveratrol as a candidate chemopreventive agent by the US National Cancer Institute.
Resveratrol (Sochinaz SA, Vionnaz, Switzerland) was provided by the Division of Cancer Prevention, National Cancer Institute (Bethesda, MD, USA). Trans-resveratrol-3-O-β-D-glucuronide (Toronto Research Chemicals, Inc., North York, Ontario, Canada) and trans-resveratrol-3-O-sulfate (SynFine Research, Inc., Richmond Hill, Ontario, Canada) were used as reference standards for the determination of conjugated resveratrol. Trans-resveratrol-13C6 (Toronto Research Chemicals, Inc.) was used as the internal standard for the determination of resveratrol. Acetonitrile, methanol, isopropanol, ammonium acetate and formic acid (all HPLC grade) were purchased from Fisher Scientific (Pittsburgh, PA, USA). HPLC-grade water was generated using a PURELAB Ultra system from ELGA (Lowell, MA, USA) followed by filtration with a Millipore (Billerica, MA, USA) 0.25 μm filter. Blank dog plasma was obtained from Bioreclamation Inc. (Westbury, NY, USA).
Twenty male and twenty female healthy naïve beagle dogs (approximately five months old; Ridglan Farms, Inc., Mount Horeb, WI, USA) were held in quarantine for approximately 4 weeks and observed daily for survival and general health status. Prior to randomization into experimental groups, each animal underwent a detailed physical examination to ensure suitability as a test animal. Dogs were housed individually in pens in accordance with standard protocols [31]. Animal rooms were held within a temperature range of approximately 20-25°C and a humidity range of approximately 30-70%. Fluorescent lighting in the animal rooms was provided on a cycle of 12 h of light followed by 12 h of darkness. Each dog was provided with 400 g of commercial chow (Certified Canine Diet 2021C, Harlan Teklad, Madison, WI, USA) daily for a minimum of 2 h during the treatment period. Drinking water was available ad libitum by automatic watering systems.
Stock solutions of resveratrol, trans-resveratrol-13C6, resveratrol-3-O-β-D-glucuronide and resveratrol-3-O-sulfate were prepared in methanol at 1, 0.1, 0.2 and 0.4 mg/mL concentrations, respectively, and stored at -20°C when not in use. Stock standards were prepared by further diluting the stock solutions in methanol-water (50:50, v/v) to 50, 100, 200, 500, 2000, 5000 and 10000 ng/mL for resveratrol and its glucuronide, and to 100, 200, 400, 1000, 2000, 4000, 10000 and 20000 ng/mL for resveratrol sulfate. The internal standard working solution was prepared by diluting the stock solution with acetonitrile to a concentration of 25 ng/mL.
Plasma samples (100 μL) were transferred to 2-mL microcentrifuge plastic vials (placed in ice and protected from light) and mixed with 10 μL of stock standards (for plasma calibrators and QC samples) and 1 mL of internal standard solution in acetonitrile. The samples were vortex-mixed for 1 min, centrifuged at 4 °C in a Sorvall RC 5C Super Speed centrifuge (Thermo Fisher Scientific, Waltham, MA, USA) at 8000 ×g for 10 min to remove precipitated proteins, and the supernatant was transferred to a clean tube and dried under nitrogen flow at room temperature (about 25 °C). After evaporation was complete, the residue was reconstituted in 100 μL of methanol with five min of sonication, added to 400 μL of water, vortex-mixed and centrifuged again. The resulting supernatant was transferred to a sample vial for instrumental analysis. For the determination of conjugated resveratrol metabolites, the protein precipitation procedure was performed instead with 1 mL of acetonitrile-methanol (1:1, v/v) solution. All other steps were the same.
Samples were analyzed on an API 3000 MS/MS system (Applied Biosystems/MDS Sciex, Foster City, CA, USA) equipped with an Agilent 1100 HPLC (Agilent Technologies, Wilmington, DE, USA) and run by Analyst™ 1.4.2 software.
Separation of resveratrol from plasma components was achieved using a Luna 3 μm C18(2) 100Å 30 × 2.0 mm column (Phenomenex, Torrance, CA, USA). The column was maintained at room temperature, the flow rate was 0.25 mL/min, and the injection volume was 25 μL. For the resveratrol determination method, the mobile phase consisted of A: 5 mM ammonium acetate in water-isopropanol (98:2, v/v) and B: methanol-isopropanol (98:2, v/v). The mobile phase gradient was as follows: after injection, initial conditions with Solvent A at 90% were held for 0.5 min, decreased to 5% in 3.5 min and held constant for 5 min, returning to initial conditions for another 3 min of reequilibration time. The mobile phase was changed for the analysis of resveratrol metabolites as follows: A: 0.1% (v/v) formic acid in water and B: 0.1% (v/v) formic acid in acetonitrile. All other chromatographic conditions were the same.
Retention times of resveratrol, resveratrol glucuronide and resveratrol sulfate were approximately 5.2, 4.0 and 4.9 min, respectively. Total run time was 12 min for each analytical run.
A turbo ion spray interface was used as the ion source, operating in negative ion mode for the resveratrol determination and with polarity switch for the metabolites determination (negative ion mode for resveratrol sulfate and positive mode for resveratrol glucuronide). Acquisition was performed in multiple reaction monitoring (MRM) mode using m/z 227 ([M-H]-) → 185 (loss of 42 (C2H2O) [32]; 233 ([M-H]-) → 191 (loss of 42 (C2H2O); 405 ([M+H]+) → 229 (resveratrol, [M+H]+); and 307 ([M-H]-) → 227 (resveratrol, [M-H]-) at unit resolution for resveratrol, resveratrol-13C6, resveratrol glucuronide and resveratrol sulfate, respectively. Ion spray voltage and collision energy were -3000 and -30 V, 4500 and 24V, and -4500 and -24 V for resveratrol, resveratrol glucuronide and resveratrol sulfate, respectively. The collision gas was nitrogen; the ion spray temperature was 450 °C; and dwell time was 200 ms.
Method validation was performed following the FDA's Guidance for Industry: Bioanalytical Method Validation [33]. Selectivity, linearity, precision, accuracy, recovery and stability were used to assess assay performance.
Selectivity was assessed by analyzing extract from six individual animals for the presence of analytical interferences and comparing the results to those obtained from spiking blank plasma sources with the analytes at the lowest limit of quantitation (LLOQ; 5 ng/mL for resveratrol and resveratrol glucuronide, 10 ng/mL for resveratrol sulfate).
Linearity was assessed using the internal standard method for resveratrol and the external standard method for its conjugated metabolites and up to eight calibrators prepared with blank dog plasma and analyte concentrations in the 5 to 1000 ng/mL (resveratrol and its glucuronide) and 10 to 2000 ng/mL (resveratrol sulfate) ranges. Curves were built from peak areas ratios to the internal standard (resveratrol) or peak areas (resveratrol metabolites) using least-squares linear regression with a (1/x2) weighting factor that was chosen based on goodness-of-fit criteria, including coefficient of determination (r2), the back-calculated concentration of individual calibrators, and minimization of the intercept value.
Precision and accuracy were determined from three validation runs with dog plasma quality control (QC) samples (n = 6) spiked at the LLOQ (5 ng/mL) and at low (12 ng/mL), mid (400 ng/mL) and high (800 ng/mL) concentrations for resveratrol and its glucuronide and corresponding concentrations of 10, 24, 800 and 1600 ng/mL, respectively, for resveratrol sulfate. Within-run precision and accuracy were assessed from the results from a single day, while between-run precision and accuracy were determined from the results from the three validation runs on different days. Dog plasma extraction recovery of resveratrol and metabolites was determined by comparison of peak area results of dog plasma QC samples (n= 6) to peak area results of extracted blank dog plasma samples spiked post extraction with analyte concentrations at the same levels. For matrix effect evaluation, the peak areas were also compared to those from the corresponding standards prepared in the reconstitution solvent.
