- Journal List
- Br J Clin Pharmacol
- v.51(5); 2001 May
- PMC2014477
Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes
Abstract
Aims
To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil.
Methods
Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1–250 µm). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate.
Results
When verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 µm for all major metabolites. The IC50 values ranged from 4.8 to 5.6 µm on preincubation of verapamil for 30 min in the presence of an NADPH-generating system. Corresponding IC50 values for diltiazem ranged from110–127 µm and from 21–27 µm, respectively. Verapamil and diltiazem inhibited testosterone 6β-hydroxylation in a time- and concentration-dependent manner, key features of mechanism-based inactivation. Values for the inactivation parameters kinact and KI were 0.15 ± 0.04 min−1 (mean ± s.d.) and 2.9 ± 0.6 µm, respectively, for verapamil and 0.07 ± 0.01 min−1 and 3.3 ± 1.5 µm, respectively, for diltiazem.
Conclusions
The IC50 values for coincubation of verapamil and diltiazem were 46- and 220-fold higher, respectively, than those reported previously for mibefradil, and 16- and 71-fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.
Introduction
The HMG-CoA reductase inhibitor (statin) simvastatin is used extensively for treatment of hypercholesterolaemia and has a major impact in the prevention of coronary heart disease (CHD) [1]. Simvastatin is an inactive lactone pro-drug that is hydrolysed in vivo to simvastatin acid, a potent competitive inhibitor of HMG-CoA reductase the rate-limiting enzyme in cholesterol biosynthesis. The statin is generally well tolerated and causes few subjective side-effects during chronic treatment [1]. Myopathy, which may present as rhabdomyolysis, is a rare but serious side-effect of statin treatment and occurs in 0.1% of patients treated with standard doses of simvastatin or other HMG-CoA reductase inhibitors [2]. The risk of developing acute rhabdomyolysis appears to increase considerably on addition of drugs such as itraconazole [3] and mibefradil [4, 5] to the stable regimen of patients taking simvastatin. The onset of rhabdomyolysis has been associated with dramatic increases in plasma concentrations of HMG-CoA reductase inhibitory activity, due to inhibition of the cytochrome P4503A4 (CYP3A4)-mediated metabolism of simvastatin by the interacting drugs [6]. Results of an in vitro study have confirmed that at therapeutic concentrations, mibefradil inhibits the metabolism of simvastatin in human liver microsomes and acts as a powerful mechanism-based inhibitor of CYP3A4 activity [7].
Since the withdrawal of mibefradil from the market 2 years ago, there has been considerable debate regarding drug interactions with simvastatin, particularly with respect to the concomitant use of other calcium channel blockers [8, 9]. Many of these drugs are weak inhibitors of CYP3A4 [10], and diltazem and verapamil in particular, have been shown to increase the plasma levels of statins when used concurrently with simvastatin or the closely related lovastatin [11, 12]. Originally it was postulated that the mechanism of interaction by diltiazem was competitive in nature [13], but a recent in vitro study has demonstrated that diltiazem-mediated inhibition of midazolam metabolism by CYP3A4 occurs primarily by metabolite intermediate complex formation, which renders the enzyme inactive [14]. Thus, the mechanism of CYP3A4 inhibition by diltiazem appears to be similar to that observed with mibefradil [7]. It has also been reported that both diltiazem and verapamil inhibit testosterone 6β-hydroxylation due to metabolite-intermediate complexation with CYP3A [15]. The mechanism of inhibition was characterized for both inhibitors but there were limited data on the kinetics of inactivation.
In the present study the inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes were investigated. In addition, the inactivation kinetics of verapamil and diltiazem were determined using incubation conditions described previously for the characterization of CYP3A4 inhibition by mibefradil [7]. Thus, it was possible to compare directly the inhibitory potencies and inactivation parameters of verapamil and diltiazem with those reported for mibefradil, a known potent inhibitor of CYP3A4 in vitro and in vivo [7].
Methods
Drugs and chemicals
Simvastatin was provided by the Merck Research Laboratories. Testosterone and its metabolite testosterone 6β-hydroxylase, dilitazem and verapamil were purchased from Sigma (London, UK). Glucose-6-phosphate (G6P) dehydrogenase (grade II) and the disodium salts of G6P and NADP were purchased from Boehringer Mannheim (Lewes, UK). Acetonitrile, ethyl acetate and methanol were obtained from Rathburn (Walkerburn, UK). All other reagents were of analytical grade and obtained from Merck (Poole, UK).
Human liver microsomes
Samples of human liver were obtained from ‘normal’ tissue taken from carcinoma patients with the approval of the Royal Hallamshire Hospital Ethics Committee and the local Coroner. The 10 samples of human liver were subsequently referred to as HL7, HL11, HL12, HL14, HL16, HL17, HL21, HL22, HL24 and HL25. There was no pathological evidence of hepatic disease in any of the liver samples used. The donors of HL14 and HL22 were female and the remaining donors were male. With the exception of the donor of HL25 who was a black Caribbean, the donors were Caucasian. None of the donors was a smoker. Drugs administered prior to or during organ removal were fentanyl, atracurium, thiopentone, morphine and droperidol.
Human liver microsomes were prepared as described previously [16] and stored at −80 °C as a suspension in 0.1 m potassium phosphate buffer (pH 7.4) containing 30% (v/v) glycerol. Microsomal protein was measured by the method of Lowry et al. [17] using bovine serum albumin as the standard.
Effects of verapamil and diltiazem on simvastatin metabolism
Incubation mixtures comprised 100 µl microsomal suspension (equivalent to 0.05–0.25 mg microsomal protein), inhibitors dissolved in 195 µl 1.15% KCl (w/v), 200 µl of a NADPH-generating system dissolved in 0.2 m potassium phosphate buffer (pH 7.4) and 5 µmol simvastatin added in 5 µl acetone. The NADPH-generating system consisted of 0.4 µmol NADP, 4 µmol G6P, 2 µmol MgCl2 and 0.4 units of G6P-dehydrogenase. Verapamil or diltiazem was either coincubated with simvastatin and microsomes before the reaction was initiated with the NADPH-generating system or preincubated with microsomes and the NADPH-generating system for 30 min at 37 °C before addition of simvastatin. Control experiments were also performed using preincubation and coincubation conditions to determine simvastatin metabolism in the absence of any inhibitor. Incubations were conducted at 37 °C and were terminated after 10 min by the addition of 0.5 ml acetone.
Preliminary experiments indicated that the final substrate concentration of 10 µm was comparable with the Km value of simvastatin and that the formation of metabolites at this concentration was linear up to 0.5 mg protein ml−1 and throughout the 10 min incubation period. A range of concentrations (0.5–250 µm) was used to investigate the effect of verapamil and diltiazem on the formation of simvastatin metabolites. Incubations were performed in triplicate at each inhibitor concentration using microsomes prepared from HL7. The experiment was repeated using microsomes from three different human livers, at single inhibitor concentrations of 5 and 20 µm for verapamil and diltiazem, respectively (approximate IC50 values).
Effects of verapamil and diltiazem on CYP3A4 activity
Testosterone 6β-hydroxylation was used as a marker of CYP3A4 activity [18]. Verapamil or diltiazem (0.5–250 µm) were either coincubated with testosterone and microsomes before the reaction was initiated with the NADPH-generating system or preincubated with microsomes and the NADPH-generating system for 30 min at 37 °C before the addition of testosterone (25 µmol in 5 µl acetone). Both sets of incubations were performed in the absence of inhibitor to determine control testosterone 6β-hydroxylase activity. The incubations were terminated after 10 min by the addition of 2 ml ethyl acetate. The substrate concentration used was comparable with the Km value of testosterone (50 µm). Incubations were performed in triplicate at each inhibitor concentration using microsomes prepared from HL7. To determine the time-dependent effect of CYP3A4 inactivation by the inhibitors, verapamil (2 µm) and diltiazem (10 µm) were preincubated in the presence of a NADPH-generating system for various times ranging from 0 to 45 min. The samples were then assayed for remaining CYP3A4 activity using testosterone (50 µm).
Microsomes prepared from 10 different human livers were preincubated with 1 µm verapamil for 30 min in the presence of an NADPH-generating system and were then assayed for remaining testosterone 6β-hydroxylase activity. Incubations were carried out in quadruplicate for each human liver. The experiment was repeated using 1 µm diltiazem.
Kinetics of CYP3A4 inactivation
Studies on the kinetics of CYP3A4 inactivation were performed using the testosterone 6β-hydroxylase assay at a substrate concentration of 250 µm, in order to minimize competitive inhibition by verapamil and diltiazem. Human liver microsomes were preincubated with 0.5, 1, 2 and 5 µm verapamil or 2, 5, 10 and 20 µm diltiazem in the presence of an NADPH-generating system for various times ranging from 0, 2, 5, 10, 15, 20 and 30 min at 37 °C. The incubation mixture was then assayed for remaining CYP3A4 activity by the addition of testosterone (125 µmol in 5 µl acetone). The reaction was terminated after 10 min by the addition of 2 ml ethyl acetate. Incubations were performed in duplicate and the experiment was carried out using microsomes prepared from three different human livers (HL7, HL12 and HL16).
In vitro metabolism of verapamil and diltiazem
The disappearance of verapamil and diltiazem in human liver microsomes was measured in order to determine a partition ratio for CYP3A4 inactivation by each of the inhibitors. Using the incubation conditions described previously for simvastatin, verapamil (0.5 nmol) and diltiazem (2.5 nmol) were incubated for various times ranging from 0 to 30 min. The reactions were terminated by the addition of 200 µl acetone. Incubations were carried out in duplicate using microsomes prepared from three different livers (HL7, HL12 and HL16).
Analytical procedures
Simvastatin and its metabolites were assayed using modifications of methods described previously [7, 19]. Ethyl acetate (2 ml) was added to the tubes containing the incubation mixture and the contents were shaken for 15 min. After centrifugation at 900 g for 5 min, the organic phase was transferred to conical glass tubes and evaporated to dryness under vacuum at 40 °C using a Buchler vortex-evaporator (Baired and Tatlock, Romford, UK). The residue was reconstituted in 200 µl mobile phase comprising water/acetonitrile (45 : 55, v/v) containing 1% triethylamine adjusted to pH 4 with orthophosphoric acid and subjected to h.p.l.c. analysis. The samples were injected onto a Waters RCM radial compression system containing a 0.8 × 10 cm NovaPak C18 cartridge, 4 µm particle size (Waters Chromatography, Watford, UK) fitted with a Guard-Pak guard column containing a C18 insert (Waters). A Model 510 chromatography pump (Waters) was used for solvent delivery at a flow rate of 2.5 ml min−1. The eluate was monitored using a SF769 variable wavelength u.v. detector (Kratos, Warrington, UK) set at 240 nm and 274 nm. Simvastatin is metabolized to several products, including the two major metabolites, 3′-hydroxy- and 6β-exomethylene-simvastatin [7, 18]. Identification of the 6β-exomethylene metabolite was made largely on the basis of its u.v. spectral characteristics, i.e. λmax = 274 nm, and also by comparison of its retention time with that reported previously [18]. The 3′-hydroxy-product was identified by its retention time and also the fact that it was the main metabolite observed at 240 nm using u.v. detection. The coefficient of variation for assay of both metabolites was less than 5% at 10 nmol ml−1 simvastatin.
The same h.p.l.c. system including the NovaPak C18 column was used to measure the formation of 6β-hydroxytestosterone and disappearance of diltiazem and verapamil. To assay 6β-hydroxytestosterone, 25 µl of a 10 µg ml−1 solution of 11β-hydroxytestosterone was added to the tubes containing the incubation mixture and 2 ml ethyl acetate. The samples were shaken for 15 min, prior to centrifugation at 900 g for 5 min. The organic phase was transferred to conical glass tubes and evaporated to dryness under vacuum at 40 °C using a Buchler vortex-evaporator. The samples were re-constituted in 200 µl mobile phase consisting of methanol/water (55 : 45, v/v) and injected onto the h.p.l.c. system. The samples were eluted from the column at a flow rate of 3 ml min−1 and were monitored by a u.v. detector set at 240 nm. The limit of determination of 6β-hydroxytestosterone was 30 pmol ml−1, and the coefficient of variation at 160 pmol ml−1 was less than 5%.
Verapamil and diltiazem were assayed by centrifugation of the incubation samples at 900 g for 5 min and injecting the supernatants directly onto the h.p.l.c. system. The samples were eluted from the column using a mobile phase consisting of acetonitrile/water (28%: 72%, v/v) containing 1% triethylamine (adjusted to pH 3.5 with orthophosphoric acid). The pump was set at a flow rate of 2.5 ml min−1 and the u.v. detector at 230 nm. The retention times of diltiazem and verapamil were 5.5 and 10.7 min, respectively. At 5 nmol ml−1 diltiazem and at 1 nmol ml−1 verapamil the coefficients of variation for assay were 6% and 5%, respectively.
Data analysis
The results were expressed as percentages of substrate consumed or metabolites formed in the presence of verapamil or diltiazem relative to the corresponding values obtained in the absence of any inhibitor (control). IC50 values were determined by a nonlinear regression analysis. The inactivation parameters kinact and KI were calculated according to the method of Silverman [20]. The initial-rate constant for inactivation (k, min−1) at each inhibitor concentration was estimated from the initial slope of the log-linear regression line of CYP3A4 activity remaining vs the preincubation time profile. Initial estimates of the inactivation parameters were then determined from the reciprocal plot of rate constants for inactivation (1/k) vs the respective inhibitor concentrations (1/I). These values were used as first estimates for iterative nonlinear regression analysis using the solver subprogram, which was implemented in Excel 97 to calculate values for kinact and KI according to the following equation:
where k is the initial rate constant for inactivation at the initial inhibitor concentration, Io; kinact is the maximum rate constant for inactivation; and KI is the inactivator concentration which produces half the maximal rate of inactivation, analogous to Km. The partition ratio was estimated from the initial disappearance rate constant of verapamil and diltiazem relative to the initial rate constant for inactivation of CYP3A4 activity at the same inhibitor concentrations.
Comparisons of CYP3A4 activities and percentage inhibition between control, verapamil and diltiazem groups were performed using a non-parametric (Kruskal–Wallis) one-way analysis of variance. Where this analysis indicated significant differences (P < 0.05) between groups, individual comparisons were made using the Mann–Whitney test.
Results
Inhibitory effects of verapamil and diltiazem on simvastatin metabolism
Verapamil and diltiazem inhibited simvastatin metabolism in a concentration-dependent manner (Figure 1a,b). In experiments where verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 µm for the formation of all major metabolites (Figure 1a). When verapamil was preincubated for 30 min in the presence of an NADPH-generating system the degree of inhibition increased, the IC50 values ranging from 4.8 to 5.6 µm. Corresponding IC50 values for diltiazem ranged from110–127 µm and from 21 to 27 µm, respectively (Figure 1b).
The experiment was repeated using microsomes from four different human livers and single inhibitor concentrations of 5 µm verapamil and 25 µm diltiazem. These concentrations were chosen because they approximated the IC50 values determined in the initial experiment. The degree of inhibition of 3′-hydroxy- and 6β-exomethylene-simvastatin formation was increased significantly in microsomes from each liver by preincubation of verapamil and dilitazem (P < 0.05) (Figure 2a,b).
Inhibition of testosterone 6β-hydroxylase activity by verapamil and diltiazem
The inhibitory effects of verapamil and diltiazem on testosterone 6β-hydroxylation were also concentration dependent (Figure 3a,b). As was observed with simvastatin, IC50 values for preincubation were approximately 5-fold lower than those obtained for coincubation. IC50 values for inhibition of testosterone 6β-hydroxylation by preincubated verapamil and diltiazem were 27 and 122 µm, respectively. In coincubation experiments, the corresponding values were 3.1 and 26 µm, respectively. These values were comparable with those obtained when using simvastatin as the CYP3A4 substrate. The inhibitory effects of verapamil and diltiazem were also found to be time-dependent (Figure 4a,b).
With preincubation in the presence of an NADPH-generating system, the inhibitory effects of 1 µm verapamil and 1 µm diltiazem on testosterone 6β-hydroxylation were investigated in microsomes prepared from 10 different human livers (Figure 5a,b). For each human liver, CYP3A4 activity was decreased significantly by preincubation with either verapamil or diltiazem (P < 0.05). Mean testosterone 6β-hydroxylase activity for all 10 human livers was reduced significantly from 1.22 ± 0.43–0.70 ± 0.27 nmol min−1 mg−1 protein (P < 0.05) after preincubation with verapamil. Testosterone 6β-hydroxylase activity after preincubation with diltiazem was reduced to 1.01 ± 0.39 nmol min−1 mg−1 protein. This was not significantly different from the control activity.
Absolute reduction in testosterone 6β-hydroxylase activity after preincubation with verapamil was significantly correlated with baseline CYP3A4 activity (rs = 0.95; P < 0.001). Thus, more extensive inactivation was observed in microsomes with a higher baseline activity (Figure 5a). On preincubation with diltiazem, absolute reduction in CYP3A4 was not highly correlated with baseline activity (rs = 0.51).
Kinetics of CYP3A inactivation by verapamil and diltiazem
Mean (± s.d., n = 3 livers) kinact and KI values were 0.15 ± 0.04 min−1 and 2.9 ± 0.6 µm, respectively, for verapamil and 0.07 ± 0.01 min−1 and 3.3 ± 1.5 µm, respectively, for diltiazem (Table 1, Figure 6). The potency of CYP3A4 inactivation by verapamil and diltiazem was characterized further by calculation of the respective partition ratios, defined as moles inhibitor metabolized per moles enzyme inactivated. These values were found to be 10.3 ± 2.0 at 1 µm verapamil and 19.7 ± 1.1 at 5 µm diltiazem.
Discussion
The results of the present study demonstrate that verapamil and diltiazem inhibit simvastatin metabolism in human liver microsomes and that verapamil is the more potent inhibitor. The IC50 values determined from the coincubation experiments range from 23 to 26 µm, for verapamil and from 110 to 127 µm for diltiazem. The inhibitory potency of each drug was increased approximately fivefold on preincubation with human liver microsomes in the presence of an NADPH-generating system. Thus, the metabolites of verapamil and diltiazem are much more potent inhibitors of simvastatin metabolism than the parent drugs. The fact that the IC50 values were similar to those obtained when using the probe CYP3A4 substrate testosterone, confirms that verapamil and diltiazem inhibit the CYP3A4-mediated metabolism of simvastatin.
Testosterone 6β-hydroxylation was inhibited in a time-and concentration-dependent manner by verapamil and diltiazem showed a trend towards saturation of the inactivation rate. The loss of catalytic activity was also dependent on the presence of an NADPH generating system. The mean values of kinact and KI for verapamil were 0.15 ± 0.04 min−1 and 2.9 ± 0.6 µm, respectively. At 1 µm verapamil, the partition ratio was estimated to be 10.3 ± 20. The values of kinact, KI and partition ratio for other mechanism-based inhibitors of CYP3A4 that have been investigated are: 1.6 min−1, 7.5 µm and 1.35, respectively, for L-754 394 [21]; 0.4 min−1, 46 µm and 9.0, respectively, for gestodene [22]; and 0.4 min−1, 2.3 µm and 1.7, respectively, for mibedrafil [7]. Of the four drugs, verapamil has the highest partition ratio. This indicates that a higher number of molecules of verapamil have to be metabolized to inactivate the same amount of enzyme as the other three drugs. Furthermore, the kinact value of verapamil is 2.7-fold lower than that of mibefradil and gestodene, and 11-fold lower than that of L-754 394. This suggests that verapamil has a lower efficiency of inactivation and is a moderate mechanism-based inhibitor of CYP3A4 compared with other drugs that have been studied so far. In the present study, the mean kinact and KI values for diltiazem were 0.07 ± 0.01 min−1 and 3.3 ± 1.5 µm, respectively. At 5 µm diltiazem, the partition ratio was estimated to be 19.7 ± 1.1. These values indicate that diltiazem is less efficient than verapamil as an inactivator of CYP3A4. Jones et al. [14] reported kinact and KI values of 0.17 min−1 and 2.2 µm, respectively, for formation of a metabolite-intermediate complex by diltiazem in microsomes from human lymphoblastoid cells expressing CYP3A4(+ b5). The 2.4-fold lower kinact value obtained in our study may be due in part to the confounding presence of CYP3A5 in human liver microsomes. This enzyme can metabolize testosterone and also undergoes mechanism-based inactivation by diltiazem, but to a lesser degree than CYP3A4 [14]. It is also possible that other cytochrome P450s may have contributed to the metabolism of testosterone at the high substrate concentration of 250 µm, which was used to determine remaining CYP3A4 activity. The net result would be an underestimation of the inactivation rate of CYP3A4. Ma et al. [15] reported kinact and KI values of 0.03 min−1 and 0.5 µm for verapamil and 0.01 min−1 and 0.5 µm for diltiazem. The methodology was not described in detail and therefore it is not possible to explain the 5- to 10-fold differences observed between their values and those obtained in our study.
Myopathy, which can rarely present as rhabdomyolysis, is an uncommon but serious side-effect of statin treatment and occurs in 0.1% of patients treated with standard doses of simvastatin [1]. The onset of acute rhabdomyolysis has been associated with dramatic increases in plasma concentrations of HMG-CoA reductase inhibitory activity, due to inhibition of simvastatin metabolism by drugs such as itraconazole [3] or mibefradil [4] that have been introduced to the dosing regimen of simvastatin. The results of this study indicate that the degree of inhibition of simvastatin metabolism by verapamil and diltiazem is much lower than that observed with mibefradil, a known potent inhibitor of CYP3A4 in vitro and in vivo [4, 7]. The IC50 values for coincubation of verapamil and diltiazem are 46-and 220-fold higher, respectively, than those reported for mibefradil, and 16- and 71-fold higher, respectively, for preincubation. These data suggest that verapamil and diltiazem are much less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and may still cause significant inhibition of CYP3A4-mediated metabolism of simvastatin in vivo during chronic therapy. The enzyme is continuously being regenerated in vivo and therefore the extent of CYP3A4 inactivation will be dependent on the turnover rate of the enzyme, as well as the inactivation parameters of the inhibitors. The fact that verapamil and diltiazem are less efficient CYP3A4 inactivators than mibefradil and other mechanism-based inhibitors studied so far, further suggests that they are less likely to cause severe drug interactions with simvastatin in vivo. To date, there have been no reports of rhabdomyolysis induced by a simvastatin–verapamil interaction and only one that was possibly induced by a simvastatin–diltiazem interaction [1].
The effects of verapamil and diltiazem on the pharmacokinetics of simvastatin and the closely related HMG-CoA reductase inhibitor, lovastatin have been investigated in healthy volunteers [11, 23]. Verapamil caused a 4.6-fold increase in the mean area under the concentration (AUC)-time curve of simvastatin [23] and diltiazem caused a fourfold increase in the mean AUC of lovastatin [11]. Verapamil (240 mg once daily) was administered for 2 days prior to simvastatin dosing, whereas the same dose of diltiazem was taken for 2 weeks prior to lovastatin dosing. The degree of interaction is dependent on CYP3A4 activity remaining after the period of administration of the mechanism-based inhibitors, which in turn is dependent on final inhibitor concentrations attained in vivo. Pretreatment with verapamil for 2 days, may not have been long enough for the inhibitor to evoke its maximum effect, thus resulting in an underestimation of the magnitude of the interaction with simvastatin. The increase in AUC of simvastatin caused by pretreatment with verapamil ranged from 1.5- to 17-fold among the 12 volunteers and the diltiazem-induced increase in lovastatin AUC ranged from 1.5- to 10.1-fold in the 10 subjects investigated. In both studies, the magnitude of interaction for each subject was dependent on their baseline hepatic CYP3A4 activity. Volunteers with high baseline activity experienced greater magnitudes of interaction whereas those with low baseline CYP3A4 activity experienced lower levels of interaction. The net result was a reduction in interindividual variability of simvastatin and lovastatin AUC after pretreatment with verapamil and diltiazem, respectively. The results of the present study reflect those obtained in vivo. Absolute reduction in testosterone 6β-hydroxylase activity after preincubation with verapamil was highly correlated with baseline CYP3A4 activity (rs = 0.95; P < 0.001). For diltiazem, the correlation was not significant but there was a definite trend. Greater inactivation was observed in human liver microsomes that had a higher baseline CYP3A4 activity. The net result was a reduction in variability of baseline CYP3A4 activity between livers (Figure 5a,b). This may have important clinical implications for the cholesterol-lowering response to simvastatin in individuals who are also taking verapamil or diltiazem. The results of a retrospective study reported previously by our group demonstrated that there was enhanced cholesterol reduction in patients who were taking simvastatin and diltiazem concurrently, and the interindividual variability in cholesterol-lowering response to simvastatin was significantly lower for patients taking diltiazem than for patients not taking diltiazem [24]. To date, no studies have been reported regarding the effect of verapamil on the cholesterol-lowering response to simvastatin.
Drug interactions with verapamil and diltiazem are likely to occur with other HMGCoA reductase inhibitors that are metabolized by CYP3A4, namely, atorvastatin and cerivastatin. However, the magnitude of interaction of these two statins with potent CYP3A4 inhibitors such as erythromycin, appears to be lower than those observed with simvastatin and lovastatin [25, 26]. Fluvastatin is metabolized primarily by CYP2C8/9 and is therefore unlikely to have a clinically significant interaction with either of the calcium channel blockers [27]. Similarly, metabolism is a minor route of pravastatin elimination, and CYP3A4 does not contribute significantly to the hepatic clearance of the drug [27].
According to the National Service Framework [28], approximately 8% of the UK population require statin treatment for secondary or primary prevention of coronary heart disease [29]. Co-prescription of simvastatin with one of the calcium channel blockers verapamil or diltiazem is likely to occur commonly. The findings of this study demonstrate that verapamil and diltiazem are not potent inhibitors of simvastatin metabolism in human liver microsomes. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.
Acknowledgments
We thank Merck Research Laboratories for providing the simvastatin. We also wish to thank Professor G.T. Tucker for providing the human liver microsomes and laboratory facilities.
References
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PROTEUS
'A GUI FOR DRAT'
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{{ list.name }}
Run DRAT!