Bench-top stability was determined by analyzing low and high level QC samples for the analyte concentrations after 4 and 24 h of storage at ambient temperature and comparing the results to those obtained from freshly prepared samples. The 24 h stability experiment was repeated for resveratrol under refrigerated conditions (approximately 4 °C). Similar experiments were performed for the long-term stability evaluation of the analytes in dog plasma after 50 days storage at -70 °C. Freeze-thaw stability of the low and high level QC samples was determined at -70 °C and over three cycles. Stability was also determined for low and high level QC samples that were extracted and stored in the instrument autosampler under refrigerated conditions (approximately 4 °C); sample extracts were injected on the LC-MS/MS instrument and the concentrations determined after approximately 6 days of storage using freshly prepared calibrators.
To evaluate the impact of sample dilution on the method's accuracy and precision, six replicate QC samples were prepared in blank dog plasma at 4000 ng/mL (resveratrol and its glucuronide) and 8000 ng/mL (resveratrol sulfate) and diluted 5-fold with additional blank plasma prior to analysis.
Resveratrol was administered to beagle dogs to evaluate the toxicity and pharmacokinetics of the agent following daily oral administration for 91 consecutive days. Animals were randomly assigned to a control or one of three treatment groups at the end of the quarantine period using a computerized body weight stratification procedure that produced similar group mean body weight values. Body weights for the animals assigned to the study ranged from 5 to 10 kg. The study groups, each consisting of four male and four female dogs, received capsules with neat doses of resveratrol at 0, 200, 600 and 1200 mg/kg (control, low, mid and high groups, respectively).
Blood samples for determination of plasma levels of resveratrol, resveratrol glucuronide and resveratrol sulfate were collected from all treated animals after the first dose and during the last week (week 13) of the study. Blood samples (approximately 3 mL) were collected from the jugular or cephalic vein into Vacutainer tubes (Fisher Scientific, Pittsburgh, PA, USA) containing EDTA at 9 time points (0, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h post-dose). Tubes were inverted several times to mix; placed on ice until centrifuged to separate plasma (within 1 h); transferred into storage tubes (0.5 mL); and stored frozen (approximately -70°C) until analyzed.
Plasma concentration-time profiles of resveratrol, resveratrol glucuronide and resveratrol sulfate for individual animals were analyzed using a noncompartmental model for extravascular administration with WinNonlin® Professional Edition software, Version 5.0.1 (Pharsight Corporation, Mountain View, CA, USA). Pharmacokinetic parameters reported for all target analytes included: time to maximum plasma concentration (Tmax), peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), and elimination half-life (t½). Clearance (CL/F) and apparent volume of distribution (Vz/F) were calculated only for resveratrol. AUC from time zero to the last measured concentration (AUC0-t) was estimated by the linear trapezoidal rule up to Cmax, followed by the log trapezoidal rule for the remainder of the curve. AUC extrapolated to infinity (AUC0-∞) is defined as AUC0-t + Ct /λ z, where λz is the disposition rate constant estimated using log-linear regression during the terminal elimination phase and Ct is the last measureable plasma concentration. Statistical comparisons of the data to assess changes due to dose level, gender, or study day were performed using Systat software (version 10.2). Data was analyzed via analysis of variance (ANOVA) followed, as necessary, by the post hoc Tukey's test (inter-group comparison) or via t-test (Day 1 vs. Week 13 and male vs. female); p≤0.05 (all comparisons); data was log-transformed (with the exception of t1/2 and Tmax); Cmax and AUC parameters were normalized to the body surface area dose (i.e., mg resveratrol/m2) prior to log-transformation [34].
No significant peaks interfering with the quantitation of resveratrol and metabolites were detected in the chromatograms of blank dog plasma at the method's LLOQ for the three analytes. Fig. 2 shows representative chromatograms of blank dog plasma extract, LLOQ (5 ng/mL or 10 ng/mL for resveratrol sulfate), and a 200 ng/mL calibrator (400 ng/mL for resveratrol sulfate) in dog plasma for each of the analytes.
Calibration curves were linear from 5 to 1000 ng/mL (resveratrol and glucuronide) and 10 to 2000 ng/mL (resveratrol sulfate). Calibrators that fell outside the range of 85 to 115% were not used to calculate the standard curve (two instances for the 200 ng/mL calibrator for resveratrol glucuronide). Mean r2 values were 0.995 or greater for all analytes. Representative regression equations for the calibration curves were y = 0.0365 x + 0.0031, y = 1780 x + 876 and y = 6340 x + 1380 for resveratrol, resveratrol glucuronide and resveratrol sulfate, respectively. The mean accuracy (% of true value) of individual calibrators used to determine the calibration curves ranged from 97 to 103%, 93 to 112% (106% without the 200 ng/mL calibrator), and 97 to 108% of the true value for resveratrol, resveratrol glucuronide and resveratrol sulfate, respectively. Between-run precision [% relative standard deviation (RSD)] for the back-calculated calibrator concentrations ranged from 1 to 8% for the three analytes.
Precision and accuracy experiment results are presented in Table 1. For all QC samples and analytes the method precision was 9 %RSD or less. Accuracy was within 15% of the true value for all determinations.
Average recovery for the low, mid and high QC replicate samples was 95, 98 and 90; 74, 77 and 73; and 83, 81 and 78% for resveratrol, resveratrol glucuronide, and resveratrol sulfate, respectively. Precision ranged from 4 to 7, 2 to 9 and 3 to 9% RSD for resveratrol, resveratrol glucuronide, and resveratrol sulfate, respectively. Comparison of the peak areas of the above experiments to those from the analytes in the reconstitution solvent did not show any significant matrix ion suppression.
Results for the LLOQ determination experiments are included in Table 1. For samples prepared at the LLOQ, method precision was 7 %RSD or less for all analytes. Accuracy was within 15% of the true value for all determinations.
The experiments designed to evaluate the bench-top stability of the target analytes in dog plasma after 4 or 24 h at room temperature had recoveries within ±10% of their nominal concentration for all analytes and concentrations, with the exception of resveratrol after 24 h (the low and high QC samples degraded to 65 and 49%, respectively, of their initial concentrations) and resveratrol glucuronide (high QC, 4 h time period, 113% recovery). Recovery of resveratrol in dog plasma improved under refrigerated conditions, at 96 and 95%, respectively, of the initial concentrations for the low and high QC samples after 24 h. The changes after three freeze-thaw cycles for the low and high QC samples were within ±10% of their nominal concentrations. The changes after six days of storage of the QC sample extracts in the instrument refrigerated autosampler were within ±10% of their nominal concentrations. No degradation was observed for resveratrol or metabolites in dog plasma after 50 days storage at -70 °C. Results for all stability experiments performed are presented in Table 2.
For the 6-replicate set of QC dog plasma samples prepared at 4000 or 8000 ng/mL and diluted 5-fold before analysis, accuracy was 98.3, 101 and 106% of the target value, with a precision of 2, 3 and 1% RSD for resveratrol, resveratrol glucuronide and resveratrol sulfate, respectively.
Representative individual animal plasma concentrations (ng/mL) of resveratrol and its metabolites are presented graphically for males and females from the low, mid and high dosing groups in Fig. 3A, B and C, respectively. Group mean value ranges for resveratrol, resveratrol glucuronide and resveratrol sulfate are summarized in Table 3.