I am a 3rd-year data scientist at Netmarble AI Center. I received M.S. in Computer Science & Engineering from Seoul National University, where I was privileged to be advised by Prof. Chong-kwon Kim. I received B.S. in Computer Science from Purdue University, West Lafayette. My research interests include data mining and graph neural networks.
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Bot Detection Model for Collusive Workers, Macro, and Automated Programs in Online Games
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This test is designed to cover common patterns used in application:
require(["[./a]","./b"])
require(["./a","./b"])
require(["../test/a","./a"])
require(["../test/a","./a"])
Surprisingly AMD as a standard still have a bit of hiccups.
Treating relative URLs on HTML level from global require is not a part of standard.
Plugins should be relative path aware, some AMD implementations on top level require() are missing those.
The MID could be used as argument rather as array of MIDs. Dojo fails to register such.
Work around: use AMD module ( PageRequire ) to replace top-level require()
.
The PageRequire will take current page URL and adjust relative MIDs to be relative to own module before
invoking the local require
version.


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Yes! Joining is free, tickets are free, and there’s nothing to pay at the door either. You just pay for your own drinks and food at the bar.
Is this for me?
If you know what a diacritic is, chances are you’re going to enjoy the evening. If you don’t, well you’re in for a treat – it’ll be a great opportunity to learn.
If you’re working with type, like it, or want to get into it, whether it’s designing it or using it, you’ll be right at home.
Essentially, if you like the idea of chatting with typographers, type designers, web developers, book designers, technologists, text designers, about fonts — then this is definitely for you. It's a great way to stay in touch with the community and keep up with what's happening in the type world.
What can I expect?
Opinionated chats about the use and misuse of fonts, feedback on material brought by members of the club and occasionally we might also have a presentation by a special guest. All of that in the usual comfortable atmosphere of a British pub.
It’s like having a drink with your friends, except they actually listen to you when you suddenly get passionate about fonts.
Should I bring anything?
Anyone can bring type specimens, books or work in progress but also we usually sketch, draw and sometimes linocut throughout the evening.
The group generally discusses the latest news in type, branding and design, so we recommend bringing some conversation material, but even that is not required.
What’s required of me then?
The type world can be scary and unapproachable and to change that we need you need to be friendly and courteous.
When talking about someone else’s work, please keep in mind that working with type can be very time consuming and takes a lot of effort. Try to explain why you think a certain way and provide constructive feedback or offer suggestions of improvements.
We will not tolerate any form of harassment.
I wish I could talk about fonts every day!
Well, you’re in luck because the community chats online regularly using Slack, a chat application that works in your browser, your phone and your desktop.
Create a free account and join the conversation.