Following oral administration, Cmax for most animals was observed within 1 to 5 h of dosing; with group mean values in the 1.7 to 9.9 μg/mL (7.5 to 43 μM) range. Statistical comparisons indicated proportional increases with the dose; however, no other consistent statistically significant changes were observed. Although Tmax appeared to shift to larger values with the dose, no consistent statistically significant changes were observed related to dose, gender, or study day. Mean t1/2 values for the different study groups were similar (ranging from 2 to 4 h). No statistically significant changes were observed for t1/2 related to dose level, gender, or study day. AUC mean values ranged from 3.6 to 44 h*μg/mL for all study groups and were proportional to the dose. Vz/F mean values ranged from 120 to 440 L/kg; CL/F mean values ranged from 22 to 110 L/h/kg. No consistent statistically significant changes were observed for Vz/F or CL/F.
Resveratrol metabolized rapidly to resveratrol glucuronide and resveratrol sulfate, producing similar plasma concentration time profiles; no significant changes were apparent for Tmax between resveratrol and its metabolites.
Tmax mean values (2 to 7 h) were similar to those observed for resveratrol and also appeared to increase with the dose. Mean Cmax values were in the 3.8 to 210 μg/mL range and statistical comparisons indicated proportional increases with the dose. Mean t1/2 values were comparable to those for resveratrol and did not change significantly among the study groups. AUC mean values ranged from 7.2 to 560 h*μg/mL for all study groups and were mostly proportional to the dose.
Tmax mean values for resveratrol sulfate were similar to those observed for resveratrol. Mean Cmax values were in the 17 to 30 μg/mL range and did not change significantly among the study groups. Mean t1/2 values ranged from 4 to 9 h and were, in general, larger than those for resveratrol. AUC mean values ranged from 40 to 170 hr*μg/mL for all study groups and although in general they increased with the dose, the changes were not proportional for Day 1 and less apparent for Week 13.
Mean molecular-weight adjusted ratios of resveratrol metabolites to resveratrol for AUC ranged from 1 to 9 for resveratrol glucuronide and from 2 to 11 for resveratrol sulfate. Although the AUC ratio for resveratrol glucuronide appeared to increase with the dose, the changes were not statistically significant. The statistical comparisons for resveratrol sulfate AUC ratios indicated a general decrease with the dose.
Initial attempts in our laboratory to use the resveratrol plasma extraction and chromatographic conditions for the conjugated metabolites analysis were unsuccessful due to poor reproducibility. Recovery for resveratrol sulfate improved from about 45% to approximately 75% with the use of acetonitrile-methanol for the extractions; although still not optimal, this proved consistent and reproducible. In addition, we found better method performance for resveratrol glucuronide with the mass spectrometer operating in positive mode and with the addition of formic acid in the mobile phase. A reference standard for resveratrol di-sulfate, another conjugated metabolite found in multiple species, was not commercially available at the time of the study, thus the method could not be validated for this metabolite.
As presented, the determination of resveratrol and target metabolites required two independent sample extractions and consequent instrument runs. Although the approach worked acceptably, the assay throughput could be substantially improved by combining the sample preparation and instrumental analysis into a single method for all analytes; in our work we could not find the right analysis conditions to achieve this. The utilization of deuterated analogs of the Phase II metabolites as internal standards, not commercially available at the time of the study, could further improve the method's performance. Additionally, if resveratrol di-sulfate reference material were to become available, the method could also be validated for its determination.
The plasma concentration individual results and concomitant concentration-time profiles for this study contained several irregularities based on expected pharmacokinetics. Some animals showed occasional delayed absorption, while others presented sudden increases in plasma concentrations approximately 8 h after oral administration, with significant prolongation of the terminal elimination half-life. This last observation is consistent with results from similar studies with resveratrol in other species and is attributed to enterohepatic recirculation [13-14]. The limited number of blood collection time points in the 8 to 24 h post-dose period for this study did not allow the modeling and estimation of the two apparent elimination phase rate constants believed to exist in the pharmacokinetic profile of resveratrol. Therefore, the pharmacokinetic parameters presented correspond to the estimation of the average elimination rate constant as permitted by the experimental data.
There were no consistent statistically significant changes in the Cmax or AUC group mean values between Day 1 and Week 13 that would indicate evidence of induction or accumulation for either resveratrol or its metabolites. Similarly, statistical comparisons of Cmax or AUC group mean values did not provide consistent evidence of differences among experimental groups due to gender. For resveratrol and resveratrol glucuronide, statistical comparison of AUC data indicated proportional increases with the dose for Day 1; however, for Week 13 AUC increases lacked proportionality to the dose. For resveratrol sulfate, changes for AUC on Day 1 were not proportional to the dose increases, while at Week 13, AUC changes were proportional to the dose changes, with one exception [low vs. high (females)].
Statistical comparison of mean AUC resveratrol glucuronide values normalized to resveratrol AUC values did not provide evidence of differences for the study groups. However, similar statistical comparisons performed for resveratrol sulfate indicated significant decreases relative to resveratrol AUC values with the dose for both Day1 and Week 13.
Details of the toxicological observations for this dog study are presented elsewhere [35].
Resveratrol pharmacokinetic results from experiments with a single oral dose in humans at 42 and 83 mg/kg (1500 and 3100 mg/m2; assuming 60 kg subjects) [36] and rats at 50 and 150 mg/kg (300 and 900 mg/m2) [13] as compared to our dog study at 200 to 1200 mg/kg (4000 to 24000 mg/m2) are as follows:
Mean Tmax values in human and rat groups were 1.5 and 1.0 h, respectively, which compares well with 1.8 and 1.1 h (male and female, respectively) for our 200 mg/kg dog dose group, although increased to 3-5 h for the higher dose groups. Dose-normalized Cmax mean values were 6.4 and 6.5, 1.5 and 5.6, and 4.3 to 13 ng/mL*kg/mg for human, rat and dog, respectively.
Mean t1/2 values were 4.2 and 8.5 h for human, 12 and 3.6 h for rat and 1.9 and 3.8 h for dog. Dose-normalized AUC mean values were 19 and 16, 27 and 17, and 20 to 37 h*ng/mL*kg/mg for human, rat and dog, respectively.
Mean AUC ratios of resveratrol glucuronide to resveratrol were 13 and 14 (sum of glucuronide isomers), 8.6 and 8.8, and 1.8 to 3.4 for human, rat and dog, respectively. Similarly, the AUC ratios for resveratrol sulfate were 22 and 23, 9.3 and 18, and 2.9 to 11 for human, rat and dog, respectively. Although comparable, these results seem to indicate more extensive conjugation of the agent in humans.
This research was supported by contract N01-CN-43304 (HHSN261200433004C) from the Division of Cancer Prevention, National Cancer Institute. The authors thank Heidi Kreuzer for assistance with the manuscript.
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text:
Extracting a common stochastic trend: Theory with some applications
This paper investigates the statistical properties of estimators of the parameters and unobserved series for state space models with integrated time series. In particular, we derive the full asymptotic results for maximum likelihood estimation using the Kalman filter for a prototypical class of such models--those with a single latent common stochastic trend. Indeed, we establish the consistency and asymptotic mixed normality of the maximum likelihood estimator and show that the conventional method of inference is valid for this class of models. The models we explicitly consider comprise a special-yet useful-class of models that may be employed to extract the common stochastic trend from multiple integrated time series. Such models can be very useful to obtain indices that represent fluctuations of various markets or common latent factors that affect a set of economic and financial variables simultaneously. Moreover, our derivation of the asymptotics of this class makes it clear that the asymptotic Gaussianity and the validity of the conventional inference for the maximum likelihood procedure extends to a larger class of more general state space models involving integrated time series. Finally, we demonstrate the utility of this class of models extracting a common stochastic trend from three sets of time series involving short- and long-term interest rates, stock return volatility and trading volume, and Dow Jones stock prices.