I am a Student at Northeastern Illinois University prusuing a Bachelor's in Environmental Studies with a minor in Geographic Information Systems
Created for Wespath Investments Management, detailing Carbon emisisons of employees who use public transportation
Co creators- Destinie Green and Dylan Brockland
Map of Wespath Carbon emission by private vehicle
Co creators- Destinie Green and Dylan Brockland
Map of Train lines and bike paths, with facility position highlighted
Co creators- Destinie Green and Dylan Brockland
GPA: Work In Progress
GPA: 3.75
Interested in passing this class
Passionate about the environment and especially marine biology. I enjoy hiking whenever I can get the time, and reading as many books as I can.


--- layout: page title: Abrigo Patterns description: A UI library for standardizing Abrigo components --- Welcome to a Pattern library for Abrigo! Here you will find standards of design and component development. Giving clear and succinct instructions of use case and implementation is key in collaboration and will minimize reworking common used components/elements.
## Design System Benefits Explain how the design system benefits users and the business. For inspiration, check out over 180 examples of design systems at [Styleguides.io](http://styleguides.io/examples). tivizes teams to use the system, and shows components in the wild. ## Contributing info If it's desirable to have people from across the organization contribute to the design system, linking to the contributing page from the homepage could be a good idea.


| ACCEPTED_LANGUAGES |
The list of languages accepted by the client (they can be set in the browser) |
| AUTH_USER |
User name if basic HTTP authentication is used |
| AUTH_PASSWORD |
User password if basic HTTP authentication is used |
| Authentication |
Function used for basic HTTP Authentication |
| CONFIG |
Configuration options, as set in the command line or in the configuration file
Attributes
| serverDir |
Directory where the Karrigell.py script stands |
| rootDir |
Root directory, from where files and scripts are served |
| outputEncoding |
The encoding used for output |
|
| COOKIE |
The cookies sent by the client to the server. Instance of the SimpleCookie class
in Python cookie module |
| HEADERS |
The request headers, sent by the user agent (browser) to the server |
| HTTP_REDIRECTION |
raise HTTP_REDIRECTION,url performs an HTTP redirection (302) to the
specified url |
| Include() |
Function used to include a file or a script in another script |
| PATH |
Script path |
| QUERY |
When a script receives form data, QUERY is a dictionary mapping field names
to field values |
| REQUEST |
When a script receives form data, REQUEST is a dictionary mapping field names
to field values (same as QUERY) |
| REQUEST_HANDLER |
An object representing the current request handler
Attributes
| client_address |
A tuple with client IP address and port,
for example ('<IP_ADDRESS>', 1825) |
| command |
The HTTP command or method (usually GET or
POST )
|
| encoding |
The encoding as returned by function guess_type in built-in
module mimetypes |
|
| RESPONSE |
The response headers sent by the server to the client, such as Content-type |
| RestrictToAdmin() |
Function used to restrict access of the script to the site administrator |
| SCRIPT_END |
Exception to stop the script execution |
| SCRIPT_ERROR |
raise SCRIPT_ERROR,msg to stop the execution of script and write msg |
| Session() |
Function that returns the session object |
| SET_COOKIE |
The Cookies sent by the server to the client. Instance of the SimpleCookie class in
Python cookie module |
| THIS |
An object representing the current script. The examples suppose that the script
path in the filesystem is C:\cygwin\home\Karrigell\webapps\demo ,
and that it is called by the url demo/thisTest.pih
Attributes
| basename |
Script base name (thisTest.pih ) |
| baseurl |
Part of the url before the script name (demo/ ) |
| code |
The script source code (or the conversion into Python code for
pih scripts)
|
| dirname |
Directory name (C:\cygwin\home\Karrigell\webapps\demo ) |
| extension |
Script extention (pih ) |
| name |
Full name of the script in the file system
(C:\cygwin\home\Karrigell\webapps\demo\thisTest.pih ) |
| parent |
The script's parent if it was included by the Include() function,
or None |
| path |
The path used by the client to request the script , including the
query string if there was one
(/demo/thisTest.pih) |
| subpath |
If the script is requested with additional arguments separated
by /, subpath is the list of these argements (see
"smart urls") |
| url |
The url used to request the script, stripped from the query string
if there was one (/demo/thisTest.pih) |
|