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Volume (Year): 150 (2009)
Issue (Month): 2 (June)
Pages: 231-247
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Econometric Society, vol. 69(1), pages 117-61, January.
- Joon Y. Park & Peter C. B. Phillips, 1999. "Nonlinear Regressions with Integrated Time Series," Working Paper Series no6, Institute of Economic Research, Seoul National University.
- Joon Y. Park & Peter C.B. Phillips, 1998. "Nonlinear Regressions with Integrated Time Series," Cowles Foundation Discussion Papers 1190, Cowles Foundation for Research in Economics, Yale University.
- Torben G. Andersen & Tim Bollerslev & Francis X. Diebold & Heiko Ebens, 2000.
"The Distribution of Stock Return Volatility,"
NBER Working Papers
7933, National Bureau of Economic Research, Inc.
- Torben G. Andersen & Tim Bollerslev & Francis X. Diebold & Heiko Ebens, 2000. "The Distribution of Stock Return Volatility," Center for Financial Institutions Working Papers 00-27, Wharton School Center for Financial Institutions, University of Pennsylvania.
- Chang-Jin Kim & Charles R. Nelson, 1999. "State-Space Models with Regime Switching: Classical and Gibbs-Sampling Approaches with Applications," MIT Press Books, The MIT Press, edition 1, volume 1, number 0262112388, March.
- Gonzalo, J. & Granger, C., 1992.
"Estimation of Common Long-Memory Components in Cointegrated Systems,"
4, Boston University - Department of Economics.
- Gonzalo, Jesus & Granger, Clive W J, 1995. "Estimation of Common Long-Memory Components in Cointegrated Systems," Journal of Business & Economic Statistics, American Statistical Association, vol. 13(1), pages 27-35, January.
- Johansen, Soren, 1988. "Statistical analysis of cointegration vectors," Journal of Economic Dynamics and Control, Elsevier, vol. 12(2-3), pages 231-254.
- Park, Joon Y, 1992. "Canonical Cointegrating Regressions," Econometrica, Econometric Society, vol. 60(1), pages 119-43, January.
- Kwiatkowski, Denis & Phillips, Peter C. B. & Schmidt, Peter & Shin, Yongcheol, 1992.
"Testing the null hypothesis of stationarity against the alternative of a unit root : How sure are we that economic time series have a unit root?,"
Journal of Econometrics,
Elsevier, vol. 54(1-3), pages 159-178.
- Kwiatkowski, D. & Phillips, P.C.B. & Schmidt, P., 1990. "Testing the Null Hypothesis of Stationarity Against the Alternative of Unit Root : How Sure are we that Economic Time Series have a Unit Root?," Papers 8905, Michigan State - Econometrics and Economic Theory.
- Denis Kwiatkowski & Peter C.B. Phillips & Peter Schmidt, 1991. "Testing the Null Hypothesis of Stationarity Against the Alternative of a Unit Root: How Sure Are We That Economic Time Series Have a Unit Root?," Cowles Foundation Discussion Papers 979, Cowles Foundation for Research in Economics, Yale University.
- Hafer, R. W. & Kutan, Ali M. & Su Zhou, 1997. "Linkage in EMS term structures: evidence from common trend and transitory components," Journal of International Money and Finance, Elsevier, vol. 16(4), pages 595-607, August.
- Andersen, Torben G & Bollerslev, Tim, 1998. "Answering the Skeptics: Yes, Standard Volatility Models Do Provide Accurate Forecasts," International Economic Review, Department of Economics, University of Pennsylvania and Osaka University Institute of Social and Economic Research Association, vol. 39(4), pages 885-905, November.
- Yoosoon Chang & Joon Park, 2002. "On The Asymptotics Of Adf Tests For Unit Roots," Econometric Reviews, Taylor & Francis Journals, vol. 21(4), pages 431-447.
- Jeff Fleming & Chris Kirby & Barbara Ostdiek, 2006. "Stochastic Volatility, Trading Volume, and the Daily Flow of Information," The Journal of Business, University of Chicago Press, vol. 79(3), pages 1551-1590, May.
- Thomas J. Sargent, 1978.
"A note on maximum likelihood estimation of the rational expectations model of the term structure,"
Staff Report
26, Federal Reserve Bank of Minneapolis.
- Sargent, Thomas J., 1979. "A note on maximum likelihood estimation of the rational expectations model of the term structure," Journal of Monetary Economics, Elsevier, vol. 5(1), pages 133-143, January.
- Modigliani, Franco & Shiller, Robert J, 1973. "Inflation, Rational Expectations and the Term Structure of Interest Rates," Economica, London School of Economics and Political Science, vol. 40(157), pages 12-43, February.
- BAUWENS, Luc & DEPRINS, Dominique & VANDEUREN, Jean-Pierre, 1997. "Modelling interest rates with a cointegrated VAR-GARCH model," CORE Discussion Papers 1997080, Université catholique de Louvain, Center for Operations Research and Econometrics (CORE).
- Karpoff, Jonathan M., 1987. "The Relation between Price Changes and Trading Volume: A Survey," Journal of Financial and Quantitative Analysis, Cambridge University Press, vol. 22(01), pages 109-126, March.
- Clark, Peter K, 1973. "A Subordinated Stochastic Process Model with Finite Variance for Speculative Prices," Econometrica, Econometric Society, vol. 41(1), pages 135-55, January.
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323 Railroad Ave,Ottawa, IL 61350 | Map
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text:
Xbox 360 Games
This page contains The Hip Hop Dance Experience Unlockables for Xbox 360 called "Achievements" and has been posted or updated on Oct 25, 2012 by vicrox.