SUBROUTINE SGGES( JOBVSL, JOBVSR, SORT, SELCTG, N, A, LDA, B, LDB, $ SDIM, ALPHAR, ALPHAI, BETA, VSL, LDVSL, VSR, $ LDVSR, WORK, LWORK, BWORK, INFO ) * * -- LAPACK driver routine (version 3.1) -- * Univ. of Tennessee, Univ. of California Berkeley and NAG Ltd.. * November 2006 * * .. Scalar Arguments .. CHARACTER JOBVSL, JOBVSR, SORT INTEGER INFO, LDA, LDB, LDVSL, LDVSR, LWORK, N, SDIM * .. * .. Array Arguments .. LOGICAL BWORK( * ) REAL A( LDA, * ), ALPHAI( * ), ALPHAR( * ), $ B( LDB, * ), BETA( * ), VSL( LDVSL, * ), $ VSR( LDVSR, * ), WORK( * ) * .. * .. Function Arguments .. LOGICAL SELCTG EXTERNAL SELCTG * .. * * Purpose * ======= * * SGGES computes for a pair of N-by-N real nonsymmetric matrices (A,B), * the generalized eigenvalues, the generalized real Schur form (S,T), * optionally, the left and/or right matrices of Schur vectors (VSL and * VSR). This gives the generalized Schur factorization * * (A,B) = ( (VSL)*S*(VSR)**T, (VSL)*T*(VSR)**T ) * * Optionally, it also orders the eigenvalues so that a selected cluster * of eigenvalues appears in the leading diagonal blocks of the upper * quasi-triangular matrix S and the upper triangular matrix T.The * leading columns of VSL and VSR then form an orthonormal basis for the * corresponding left and right eigenspaces (deflating subspaces). * * (If only the generalized eigenvalues are needed, use the driver * SGGEV instead, which is faster.) * * A generalized eigenvalue for a pair of matrices (A,B) is a scalar w * or a ratio alpha/beta = w, such that A - w*B is singular. It is * usually represented as the pair (alpha,beta), as there is a * reasonable interpretation for beta=0 or both being zero. * * A pair of matrices (S,T) is in generalized real Schur form if T is * upper triangular with non-negative diagonal and S is block upper * triangular with 1-by-1 and 2-by-2 blocks. 1-by-1 blocks correspond * to real generalized eigenvalues, while 2-by-2 blocks of S will be * "standardized" by making the corresponding elements of T have the * form: * [ a 0 ] * [ 0 b ] * * and the pair of corresponding 2-by-2 blocks in S and T will have a * complex conjugate pair of generalized eigenvalues. * * * Arguments * ========= * * JOBVSL (input) CHARACTER*1 * = 'N': do not compute the left Schur vectors; * = 'V': compute the left Schur vectors. * * JOBVSR (input) CHARACTER*1 * = 'N': do not compute the right Schur vectors; * = 'V': compute the right Schur vectors. * * SORT (input) CHARACTER*1 * Specifies whether or not to order the eigenvalues on the * diagonal of the generalized Schur form. * = 'N': Eigenvalues are not ordered; * = 'S': Eigenvalues are ordered (see SELCTG); * * SELCTG (external procedure) LOGICAL FUNCTION of three REAL arguments * SELCTG must be declared EXTERNAL in the calling subroutine. * If SORT = 'N', SELCTG is not referenced. * If SORT = 'S', SELCTG is used to select eigenvalues to sort * to the top left of the Schur form. * An eigenvalue (ALPHAR(j)+ALPHAI(j))/BETA(j) is selected if * SELCTG(ALPHAR(j),ALPHAI(j),BETA(j)) is true; i.e. if either * one of a complex conjugate pair of eigenvalues is selected, * then both complex eigenvalues are selected. * * Note that in the ill-conditioned case, a selected complex * eigenvalue may no longer satisfy SELCTG(ALPHAR(j),ALPHAI(j), * BETA(j)) = .TRUE. after ordering. INFO is to be set to N+2 * in this case. * * N (input) INTEGER * The order of the matrices A, B, VSL, and VSR. N >= 0. * * A (input/output) REAL array, dimension (LDA, N) * On entry, the first of the pair of matrices. * On exit, A has been overwritten by its generalized Schur * form S. * * LDA (input) INTEGER * The leading dimension of A. LDA >= max(1,N). * * B (input/output) REAL array, dimension (LDB, N) * On entry, the second of the pair of matrices. * On exit, B has been overwritten by its generalized Schur * form T. * * LDB (input) INTEGER * The leading dimension of B. LDB >= max(1,N). * * SDIM (output) INTEGER * If SORT = 'N', SDIM = 0. * If SORT = 'S', SDIM = number of eigenvalues (after sorting) * for which SELCTG is true. (Complex conjugate pairs for which * SELCTG is true for either eigenvalue count as 2.) * * ALPHAR (output) REAL array, dimension (N) * ALPHAI (output) REAL array, dimension (N) * BETA (output) REAL array, dimension (N) * On exit, (ALPHAR(j) + ALPHAI(j)*i)/BETA(j), j=1,...,N, will * be the generalized eigenvalues. ALPHAR(j) + ALPHAI(j)*i, * and BETA(j),j=1,...,N are the diagonals of the complex Schur * form (S,T) that would result if the 2-by-2 diagonal blocks of * the real Schur form of (A,B) were further reduced to * triangular form using 2-by-2 complex unitary transformations. * If ALPHAI(j) is zero, then the j-th eigenvalue is real; if * positive, then the j-th and (j+1)-st eigenvalues are a * complex conjugate pair, with ALPHAI(j+1) negative. * * Note: the quotients ALPHAR(j)/BETA(j) and ALPHAI(j)/BETA(j) * may easily over- or underflow, and BETA(j) may even be zero. * Thus, the user should avoid naively computing the ratio. * However, ALPHAR and ALPHAI will be always less than and * usually comparable with norm(A) in magnitude, and BETA always * less than and usually comparable with norm(B). * * VSL (output) REAL array, dimension (LDVSL,N) * If JOBVSL = 'V', VSL will contain the left Schur vectors. * Not referenced if JOBVSL = 'N'. * * LDVSL (input) INTEGER * The leading dimension of the matrix VSL. LDVSL >=1, and * if JOBVSL = 'V', LDVSL >= N. * * VSR (output) REAL array, dimension (LDVSR,N) * If JOBVSR = 'V', VSR will contain the right Schur vectors. * Not referenced if JOBVSR = 'N'. * * LDVSR (input) INTEGER * The leading dimension of the matrix VSR. LDVSR >= 1, and * if JOBVSR = 'V', LDVSR >= N. * * WORK (workspace/output) REAL array, dimension (MAX(1,LWORK)) * On exit, if INFO = 0, WORK(1) returns the optimal LWORK. * * LWORK (input) INTEGER * The dimension of the array WORK. * If N = 0, LWORK >= 1, else LWORK >= max(8*N,6*N+16). * For good performance , LWORK must generally be larger. * * If LWORK = -1, then a workspace query is assumed; the routine * only calculates the optimal size of the WORK array, returns * this value as the first entry of the WORK array, and no error * message related to LWORK is issued by XERBLA. * * BWORK (workspace) LOGICAL array, dimension (N) * Not referenced if SORT = 'N'. * * INFO (output) INTEGER * = 0: successful exit * < 0: if INFO = -i, the i-th argument had an illegal value. * = 1,...,N: * The QZ iteration failed. (A,B) are not in Schur * form, but ALPHAR(j), ALPHAI(j), and BETA(j) should * be correct for j=INFO+1,...,N. * > N: =N+1: other than QZ iteration failed in SHGEQZ. * =N+2: after reordering, roundoff changed values of * some complex eigenvalues so that leading * eigenvalues in the Generalized Schur form no * longer satisfy SELCTG=.TRUE. This could also * be caused due to scaling. * =N+3: reordering failed in STGSEN. * * ===================================================================== * * .. Parameters .. REAL ZERO, ONE PARAMETER ( ZERO = 0.0E+0, ONE = 1.0E+0 ) * .. * .. Local Scalars .. LOGICAL CURSL, ILASCL, ILBSCL, ILVSL, ILVSR, LASTSL, $ LQUERY, LST2SL, WANTST INTEGER I, ICOLS, IERR, IHI, IJOBVL, IJOBVR, ILEFT, $ ILO, IP, IRIGHT, IROWS, ITAU, IWRK, MAXWRK, $ MINWRK REAL ANRM, ANRMTO, BIGNUM, BNRM, BNRMTO, EPS, PVSL, $ PVSR, SAFMAX, SAFMIN, SMLNUM * .. * .. Local Arrays .. INTEGER IDUM( 1 ) REAL DIF( 2 ) * .. * .. External Subroutines .. EXTERNAL SGEQRF, SGGBAK, SGGBAL, SGGHRD, SHGEQZ, SLABAD, $ SLACPY, SLASCL, SLASET, SORGQR, SORMQR, STGSEN, $ XERBLA * .. * .. External Functions .. LOGICAL LSAME INTEGER ILAENV REAL SLAMCH, SLANGE EXTERNAL LSAME, ILAENV, SLAMCH, SLANGE * .. * .. Intrinsic Functions .. INTRINSIC ABS, MAX, SQRT * .. * .. Executable Statements .. * * Decode the input arguments * IF( LSAME( JOBVSL, 'N' ) ) THEN IJOBVL = 1 ILVSL = .FALSE. ELSE IF( LSAME( JOBVSL, 'V' ) ) THEN IJOBVL = 2 ILVSL = .TRUE. ELSE IJOBVL = -1 ILVSL = .FALSE. END IF * IF( LSAME( JOBVSR, 'N' ) ) THEN IJOBVR = 1 ILVSR = .FALSE. ELSE IF( LSAME( JOBVSR, 'V' ) ) THEN IJOBVR = 2 ILVSR = .TRUE. ELSE IJOBVR = -1 ILVSR = .FALSE. END IF * WANTST = LSAME( SORT, 'S' ) * * Test the input arguments * INFO = 0 LQUERY = ( LWORK.EQ.