Boxshot & Details
- Developer: Inis
- Publisher: Ubisoft
- Genre: Rhythm / Music
- Release: Nov 13, 2012
- ESRB: Teen
Complete one of the following achievements to collect their Xbox Live Gamerscore points:
|How to Unlock:
|Ain't No Stoppin' Me (20 GP)
|Win 3 consecutive times in Dance Battle
|B-Boy Stance (20 GP)
|Both players strike the final pose together
|Beat Down! (10 GP)
|Win for the first time in Dance Battle
|Bring It! (40 GP)
|Win 20 times in Dance Battle
|Dress To Impress (10 GP)
|Customize and save both male and female avatars in the Wardrobe
|Everybody In The House! (10 GP)
|Watch the Credits to the end
|First Steps (10 GP)
|Play 1 song on any difficulty
|Get Schooled (10 GP)
|Practice 1 dance in Power Skooling
|Goin' Every Out (30 GP)
|Earn SWAG! on Go Hard difficulty in Dance Party
|Gold Triple A (50 GP)
|Earn SWAG! on 3 Go Hard songs consecutively in Dance Party
|Got The Swag (30 GP)
|Both players earn SWAG! on the same song together in Dance Party
|Hype It Harder! (50 GP)
|Earn 20 HYPE!! In 1 song
|Hype Up The Crowd (10 GP)
|Both players earn HYPE!! on a dance at the same time in Dance Party
|I Work Out (30 GP)
|Cumulatively burn 250 kcal or more in Dance Marathon
|It Takes Two (10 GP)
|Play a song with another player for the first time
|Keep It Rockin' (40 GP)
|Play 50 songs in total on any difficulty
|Knowledge Me (20 GP)
|Practice 5 songs in Power Skooling
|Locate Your Turf (20 GP)
|Dance at every 6 venues in Dance Party
|Look At Me Now (50 GP)
|Successfully perform 10 final poses consecutively
|Mad Mack Skills (20 GP)
|Earn SWAG! on Mack Skills difficulty in Dance Party
|Many Styles (30 GP)
|Customize and save features or styles 20 times in the Wardrobe
|Meet My Homies (20 GP)
|Encounter every reference dancers in single and multiplayer modes
|Original Flavor (20 GP)
|Customize every of your avatar features and styles in the Wardrobe
|Paid Your Dues (10 GP)
|Earn SWAG! on Newbie difficulty in Dance Party
|Rewind! Rewind! (20 GP)
|Play the same song 5 times on any difficulty
|Risin' Up! (20 GP)
|Play 1 song on Go Hard
|Rock It Harder! (60 GP)
|Play 200 songs in total on any difficulty
|Sexy And Ya Know It (60 GP)
|Cumulatively burn 500 kcal or more in Dance Marathon
|Silver Triple A (30 GP)
|Earn SWAG! on 3 Mack Skills songs consecutively in Dance Party
|Slow It Down (10 GP)
|Activate Slow Tempo Mode in Power Skooling
|Step Up! (10 GP)
|Battle someone for the first time in Dance Battle
|Stupid Tough (60 GP)
|Clear 250 dances in Dance Marathon
|That's My Jam (40 GP)
|Play the same song 20 times on any difficulty
|Tough Enough (30 GP)
|Clear 100 dances in Dance Marathon
|Tough Guy (10 GP)
|Challenge Dance Marathon for the first time
|Warp Speed Ahead! (10 GP)
|Trigger Star Drive before the other player's Star Drive runs out in Dance Party or Dance Battle
|Wear Out The Record (30 GP)
|Dance every 40 songs
|Welcome! (10 GP)
|Play The Hip Hop Dance Experience
|What Handicap? (20 GP)
|Win a Dance Battle on a higher difficulty stage than your opponent
|You Know My Steez (10 GP)
|Customize and save the player avatar for the first time in the Wardrobe
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Please Submit a Problem for any incomplete, non-working or fake cheat listed above.
If you know other secrets, hints, glitches or level guides, then please Submit your Cheats and share your insights with other players.
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Sponsored Links


text:
Graham wakes up on the wrong side of the universe.
Writing: Graham Stark, Paul Saunders
Appearing: Graham Stark, Paul Saunders
That Sound Efftect: Yeah, From Myst
Special Thanks: Bruce Saunders
LoadingReadyRun is our flagship sketch comedy series. Launched in 2003 we've produced a new, original short every week without fail. With a different style each week, there's hopefully something for everyone.
LoadingReadyLIVE Ep10 - Happy Birthday
Someone on the show is having a birthday! You'll never guess that it's actually the website.
Before & After Pokemon GO
Everything seems so different since before we had Pokemon GO.
The LoadingReadyRumble 2
As our 11th complete season comes to a close, we decided the best way to remember everyone's[…]
A Little Drummer Boy
This seemed like such a great plan on parchment.
The Xth Way to Y
Also known as: Ways to End "X Ways to Y"
Not on Twitter
You can do your part to make things still be fun.


text:
Ahlois, Aloess, Alois, Aloisio, Aloisius, Aloisio, Aloj, Alojzy, Aloys, Lewis, Louis
Aloysius Tanner, Aloysius Waldron, Aloysius Groom, Aloysius Tait, Aloysius Cairns
Aloysius was ranked top 642 in American in year 1930 and most recently ranked 1213 in American in year 2011 More about rank of Aloysius
The name is Latinized from Aloys, a Provençal form of Louis. It was commonly used in medieval Italy, and was borne by the Jesuit Saint Aloysius Gonzaga (1568-1591) from Lombardy.
was an American player in Major League Baseball over three decades. His nickname was Bucketfoot Al.A "bucketfoot" hitter who strode toward third base when hitting, Simmons starred as an outfielder for the Philadelphia Athletics during their heyday in the early 1930s, then went on to play for the Chicago White Sox, Detroit Tigers, Washington Senators, Boston Braves, Cincinnati Reds, and Boston Red Sox.
Aloysius also appears in following countries/origins/languages: Danish, Dutch, French, German, Latin
Baby boy name meaning Renowned Warrior. in English. Aloysius also named in Danish, Dutch, French, German, Latin for boy . We have received lots of suggestion from our website users on baby names. We are thankful for all the contribution on meaning of boy name Aloysius. What does the name Aloysius mean in other origin if you know then please suggest. Further suggestion or detail on what is the meaning of name Aloysius. History of name and famous personality with Aloysius will help to update our database and other website users.
Name Of The Day
List of English baby names, English babies names, English baby names and meanings has been compiled from various resources. Please use this up to date list of English name as a reference to name your kid/child. This vast database of English names has been compiled from various references and suggestions provided by our web site users and resources partners. This information is developed to primarily serve as a reference. We are unable to respond on request for personalized assistance at the moment. Thank you for your support. Largest list of English baby names with meanings, numerology, popularity and comments.


text:
Teena Olsen of Sacramento, Calif., shows how she made this side-moon marble nail art design.
Teena Olsen (@tee_ohh) of Sacramento, Calif., shows how she made this side-moon marble nail art design.
1. Prep the nail for gel-polish application, apply base coat, and cure.
2. Apply another thin layer of base coat, allowing polish to drag easier. Use LeChat Perfect Match Beauty Bride-to-Be, Mi AMour, Utaupia, and Orly GelFX in Rage to place large dots of color around the perimeter of the nail, leaving one side open. Do not cure.
3. Use a fine art brush or a small dotting tool to drag the dots toward the center of the nail and cure. Apply a small amount of gel to the center of the nail and place the stones into the gel then cure.
4. Apply two coats of gel top coat to set the stones and cure each layer.
Celebrating Our Gelish Play at Home S. 4 Winners11 photos
CND VIP Brand Summit16 photos
Learn More
What are reasonable terms for a non-compete contract?
How do I announce to my clients that I will be moving to a new salon?
The new products I'm using are adding time to each appointment. How do I adjust my schedule?
Why isn't my Gelish application curing properly?
What's the cause of the pinkish-red oval area on the pad of my client's toes?
Get a free preview issue and a Free Gift
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text:
- Dependable Lawn Mowing in Harrisonburg, VA
- Convenient Harrisonburg Lawn Mowing Services
- Professional Lawn Mowing Harrisonburg, VA Contractors
Lawn Mowing in Harrisonburg, VA
Caring for the beauty and health of your home's lawn can be very frustrating and very time consuming which often leads homeowners to neglect lawn mowing in Harrisonburg, VA to the detriment of their home's curbside appeal and property value. That said, there's a simple way to have your home's lawn mowing in Harrisonburg, VA handled expertly, conveniently, and dependably through the experience Harrisonburg lawn mowing professionals here at Help You Services.
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Harrisonburg lawn mowing services performed by Help You Services professionals are completed with the abundance of skill, professionalism, and reliable convenience which today's busy homeowners deserve with their landscaping services. Each and every Harrisonburg lawn mowing service which is provided by the Help You Services team of lawn mowers in Harrisonburg, VA is specially tailored to the availability and preferences of the individual homeowner in question making the high quality service as efficient and satisfying as possible. If you're interested in learning more about the Help You Services lawn mowing Harrisonburg, VA services in your area then take a moment to speak with our friendly and knowledgeable contractors at (888) 441-9939. You'll be provided with a comprehensive overview of what Help You Services can provide you in terms of Harrisonburg lawn mowing services as well as a free at-home consultation and estimate for those services.