-1 ) IF( IJOBVL.LE.0 ) THEN INFO = -1 ELSE IF( IJOBVR.LE.0 ) THEN INFO = -2 ELSE IF( ( .NOT.WANTST ) .AND. ( .NOT.LSAME( SORT, 'N' ) ) ) THEN INFO = -3 ELSE IF( N.LT.0 ) THEN INFO = -5 ELSE IF( LDA.LT.MAX( 1, N ) ) THEN INFO = -7 ELSE IF( LDB.LT.MAX( 1, N ) ) THEN INFO = -9 ELSE IF( LDVSL.LT.1 .OR. ( ILVSL .AND. LDVSL.LT.N ) ) THEN INFO = -15 ELSE IF( LDVSR.LT.1 .OR. ( ILVSR .AND. LDVSR.LT.N ) ) THEN INFO = -17 END IF * * Compute workspace * (Note: Comments in the code beginning "Workspace:" describe the * minimal amount of workspace needed at that point in the code, * as well as the preferred amount for good performance. * NB refers to the optimal block size for the immediately * following subroutine, as returned by ILAENV.) * IF( INFO.EQ.0 ) THEN IF( N.GT.0 )THEN MINWRK = MAX( 8*N, 6*N + 16 ) MAXWRK = MINWRK - N + $ N*ILAENV( 1, 'SGEQRF', ' ', N, 1, N, 0 ) MAXWRK = MAX( MAXWRK, MINWRK - N + $ N*ILAENV( 1, 'SORMQR', ' ', N, 1, N, -1 ) ) IF( ILVSL ) THEN MAXWRK = MAX( MAXWRK, MINWRK - N + $ N*ILAENV( 1, 'SORGQR', ' ', N, 1, N, -1 ) ) END IF ELSE MINWRK = 1 MAXWRK = 1 END IF WORK( 1 ) = MAXWRK * IF( LWORK.LT.MINWRK .AND. .NOT.LQUERY ) $ INFO = -19 END IF * IF( INFO.NE.0 ) THEN CALL XERBLA( 'SGGES ', -INFO ) RETURN ELSE IF( LQUERY ) THEN RETURN END IF * * Quick return if possible * IF( N.EQ.0 ) THEN SDIM = 0 RETURN END IF * * Get machine constants * EPS = SLAMCH( 'P' ) SAFMIN = SLAMCH( 'S' ) SAFMAX = ONE / SAFMIN CALL SLABAD( SAFMIN, SAFMAX ) SMLNUM = SQRT( SAFMIN ) / EPS BIGNUM = ONE / SMLNUM * * Scale A if max element outside range [SMLNUM,BIGNUM] * ANRM = SLANGE( 'M', N, N, A, LDA, WORK ) ILASCL = .FALSE. IF( ANRM.GT.ZERO .AND. ANRM.LT.SMLNUM ) THEN ANRMTO = SMLNUM ILASCL = .TRUE. ELSE IF( ANRM.GT.BIGNUM ) THEN ANRMTO = BIGNUM ILASCL = .TRUE. END IF IF( ILASCL ) $ CALL SLASCL( 'G', 0, 0, ANRM, ANRMTO, N, N, A, LDA, IERR ) * * Scale B if max element outside range [SMLNUM,BIGNUM] * BNRM = SLANGE( 'M', N, N, B, LDB, WORK ) ILBSCL = .FALSE. IF( BNRM.GT.ZERO .AND. BNRM.LT.SMLNUM ) THEN BNRMTO = SMLNUM ILBSCL = .TRUE. ELSE IF( BNRM.GT.BIGNUM ) THEN BNRMTO = BIGNUM ILBSCL = .TRUE. END IF IF( ILBSCL ) $ CALL SLASCL( 'G', 0, 0, BNRM, BNRMTO, N, N, B, LDB, IERR ) * * Permute the matrix to make it more nearly triangular * (Workspace: need 6*N + 2*N space for storing balancing factors) * ILEFT = 1 IRIGHT = N + 1 IWRK = IRIGHT + N CALL SGGBAL( 'P', N, A, LDA, B, LDB, ILO, IHI, WORK( ILEFT ), $ WORK( IRIGHT ), WORK( IWRK ), IERR ) * * Reduce B to triangular form (QR decomposition of B) * (Workspace: need N, prefer N*NB) * IROWS = IHI + 1 - ILO ICOLS = N + 1 - ILO ITAU = IWRK IWRK = ITAU + IROWS CALL SGEQRF( IROWS, ICOLS, B( ILO, ILO ), LDB, WORK( ITAU ), $ WORK( IWRK ), LWORK+1-IWRK, IERR ) * * Apply the orthogonal transformation to matrix A * (Workspace: need N, prefer N*NB) * CALL SORMQR( 'L', 'T', IROWS, ICOLS, IROWS, B( ILO, ILO ), LDB, $ WORK( ITAU ), A( ILO, ILO ), LDA, WORK( IWRK ), $ LWORK+1-IWRK, IERR ) * * Initialize VSL * (Workspace: need N, prefer N*NB) * IF( ILVSL ) THEN CALL SLASET( 'Full', N, N, ZERO, ONE, VSL, LDVSL ) IF( IROWS.GT.1 ) THEN CALL SLACPY( 'L', IROWS-1, IROWS-1, B( ILO+1, ILO ), LDB, $ VSL( ILO+1, ILO ), LDVSL ) END IF CALL SORGQR( IROWS, IROWS, IROWS, VSL( ILO, ILO ), LDVSL, $ WORK( ITAU ), WORK( IWRK ), LWORK+1-IWRK, IERR ) END IF * * Initialize VSR * IF( ILVSR ) $ CALL SLASET( 'Full', N, N, ZERO, ONE, VSR, LDVSR ) * * Reduce to generalized Hessenberg form * (Workspace: none needed) * CALL SGGHRD( JOBVSL, JOBVSR, N, ILO, IHI, A, LDA, B, LDB, VSL, $ LDVSL, VSR, LDVSR, IERR ) * * Perform QZ algorithm, computing Schur vectors if desired * (Workspace: need N) * IWRK = ITAU CALL SHGEQZ( 'S', JOBVSL, JOBVSR, N, ILO, IHI, A, LDA, B, LDB, $ ALPHAR, ALPHAI, BETA, VSL, LDVSL, VSR, LDVSR, $ WORK( IWRK ), LWORK+1-IWRK, IERR ) IF( IERR.NE.0 ) THEN IF( IERR.GT.0 .AND. IERR.LE.N ) THEN INFO = IERR ELSE IF( IERR.GT.N .AND. IERR.LE.2*N ) THEN INFO = IERR - N ELSE INFO = N + 1 END IF GO TO 40 END IF * * Sort eigenvalues ALPHA/BETA if desired * (Workspace: need 4*N+16 ) * SDIM = 0 IF( WANTST ) THEN * * Undo scaling on eigenvalues before SELCTGing * IF( ILASCL ) THEN CALL SLASCL( 'G', 0, 0, ANRMTO, ANRM, N, 1, ALPHAR, N, $ IERR ) CALL SLASCL( 'G', 0, 0, ANRMTO, ANRM, N, 1, ALPHAI, N, $ IERR ) END IF IF( ILBSCL ) $ CALL SLASCL( 'G', 0, 0, BNRMTO, BNRM, N, 1, BETA, N, IERR ) * * Select eigenvalues * DO 10 I = 1, N BWORK( I ) = SELCTG( ALPHAR( I ), ALPHAI( I ), BETA( I ) ) 10 CONTINUE * CALL STGSEN( 0, ILVSL, ILVSR, BWORK, N, A, LDA, B, LDB, ALPHAR, $ ALPHAI, BETA, VSL, LDVSL, VSR, LDVSR, SDIM, PVSL, $ PVSR, DIF, WORK( IWRK ), LWORK-IWRK+1, IDUM, 1, $ IERR ) IF( IERR.EQ.1 ) $ INFO = N + 3 * END IF * * Apply back-permutation to VSL and VSR * (Workspace: none needed) * IF( ILVSL ) $ CALL SGGBAK( 'P', 'L', N, ILO, IHI, WORK( ILEFT ), $ WORK( IRIGHT ), N, VSL, LDVSL, IERR ) * IF( ILVSR ) $ CALL SGGBAK( 'P', 'R', N, ILO, IHI, WORK( ILEFT ), $ WORK( IRIGHT ), N, VSR, LDVSR, IERR ) * * Check if unscaling would cause over/underflow, if so, rescale * (ALPHAR(I),ALPHAI(I),BETA(I)) so BETA(I) is on the order of * B(I,I) and ALPHAR(I) and ALPHAI(I) are on the order of A(I,I) * IF( ILASCL )THEN DO 50 I = 1, N IF( ALPHAI( I ).NE.ZERO ) THEN IF( ( ALPHAR( I )/SAFMAX ).GT.( ANRMTO/ANRM ) .OR. $ ( SAFMIN/ALPHAR( I ) ).GT.( ANRM/ANRMTO ) ) THEN WORK( 1 ) = ABS( A( I, I )/ALPHAR( I ) ) BETA( I ) = BETA( I )*WORK( 1 ) ALPHAR( I ) = ALPHAR( I )*WORK( 1 ) ALPHAI( I ) = ALPHAI( I )*WORK( 1 ) ELSE IF( ( ALPHAI( I )/SAFMAX ).GT.( ANRMTO/ANRM ) .OR. $ ( SAFMIN/ALPHAI( I ) ).GT.( ANRM/ANRMTO ) ) THEN WORK( 1 ) = ABS( A( I, I+1 )/ALPHAI( I ) ) BETA( I ) = BETA( I )*WORK( 1 ) ALPHAR( I ) = ALPHAR( I )*WORK( 1 ) ALPHAI( I ) = ALPHAI( I )*WORK( 1 ) END IF END IF 50 CONTINUE END IF * IF( ILBSCL )THEN DO 60 I = 1, N IF( ALPHAI( I ).NE.ZERO ) THEN IF( ( BETA( I )/SAFMAX ).GT.( BNRMTO/BNRM ) .OR. $ ( SAFMIN/BETA( I ) ).GT.( BNRM/BNRMTO ) ) THEN WORK( 1 ) = ABS(B( I, I )/BETA( I )) BETA( I ) = BETA( I )*WORK( 1 ) ALPHAR( I ) = ALPHAR( I )*WORK( 1 ) ALPHAI( I ) = ALPHAI( I )*WORK( 1 ) END IF END IF 60 CONTINUE END IF * * Undo scaling * IF( ILASCL ) THEN CALL SLASCL( 'H', 0, 0, ANRMTO, ANRM, N, N, A, LDA, IERR ) CALL SLASCL( 'G', 0, 0, ANRMTO, ANRM, N, 1, ALPHAR, N, IERR ) CALL SLASCL( 'G', 0, 0, ANRMTO, ANRM, N, 1, ALPHAI, N, IERR ) END IF * IF( ILBSCL ) THEN CALL SLASCL( 'U', 0, 0, BNRMTO, BNRM, N, N, B, LDB, IERR ) CALL SLASCL( 'G', 0, 0, BNRMTO, BNRM, N, 1, BETA, N, IERR ) END IF * IF( WANTST ) THEN * * Check if reordering is correct * LASTSL = .TRUE. LST2SL = .TRUE. SDIM = 0 IP = 0 DO 30 I = 1, N CURSL = SELCTG( ALPHAR( I ), ALPHAI( I ), BETA( I ) ) IF( ALPHAI( I ).EQ.ZERO ) THEN IF( CURSL ) $ SDIM = SDIM + 1 IP = 0 IF( CURSL .AND. .NOT.LASTSL ) $ INFO = N + 2 ELSE IF( IP.EQ.1 ) THEN * * Last eigenvalue of conjugate pair * CURSL = CURSL .OR. LASTSL LASTSL = CURSL IF( CURSL ) $ SDIM = SDIM + 2 IP = -1 IF( CURSL .AND. .NOT.LST2SL ) $ INFO = N + 2 ELSE * * First eigenvalue of conjugate pair * IP = 1 END IF END IF LST2SL = LASTSL LASTSL = CURSL 30 CONTINUE * END IF * 40 CONTINUE * WORK( 1 ) = MAXWRK * RETURN * * End of SGGES * END


Fire engulfs buildings in Lagos community
by Ifeoluwa AdediranThe Lagos States Emergency Agency (LASEMA) has confirmed another incident of fire outbreak in Lagos. The fire outbreak occurred at Kano street, Ebute Metta Lagos.
Firefighters were said to have arrived at the scene to quench the fire.
According to a statement by Nosa Okunbor, the spokesperson of LASEMA, several shanties in the area have been gutted by fire. The cause could not be ascertained.
“The intensity of the fire has spread to the adjoining buildings. No loss of life nor injury sustained but properties worth fortune had been destroyed,” Mr Okunbor said.
Read also: 28 hours after outbreak, first responders battle Lagos building fire
Mr Okunbor added that the Lagos State fire service, police and other first responders are at the scene of the incident working together to curtail the spread of the fire.
However, the fire truck later ran out of water.
This led to a frustrated crowd attacking the firefighters at about 3:24 p.m. The crowd also warned officials not to take photos. They said they lost properties worth millions to the fire outbreak.
The angry mob have also have hampered the recovery process with their irate attitude and constituted a source of security threat to all government officials and responders at the incident scene, Mr Okunbor said.
Nevertheless, the recovery process is still ongoing. LASEMA team and other responders still at the incident site, he said.


Enter in the text field below with the pointing device or with the keyboard (with the tab key or with the "T" accesskey) and then enter some text into it. A message in green should then have appeared on its right-hand side indicating that such text field has received focus. In order to pass this.test,the tester should not have to move the pointing device outside the text field.


Shrektastic! by blindmouseone
Shrek a large, green, physically intimidating ogre, with an accent described by Mike Myers as "a Scottish guy who's lived in Scarborough for 40 years". Even though his background is something of a mystery, in the musical, it is revealed that on his seventh birthday Shrek was sent away by his parents because it was an ogre tradition (like in the book where his parent send him away). He is seen traveling alone, either being screamed at or teased by passers-by. The only time he receives a pleasant greeting is a wave from a young Fiona, who is promptly led away by her parents. After scaring away an angry mob, he arrives at his swamp, enters an outhouse and literally breaks out as the adult Shrek. Though surly, misanthropic, and venomously cranky, Shrek is peaceful and doesn't care to hurt anyone, but he just wants to live his life in solitude and be left alone. Shrek is befriended by Donkey, an excitable, hyperactive, and talking donkey.
My Shrek Characters
| Character | Type | Picture | Habits |
|---|---|---|---|
| Shrek | Hero | Swamp dweller. Snake inflator. Peasant scarer. | |
| Lord Farquaad | Villain | Gingerbreadman tormentor. Incurable romantic. | |
| Gingerbreadman | Dubious Character | Fashionista (loves gumdrop buttons!) Friend of Muffin Man (who lives on Drury Lane). |
Characters
Shrek
Shrek lives in an Ogre Swamp, which is green and murky, like any other swamp. The swamp contains small and big ponds of muddy water and it also has geysers that squirt out mud.
Lord Farquaad
Lord Farquaad is the comically short-in-stature, ruthless ruler of Duloc.
In his pursuit of perfection, Farquaad attempts to rid his Kingdom of Fairy Tale creatures, offering a bounty for their capture and then exiling imprisoned creatures to Shrek's swamp.
Gingerbreadman
The Gingerbread Man, or "Gingy", is a live talking gingerbread man, and one of Shrek's friends. Based on the fairy tale The Gingerbread Man, he was created by The Muffin Man. He is small and a fast runner, making him difficult to catch.


Bloody Mary Mix
- ⏲ Prep time: 5 min
- 🍳 Cook time: 5 min
- 🍽 Servings: 8
Ingredients
- 1 (46 fluid ounce) bottle tomato-vegetable juice cocktail
- 1 fruit, without seeds lemons, juiced
- 1 teaspoon brown sugar
- 1 tablespoon steak sauce
- 1 tablespoon Worcestershire sauce
- 1 teaspoon prepared horseradish
- 1 teaspoon hot pepper sauce
- ½ teaspoon celery salt
Directions
- In a large pitcher, combine juice cocktail, lemon juice and brown sugar. Season with Worcestershire sauce, horseradish, hot sauce and celery salt. Cover, and refrigerate 8 to 12 hours to allow flavors to meld.
Contribution
Front3ndNinja - Website
Recipe tags:
drink
sweet
breakfast


'We've hit a new low' - Ireland fans criticise Eriksen chant
by James CoxIreland fans criticised those who took part in a chant aimed at Christian Eriksen during Ireland's 1-1 Euro 2020 qualifying draw with Denmark at the Aviva Stadium last night.
Ireland put in a great performance but ultimately fell just short of qualification, with the play-offs to come.
Denmark's star man Eriksen didn't have a great game but some fans felt chants aimed at him during the game were a step too far.
They stemmed from rumours about an affair between Eriksen's partner and his Tottenham teammate Jan Vertonghen.
Eriksen subsequently rubbished the rumour but he was targeted with chants of "Jan Vertonghen, he's shagging your wife".
While a large number of Irish fans took part, they've been criticised by others who felt it was out of order.


It includes functions for applying methodologies utilized for single-process kinetic analysis of solid-state processes were recently summarized and described in the Recommendation of ICTAC Kinetic Committee. These methods work with the basic kinetic equation. The Methodologies included refers to Avrami, Friedman, Kissinger, Ozawa, OFM, Mo, Starink, isoconversional methodology (Vyazovkin) according to ICATAC Kinetics Committee recommendations as reported in Vyazovkin S, Chrissafis K, Di Lorenzo ML, et al. ICTAC Kinetics Committee recommendations for collecting experimental thermal analysis data for kinetic computations. Thermochim Acta. 2014;590:1-23. <doi:10.1016/J.TCA.2014.05.036> .
| Version: | 0.1.0 |
| Imports: | MASS, devEMF, segmented, sfsmisc, smoother, pracma, data.table, broom, colorRamps, minpack.lm, tools, baseline, graphics |
| Published: | 2018-08-31 |
| Author: | Serena Berretta [aut] and Giorgio Luciano [aut,cre], Kristian Hovde Liland [ctb] |
| Maintainer: | Serena Berretta <serena.berretta at ge.imati.cnr.it> |
| License: | GPL-2 |
| NeedsCompilation: | no |
| CRAN checks: | takos results |
| Reference manual: | takos.pdf |
| Package source: | takos_0.1.0.tar.gz |
| Windows binaries: | r-devel: takos_0.1.0.zip, r-release: takos_0.1.0.zip, r-oldrel: takos_0.1.0.zip |
| OS X binaries: | r-release: takos_0.1.0.tgz, r-oldrel: takos_0.1.0.tgz |
Please use the canonical form https://CRAN.R-project.org/package=takos to link to this page.


Collection
National curriculum assessments: information for parents
Information for parents about the 2016 key stage 1 and key stage 2 national curriculum tests (often referred to as SATs).


Dummy Heading
Professor Department of Computer Science University of Texas at Dallas
ProfessorDepartment of Computer Science University of Texas at Dallas
Senior Lecturer Department of Computer Science University of Texas at Dallas
Web DeveloperGraduate Student of Computer Science
DeveloperGraduate Student of Computer Science
UX DesignerGraduate Student of HCI
UX DesignerStudent of Arts and Technology
DataScience DeveloperGraduate Student of Computer Science
UX DesignerStudent of Game and Interactive Media Design


(Auto Save save's after every edit)
Settings save automatically!
Include scripts or styles here, for example JQuery or bootstrap. To edit the <head>
directly, do it belowarrow_downward
copyright 2019 Vibhaas Srivastava MIT LICENSE
HTML Helper was created with the aim of helping people write HTML code(especially in my school) and because I wanted to write in my own editor!
Check it out on github: open_in_newGithubCopyright 2019 Vibhaas Srivastava
Permission is hereby granted, free of charge, to any person obtaining a copy of this software and associated documentation files (the "Software"), to deal in the Software without restriction, including without limitation the rights to use, copy, modify, merge, publish, distribute, sublicense, and/or sell copies of the Software, and to permit persons to whom the Software is furnished to do so, subject to the following conditions:
The above copyright notice and this permission notice shall be included in all copies or substantial portions of the Software.
 IN NO EVENT SHALL THE AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN THE SOFTWARE.


Classes
The following classes are available globally.
-
ApolloDebugServer
is a HTTP server to communicate withapollo-client-devtools
.The server works even after the app moves to the background for a while. When the server is released, it stops itself automatically.
See moreDeclaration
Swift
public class ApolloDebugServer
extension ApolloDebugServer: DebuggableNetworkTransportDelegate
-
DebuggableNormalizedCache
is a bridge betweenApolloDebugServer
andApolloStore
.You should instantiate both
See moreApolloDebugServer
andApolloStore
with the same instance of this class.Declaration
Swift
public class DebuggableNormalizedCache
extension DebuggableNormalizedCache: NormalizedCache
-
Undocumented
See moreDeclaration
Swift
open class DebuggableRequestChainNetworkTransport : RequestChainNetworkTransport, DebuggableNetworkTransport
-
DebugInitializeInterceptor
is an interceptor that notifies that an operation begins.DebugInitializeInterceptor
is intended to be put before all the rest interceptors.Typically you don’t need to use this class directly but if you want to assemble your custom interceptor chain, you need to put this class at the right place.
See moreDeclaration
Swift
public class DebugInitializeInterceptor : ApolloInterceptor
-
DebuggableInterceptorProvider
wraps another interceptor and provides interceptors configured forApolloDeveloperKit
.
See moreDebuggableInterceptorProvider
prependsDebugInitializeInterceptor
at first, then appendsDebuggableResultTranslateInterceptor
at last only when the operation comes fromApolloDeveloperKit
.Declaration
Swift
public class DebuggableInterceptorProvider : InterceptorProvider
-
DebuggableResultTranslateInterceptor
is an interceptor that translates legacy response to GraphQLResult.Since Apollo 0.34.0, Apollo parses returned raw GraphQL response along
GraphQLSelectionSet.selections
inLegacyParsingInterceptor.interceptAsync(chain:request:response:completion:)
and store the result inHTTPResponse.parsedResponse
. This change makes it difficult to query an arbitrary operation becauseGraphQLSelectionSet.selections
cannot change its return value at runtime.However, at least for the time being we can use
HTTPResponse.legacyResponse
, which doesn’t checkGraphQLSelectionSet.selections
instead ofHTTPResponse.parsedResponse
.DebuggableResultTranslateInterceptor
is intended to be put afterLegacyParsingInterceptor
and it substitutesHTTPResponse.legacyResponse
forHTTPResponse.parsedResponse
, only when the operation comes fromApolloDeveloperKit
.Typically you don’t need to use this class directly but if you want to assemble your custom interceptor chain, you need to put this class at the right place.
See moreDeclaration
Swift
public class DebuggableResultTranslateInterceptor : ApolloInterceptor