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Generally speaking, actively growing grass should be mowed once a week to maintain the optimal level of health and beauty for your lawn. Help You Services lawn mowing Harrisonburg, VA professionals are highly experienced with the wide variety of grass species and Harrisonburg lawn mowing equipment on the market today and are available to provide weekly, biweekly, monthly, or individual specialty services depending on the request of the homeowner in question. To schedule your lawn mowing in Harrisonburg, VA call (888) 441-9939 and speak with your local Harrisonburg lawn mowing professionals.
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Harrisonburg lawn mowing services involve a number of considerations which affect the price of service including the size of the lawn being serviced, the frequency of servicing, and the particular equipment needed to best serve your specific lawn. For all these reasons, estimates for lawn mowing in Harrisonburg, VA are not provided until the Help You Services professionals perform a free at-home consultation for the project. To schedule yours call (888) 441-9939 today! This consultation is completely free and carries no obligation to hire. It is simply an informative, personally tailored overview of the scheduling, care, and specifics of your unique lawn mowing Harrisonburg, VA needs.
Lawn Mowing Companies
C & L Excavating and Lawn Service
104 N River Rd
Bridgewater, VA 22812
J & D Landscaping Maintenance Inc
1458 Linden St
Harrisonburg, VA 22801
Crossroads Gardens
4309 N Valley Pike
Harrisonburg, VA 22802
ACF Environmental
767 Pleasant Valley Rd
Harrisonburg, VA 22801
Mast Landscapes
917 Cottontail Trl
Mount Crawford, VA 22841
Eyedeal Landscaping LLC
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text:
The body of a missing Winona State student was reportedly found Tuesday morning.
According to Winona Daily News, the Wabasha County Dive Rescue recovered the body of Chukwudi Benjamin Onyeaghala around 10 A.M.
A resident near Homer reported they had seen something in the river near their home around 9:15 A.M.
The body will be taken to the Olmsted County Medical Center for an autopsy.
According to the Winona County Sheriff's department, Onyeaghala was last seen on a security camera overlooking a university boat on the Winona Levee on Friday, October 7th.
The camera captured a brief moment of Onyeaghala walking down the side walk along the river around midnight.
A boat owner on the levee found two spots of blood on his boat Saturday morning, but authorities say they have no reason to believe foul play was involved in this case at this time.


text:
FREE SHIPPING* on orders of $59 or more. Ends at 11:59PM 12/10/16.
FREE SHIPPING* on orders of $59 or more. Ends at 11:59PM 12/10/16.
Your coupon will be applied to the highest regular-price, eligible item in your cart.
Offer good for one item at regular price only. Limit one coupon per customer per day. Must present coupon at time of purchase. Offer is not valid with any other coupon, discount or previous purchase. One cut or one bolt of fabric or trim "by the yard" equals one item. Online fabric & trim discount is limited to 10 yards, single cut. Excludes Heidi Swapp™ Minc.™ Foil Applicator, CRICUT® products, Gemini Machine™ Crafters Companion, Silhouette CAMEO® Machine, candy & snack products, gum & mints, helium tanks, gift cards, custom orders, special orders, labor, rentals or class fees. Cash Value 1/10¢.
Make a statement with on-trend decor pieces.
The makings of holiday memories start here.
Fabric for your DIYs - stuffable and otherwise.
Unwrap happiness with papercrafted goodies.
Greet the season with foliage and flowers.
Everything for holiday baking and party making.
Get the supplies every artist is pining for.
Cozy on up to all sorts of needle art lovelies.
Put the finishing touches on Christmas.
Because handmade is what's in.
Time to match accessories to your personality.
White Feather-Midweight Fusible Interfacing is 20" wide and 90% polyester & 10% rayon blend. Fusible for Featherweight to midweight fabrics. This non woven interfacing is for woven's and knits. Use for Challis, Chambray, Jersey, Broadcloth and linen. Fusing is not recommended for triacetate, lace, seersucker or rainwear.
CARE INSTRUCTIONS - Machine Wash, Warm; Tumble Dry; Remove Promptly.
Available in 1-yard increments. Average bolt size is approximately 40 yards. Price displayed is for 1-yard. Enter the total number of yards you want to order.
I love it! Add to wish list


text:
OPEN ME!! A Christmas Gift to the Brethren
Calling all lurkers! Now is your chance to do the right thing, and buy a subscription to the best BBQ site on the web. We know you secretly love this place, and who wouldn't? Great threads, pron, recipes, throwdowns, advice, and the nicest folks to be found at any BBQ site... period. :thumb:
So, why not support this great place, and pitch in to help keep it running? All you've got to do is buy your subscription anytime in the next week, and you'll be in the running for a great Christmas gift courtesy of the Brethren. Subscriptions start at just $25. Just post a message in this thread with the typed words, "Count me in!" to have your name entered. :whoo:
Being it's Christmas, we don't want to leave anyone out, so we're including everyone who bought a subscription this year. That's right... this means YOU!! Anyone who's subscribed, or renewed their subscription in any part of 2012 would be eligible. So, folks still have until midnight (their local time) of December 31, 2012 to either sign up, or re-up. Maybe it'll give some folks the little nudge they need to pull the trigger. :wink:
Oh... and the prize? The drawing is for one 18.5" Weber Smokey Mountain with cover, delivered. So don't miss out. Remember, in order to be eligible, you must have purchased a subscription anytime in the year 2012, and post in this thread with the words "Count me in!" to be entered. :clap2:
Merry Christmas to everyone, and good luck!! :first:
Great Post Tish Thank You Count me In I renewed in 2012 my my anni and will do so again in 2013. This place ROCKS No problem here in contributing to it. I get much more out of it then what I donate
Count me in
I too renewed in 2012 I believe.
Please DO NOT INCLUDE ME in the drawing!!!!!!!!!
Thanks in advance.
Count me in!.
Count me in!
Merry Christmas, Tish!
Do NOT include me, just want to tell you how wonderful you are. :love:
Tish, thanks for doing this! Count me in!
Merry Christmas, "Count me in!"
I believe I renewed in 2012 as well, do NOT count me in. Just wanted to let everyone know how much I appreciate this site. Merry Christmas to all!
Count me in! I just joined about a month or so ago and let me tell you, I have learned so much in that short time and have enjoyed the greatest people in BBQ.!
Love the site Count me in!
Merry Christmas to all the brethren and.......count me in!
Sent from my Nexus using Tapatalk 2
Count me in!
Merry Christmas!!!
Count me in!
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text:
The Brother Mike Tapes: 1985 from rodd perry on Vimeo.
For 16 years, from the age of 12 to 28, Mike Cohen secretly recorded his interactions with his parents. Years later, Cohen's friend, Rodd Perry, decided to take one of these vintage recordings and animate it.
The result is pure gold.
In the video above, which has racked up more than 230,000 views this week, watch the drama unfold when Cohen's parents walk into his room and give him an earful. The audio in the clip is said to have been recorded in 1985, during one of Cohen's visits home during college.
In a post on Reddit this week, Perry explained that the video was his "first attempt" at animation. He said he used both Photoshop and Final Cut to create the viral clip.
Watch the video above.
Also on HuffPost:
More:Rodd Perry Mike Cohen Guy Records Parents Fighting Guy Records Parents Arguing Guy Records Argument Parents
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text:
|Welcome to
|675 COLLEGE DRIVE, BATAVIA, OHIO large,
14,000 SF with plenty of parking and good
|Professionally selling anything, anytime, anywhere!!!
|2010 Craig Lytle Auctioneer.com Site designed by David Carpenter
to 90210
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|Tuesday December 13th at 10 am
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|Saturday December 17th
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Weekly auction
|Saturday December 10th at 10 am
Storage Facility 4 units
Queen City Storage
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text:
Note: Sample below may appear distorted but all corresponding word document files contain proper formattingExcerpt from essay:
Bouncken and Winker (2008) explain that challenges include global innovation teams being confronted with the team members' various national cultures.
National cultures, Bouncken and Winker point out (2008), influence the behavior, cognitive models and values of the individual. These same cultures, albeit may also contribute to challenges relating to the individual's understanding, along with his/her working relationship. Diversity on team members' backgrounds may increase creativity. Nevertheless, team functioning and team processes constant significant factors that form the outcome: Innovation. On the other hand, when diversity starts to threaten group processes, the ensuing actions may, in turn, spoil creativity and the intended implementation of innovation. A manager who does not include all team members in the decision making process or allows particular individuals on a team to dominate discussions increases the potential for challenges with/in a multi-cultural team to increase. The cohesion connecting the team members, as well as their commitment to the organization evolves from creativity and innovation. When team members do not participate in team decision making, albeit, their commitment to the team's tasks, which consequently links to their commitment to the organization decreases and/or dissipates.
Through the moderators of language and past intercultural experience, numerous results of diversity studies indicate that when ethnical diversity is considered in only one country, this contributes to only limited potential that the knowledge gained will be put into practice. In addition, team research that only considers college students and measures effects of ethnical diversity on team performance may only prove applicable to colleges students as these individuals do not likely possess the amount of cultural experience employees in an international firm would have gained from their employment. Solely considering national diversity does not suffice. Bouncken and Winker (2008) conclude that teams possessing identical degrees of national diversity may hold varying degrees of cultural diversity and, in turn, function differently (Conclusion section, ? 3).
In the article, "How diversity makes a team click," Kelley Holland (2007) concurs that multicultural teams may be particularly challenging to manage. Along with language barriers, communication styles frequently differ from one culture to culture, as may traditional views relating to hierarchy and decision-making processes. "The potential for misunderstanding, bungled efforts and ill will is enormous" (Holland, 2007, ? 6). Success follows understanding and accepting the differences on a multicultural team, and then utilizing the differences to enhance the way the team evaluates issues, situations and concerns and from the analyses makes decisions.
Timothy D. Golden, Assistant Professor of Management, Rensselaer Polytechnic Institute and John F. Veiga (2005) Professor of Management, University of Connecticut, assert in the study, "Spanning boundaries and borders: Toward understanding the cultural dimensions of team boundary spanning," that boundary spanning may be constitute the chain of competition for multicultural teams in the contemporary globalized economy. Deliberate efforts by a team to communicate frequently with individuals outside the team to promote the team, obtain resources, and protect the team from intrusion are known as team boundary spanning. This practice purportedly constitutes the best way to assert the team's progress. As the number of cross cultural teams rapidly increase, for boundary spanning to effectively work within a organization, managers need to understand the cultural orientations of each of the team members (Golden & Veiga)
As individuals make up teams and each individual possesses his/her personal assumptions and preferences, when members gather to achieve team goals, they will likely bring assumptions and preferences the formed from different prior life experiences, especially those due to their culture. To achieve team goals and objectives, nevertheless, "members develop team-level strategies for interacting with their environment such as choosing to boundary span or not" (Golden & Veiga, 2005, Aggregating team...section, ? 1). How the assumptions the individual team members possess, along with their preferences, nevertheless, do materialize and are reflected in their team's general approach to its organizational environment.
Golden and Veiga (2005) state that the actions a team adopts, according to research, will likely reflect the views the majority of individual team members hold. Still, "as the vast and growing cross-cultural research has shown, team actions are likely to be greatly complicated by the individual cultural differences of its members" (Golden & Veiga, Aggregating team...section, ? 1). Although a number of cultural differences may also exist within countries, national cultural values appear to vary methodically more across cultures than they do within the culture.
Despite technological advances, along with the start up of new markets and unprecedented levels of migration, Mulkeen (2008) asserts, neither governments nor organizations have invested sufficient time to learning how to harness the opportunities the new multicultural working and social environment presents. As noted at this study's start, unless the organization invests the time to comprehend how to best manage the integration of employees from different cultures, they may lose opportunities to create an effective international team.
Mulkeen (2008) further asserts that prior to the advent of multicultural workforces, mono-cultural teams constituted the norm. Excluding slight variations in personal communication style, "each team member shared the same cultural background and understood the rules of engagement. Each employee would know how to relate to his or her colleagues and work towards a common goal" (Mulkeen, 2008, ? 3). With the shift is made from mono-cultural to multicultural teams, however, the manager, as well as the individual team member faced unique challenges, which included differing forms of communication and perhaps unfamiliar business cultures.
The manager's role, Mulkeen (2008) explains, is to nurture effective collaboration in the working environment so the team may achieve its desired goals. As multicultural team members may each possess different ideas of the way to manage tasks and projects, managing a team consisting of numerous nationalities varies dramatically to the managing a mono-cultural team. "A truly effective manager takes the time to understand his or her staff and will gradually adopt a 'third' culture: A new set of styles and processes which combine the cultural preferences pertinent to those in the team and find the best fit for the group" (Mulkeen, 2008, ? 6). This process involves the manager identifying and understanding the impact individual's communication style makes. Mulkeen points out:
A principal difference in communication style is whether a culture is 'high' or 'low' context. Cultures vary in the extent to which the context of their communication is implicit or explicit, which also influences the value they place on their relationships or on rules. In a high-context culture (found in countries such as Spain, Mexico and France), communication relies on body language and assumed knowledge, and the context is left unsaid. Conversely, in a low-context culture (found in countries such as Germany, Canada, the UK and the USA), communication is much more direct and words are used to explain the context explicitly (Mulkeen, 2008, ?? 7- 8).
To avoid causing offence or misunderstanding when a person from a high-context culture communicates with another individual from a low-context culture, he/she needs a particular amount of accommodation or adaptation. A person from a low-context culture may feel he/she is not being caught up to speed by a team member from a high-context culture, who assumes all members share the same knowledge. A high-context individual, on the other hand, may feel he/she is being patronized or perhaps feel bored by the level of detail given his/her low-context counterpart give him/her. An international team manager needs to be cognizant of these and other challenges and also secure salient solutions to minimize conflict in the team and maximize successful group communication within the group (Mulkeen, 2008).
One primary difference in business practices across cultures involves the amount of emphasis the individual or the group or team as a whole merits. This type tension between individualism (noted in countries like the USA, the UK, Australia and Germany) and collectivism (noted in countries in the Middle East as well as Singapore and Mexico) may impact the way individuals perceive their roles in the team. To effectively counter this challenge, expectations regarding the team member needs to be mutually understood from the start (Mulkeen, 2008).
Mulkeen (2008) asserts that attitudes towards risk, hierarchy, collectivism and individualism, as well as communication styles, represent a few vital areas the competent multicultural team manager regularly addresses to counter the development or friction within the team and/or permitting it to flourish. Cross-cultural competency proves to be an essential characteristic for managers in multinational companies. Whether or not a manager possess this trait may make the difference between an organization succeeding or failing in today's global economy. With a myriad differences to consider in managing a multicultural team, the manager also has to determine which strategy for managing the diverse individuals works best, yet simultaneously creates an effective framework for running the team so each person feels comfortable in his/her environment.
Multi-Cultural Team Cohesion Benefits.
Luo & Shenkar point out a number of ways global language design benefits performance in an organization:
Global language design affects corporate performance via…[continue]
"Abstract When An Individual Does" (2009, June 20) Retrieved December 10, 2016, from http://www.paperdue.com/essay/abstract-when-an-individual-does-21063
"Abstract When An Individual Does" 20 June 2009. Web.10 December. 2016. <http://www.paperdue.com/essay/abstract-when-an-individual-does-21063>
"Abstract When An Individual Does", 20 June 2009, Accessed.10 December. 2016, http://www.paperdue.com/essay/abstract-when-an-individual-does-21063
Key Facts -- In this case there are really three key facts: 1) Sterling contracted with NoBugs to perform according to a specific set of instructions, which was expected and happened over the course of years. 2) NoBugs failed to meet specifications caused by a slight miscalibration of their equipment. 3) This miscalibration cased a previously hidden flaw to occur in Sterling's system. Analysis - While NoBugs did replace all the
Individual Evaluation of the Completed Process by Answering the Following Questions: Catchball is a concept called Hoshin Kanri. After the Second World War, Hoshin Kanri was a system to create policy management in Japanese companies. 'Hoshin' is a Japanese word that means pointing the direction and 'Kanri' means control. (Ten Step, 2003) The process is complex in the sense that the management creates the policy or attempts to create a
Of these, twenty were of different first languages learning Hungarian and thirteen were of Hungarian as first language learning English." (P 8). Based on this argument, age is not only the intrinsic factor that influences language acquisition. Typically, educational and maturational factors contribute to the language acquisition. With this claim, there could be a new hypothesis that reveal young= better and adult =better. Singleton (2005) conclusion on CPH is that "Critical
Individual Miami School District Negotiation Quality of education is very important for the children intellectual and social development. Many parents often base their home buying decisions on the quality of schools at the locations of the future houses. Parents need to consider the overall effect of both primary and secondary education of their children since development of mental and habits of children depend on the quality of schools the children receive.
The title of the painting comes from Latin and means "Man, heroic and sublime," going back, in fact, to an essay that the painter wrote, in which he asks "If we are living in a time without a legend that can be called sublime, how can we be creating sublime art?." This is, in part, his answer. According to some interpretations, the thin lines are a show of admiration for
V. Government System RARPA The government introduced the RARPA Program which is abbreviated for the:: "Recording and Recognition of Progress and Achievement Summary of the Evaluation Report" in relation to the Pilot Projects April 2003 to March 2004 Learning and Skills Development Agency National Institute of Adult Continuing Education 2004 August. Since 2002 the Learning and Skills Council (LSC) has focused its efforts on establishing an appropriate method of recognizing and
Individual Rights VS. Public Order Individual right - the right to privacy VS. public order - the need to use surveillance Cameras to deter crime. The Surveillance cameras are regularly connected to machines for taping the proceedings, but nobody looks at these tapes unless something untoward happens. These cameras are on the march and have spread to gas stations, ATMs, mini-marts, sporting events as also on the streets. After the attack on


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Jasper Fontenot
Brown's Furniture was opened for business in 1939 by Mr. Herbert Brown. The first location to be launched was Opelousas. Stores in Ville Platte, Baton Rouge and Lafayette soon followed, and during the 40's Wayne Gilmore and R...
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If you're not a regular in the social circuit, you may have some questions regarding what constitutes cocktail attire for the Red Hot Mardi Gras Ball on January 30th. Not to worry, we're here to help.
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Hi, I'm Bonita! I am a very sweet but shy girl, but once I get to know you I love to play! I do really well walking on a leash and I adore other dogs.I need to be primarily an inside dog. I'm ok with kids and cats. Take me home today?
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text: I think an awesome theme would be one with the Marvel characters? could someone make this? like each icon is a different Marvel Character like Spiderman, Hulk, Iron Man, characters from Justice League, Fantastic 4, and others yes or no? EDIT: Zigg says he'll make it if enough people like it, so vote yes!


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Submit News
Samsung Reveals Quad-Core Exynos 4 for Galaxy S3 Superphone
Jason Mick
April 26, 2012 1:19 PM
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New chip is likely to power the Galaxy S3
With the Galaxy S3 super-phone from the
world's top Android phonemaker
, Samsung Electronics Comp., Ltd. (
), set to launch at a special event in London, UK on May 3, the hot question on everyone's mind is what might be inside. Samsung might have tipped its hand regarding the system-on-a-chip (SoC) driving the phone, today announcing its quad-core variant of the fourth generation of
While Samsung continues to play with Texas Instruments Inc.'s (
) OMAP processors (a potential acquisition target), the South Korean firm still makes much of its CPUs in-house. It's a pretty poorly kept secret that Samsung also manufactures
virtually all the CPUs for its smartphone arch-nemesis
Apple, Inc.'s (
) iPad and iPhone.
Even as the firm is rumored to be preparing
its fifth generation
Exynos 5
chip for PC offerings, the
4 quad core -- clocked at 1.4 GHz -- represents the company's direct response to its competitors quad core designs like NVIDIA Corp.'s (
Tegra 3
and Qualcomm Inc.'s (
SnapDragon 4
. Samsung claims that despite adding two cores, the die-shrink from 45 nm to 32 nm allowed it to drop power draw by 20 percent, while doubling computation power.
The new chip is built on Samsung's
mature 32 nm high-K metal gate (HKMG) technology
, a process refinement that helps fight leakage, the power losses that plague the semiconductor world's ever-shrinking circuits.
Each core on the chip can be switched off via so-called "hot plug" technology. The chip also packs dynamic voltage and frequency scaling (DVFS) for its cores, allowing them to be selectively underclocked based on workloads.
The Exynos 4 quad-core will drive the Galaxy S3. [Image Source: Samsung via Anandtech]
The only disappointment is that the GPU onboard the chip is not expected to get a bump [
], instead using the
same old Mali-400 MP4 intellectual property core
from ARM Holdings Plc. (
). That means that Samsung is
unlikely to be able to keep pace with nemesis Apple
in GPU performance, although the Galaxy S3 aims to be very competitive with Apple's smartphone CPUs. The core does receive one minor graphical improvement in getting a 1080p hardware codec engine, capable of shooting 30 fps HD video and piping out video of HDMI 1.4.
The new Samsung chip is the same size as the first-generation dual-core
Exynos 4
and fully compatible with its predecessor's pin-out. Hence the chip is expected to be a very easy upgrade to existing handsets, given its lower power draw.
The chip is currently in mass production with most of the early stock likely going toward the Galaxy smartphones, which sell tens of millions of units a quarter globally.
The chip will be planted in the Galaxy S3, which launches in just over a week
[Image Source: Samsung]
Hankil Yoon, Senior Vice President of Product Strategy Team, Samsung's Mobile Communications Business kills any suspense about whether the chip will wind up in the Galaxy S3, candidly sharing, "The application processor is a crucial element in providing our customers with a PC-like experience on mobile devices. Samsung's next Galaxy device, which will be officially announced soon, offers uncompromised performance and ground breaking multi-tasking features, thanks to Exynos 4 Quad's powerful performance and efficient energy management technology."
Samsung [press release]
Anandtech (GPU)
"It looks like the iPhone 4 might be their Vista, and I'm okay with that." -- Microsoft COO Kevin Turner
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"Schwedenplatz~ synagogue" Museum Judenplatz - Jewish Square Tip by Audrey118
Museum Judenplatz - Jewish Square, Vienna: 40 reviews and 93 photos
This is probably the most important Jewish temple in Vienna. It is the only Jewish temple to survive the Nazis during the Crystal Night of 9-10 Nov 1938.
Worthy to take note of the history is that during Jospeh II, no non Christian building is allowed to show its facade towards the street, and thus the facade is modified with the temple built inside a complex.
Address: Judenplatz 8, 1010 Wien
Directions: At F�rbergasse & Wipplingerstra�e
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Play: Just Park It 2
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Description: Just Park It 2
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