The Typed OM is an extension to the existing CSS Object Model (CSSOM) that exposes CSS values as typed JavaScript objects, instead of a simple strings like they are today. Trying to convert strings in to meaningful types and back today can have a big performance overhead, so this will allow us to work with CSS values in a much more performant way
With the Typed OM, CSS values are now members of a new base class, CSSStyleValue
. There are a number of subclasses of the CSSStyleValue
that more precisely describe a type of CSS Value:
CSSKeywordValue
- CSS Keywords and other identifiers (like
inherit
orgrid
) CSSPositionValue
- Position (
x
andy
) values CSSImageValue
- An object representing the value properties for an image
CSSUnitValue
- Numeric values that can be expressed as a single value with single unit (like
50px
) or a single value or percentage without a unit CSSMathValue
- Complicated numeric values, like you would find with
calc
,min
, andmax
. This includes subclassesCSSMathSum
,CSSMathProduct
,CSSMathMin
,CSSMathMax
,CSSMathNegate
, andCSSMathInvert
CSSTransformValue
- A list of CSS transforms consisting of
CSSTransformComponent
s, includingCSSTranslate
,CSSRotate
,CSSScale
,CSSSkew
,CSSSkewX
,CSSSkewY
,CSSPerspective
, and/orCSSMatrixComponent


My name is Brian Munyinyi Kamau I was born in 27th October 1997.My Parents are Francis Kamau and Lydiah Wanjiru. I attended Wahundura High School and later on Moringa School where I am currently studying. Our home is at Gatundu South in Kiambu County in Kenya. I have worked in different industries as a casual labourer to sustain my living and hope to get a formal job after I graduate.
I joined programming because I've always wanted to develop applications but lacked the knowledge and resources. Moringa has been of great help to me since I now get first hand programming knowledge from Moringa's staff who will be of great help to me in achieving my programming dream.
After Moringa School I expect to gain programming experience that I will use to satisfy my application development interests by developing functioning and reliable applications.


You have arrived at an NEII Viewer experimental staging site. Users seeking robust operational data should go direct to neii.gov.au/viewer. This site is used for user acceptance testing including experimental work with supporting web data services.
Visit operational NEII Viewer


India, U.S. in talks to resolve trade issues: Raveesh Kumar
“Discussions have been going on between the two sides,” says External Affairs Ministry Spokesperson Raveesh Kumar
by ReutersIndia and the United States are in talks to resolve trade issues and both New Delhi and Washington hope to find an early solution, External Affairs Ministry Spokesperson Raveesh Kumar said on November 21.
“Discussions have been going on between the two sides,” Mr. Kumar said in a news conference.
“We remain optimistic that a solution will be found very soon,” he added.
The two countries have been locked in trade disputes for months, slapping higher tariffs on each other’s products and the U.S. withdrawing a key concession to India.


--- layout: post title: Installing Anafora Text Annotation Tool on Ubuntu Linux excerpt: How to install the Anafora Text Annotation Tool on Ubuntu Linux categories: nlp ---
As part of a project I'm currently working on we've been looking for a centralized text annotation tool that we can use. After looking at several (eHost, Brat, Semantator, Knowtator all had something that didn't meet our requirements) we found Anafora. It's pretty raw in some respects, but we were able to get it working and it seems to meet most of our requirements for now.
Since we spent a couple days working through issues I thought I'd write up a guide for how to install the tool on an Ubuntu Linux box. That has been tested on an Ubuntu Linux 14.04 EC2 instance running on Amazon Web Services utilizing Anafora version 1.0.0. We're utilizing the Apache web server.
Anafora is a Python Django web app, so it requires Python, Django and the Apache WSGI module be installed to run. The wiki document from the project was very helpful in getting this going.
Create a user and install the Anafora software in the new user's home directory using the following
sequence of commands. You will need to be logged in as a user with sudo
permissions.
sudo useradd -m -d /home/anafora anafora sudo passwd anafora sudo groupadd anaforaadmin su - anafora wget https://github.com/weitechen/anafora/archive/v1.0.0.tar.gz mv v1.0.0.tar.gz anafora-1.0.0.tar.gz tar xvfz anafora-1.0.0.tar.gz exit sudo chgrp -R www-data /home/anafora/anafora-1.0.0 sudo chmod -R g=rwx /home/anafora/anafora-1.0.0
mod_wsgi
sudo apt-get install apache2 apache2-utils python-django libapache2-mod-wsgi
mod_auth_digest
and create auth_user
file with initial user anaforasudo ln -sf /etc/apache2/mods-available/auth_digest.load /etc/apache2/mods-enabled/auth-digest.load su - anafora htdigest -c /home/anafora/anafora-1.0.0/anafora.htdigest anafora anafora echo "annotatorGroup: anafora" > /home/anafora/anafora-1.0.0/anafora.authgroup
Insert the following block inside the <VirtualHost *:80></VirtualHost>
tags in the
/etc/apache2/sites-available/000-default.conf
file
<Location /anafora> AuthType Digest AuthName "anafora" AuthDigestProvider file AuthUserFile /home/anafora/anafora-1.0.0/anafora.htdigest Require valid-user </Location>
In the /etc/apache2/mods-available/alias.conf
file put the following inside the <IfModule alias_module></IfModule>
tags.
Alias /anafora/static /home/anafora/anafora-1.0.0/src/main/static
At the end of the /etc/apache2/apache2.conf
file put the following
WSGIScriptAlias /anafora /home/anafora/anafora-1.0.0/src/main/web/wsgi.py
Edit the /home/anafora/anafora-1.0.0/src/main/web/wsgi.py
file. Replace all of the content with the following
import os, sys if '/home/anafora/anafora-1.0.0/src/main' not in sys.path: sys.path.append('/home/anafora/anafora-1.0.0/src/main') os.environ['DJANGO_SETTINGS_MODULE'] = 'settings' import django.core.handlers.wsgi application = django.core.handlers.wsgi.WSGIHandler()
First we have to get the settings.py
file in the right place
mv /home/anafora/anafora-1.0.0/src/main/web/settings.py /home/anafora/anafora-1.0.0/src/main
Now go into the settings.py
file and set the following variables to the given value
TIME_ZONE = 'America/Chicago' STATIC_ROOT = '/home/anafora/anafora-1.0.0/src/main/static' STATIC_URL = '/static/' ROOT_URL = '/anafora' SECRET_KEY = 'changeme' TEMPLATE_DIRS = ("/home/anafora/anafora-1.0.0/src/Templates") ANAFORA_PROJECT_FILE_ROOT = "/home/anafora/anafora-project-root" GROUP_FILE = '/home/anafora/anafora-1.0.0/anafora.authgroup' ADMIN_GROUPNAME = 'anaforaadmin' ANAFORA_PROJECT_SETTING_FILENAME = ".setting.xml"
There is some problem with some of the references to static files in the pages, so we need to copy
the themes
directory
cp -av /home/anafora/anafora-1.0.0/src/main/static/css/themes /home/anafora/anafora-1.0.0/src/main/static
That's it! Your installation is ready to go. You will have to create a project in the
/home/anafora/anafora-project-root
directory. Follow the excellent Anafora User/Administrator
Manual to setup a project.
Once you have your project setup you can run apache start
or apache restart
as appropriate and
go to http://myanaphora/anafora to get started.
I'll do a quick write up of a few operational things (like creating new users, formatting an Anafora corpus, etc) in a follow up post soon.


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--- layout: standard title: "Responsiveness" slug: responsive ---
Metro UI 4 Jekyll supports following general screen size rules:
| Device Size | Device Type | Container size | Typography |
|---|---|---|---|
| min 1200 | Large desktops | 1140px | html > font-size 70% |
| min 1024 | Desktops | 940px | html > font-size 62.5% |
| max 1024 | Tablet landscape | 940px | html > font-size 62.5% |
| max 768 | Tablet portrait | 720px | html > font-size 62.5% |
| max 640 | Phone landscape | 100% | html > font-size 60% |
| max 480 | Phone portrait type 1 | 100% | html > font-size 45% |
| max 360 | Phone portrait type 2 | 100% | html > font-size 40% |
| max 320 | Phone portrait type 3 | 100% | html > font-size 40% |
First create a page wrapper with class .container
. This wrapper will change size for any devices.
<div class="container"> ...content here... </div>
Dimensions of the basic elements of typography expressed in rem
units relative to the font size specified for html.
Grid changes its behavior for different screen resolutions.
| Tablet landscape, desktop and lage | Grid has default behavior |
| Tablet portrait |
Grid has next behavior:
|
| Phones | All cells change self size to 100% |
Grid with fluid subclass currently is unchanged.
Metro UI 4 Jekyll provides helper classes to control the visibility of elements on different types of devices:
Helpers for hide elements |
|
| .no-large | element is not shown on the big screen |
| .no-desktop | element is not shown on the desktop |
| .no-tablet | element is not shown on the all tablets and phones |
| .no-tablet-portrait | element is not shown on the tablets with portrait orientation and phones |
| .no-phone | element is not shown on the all phones |
Helpers for show elements |
|
| .on-large | element is shown on the big screen |
| .on-desktop | element is shown on the desktop |
| .on-tablet | element is shown on the all tablets |
| .on-phone | element is shown on the all phones |
If you have something that does not work as in the demo, see the demo source code


THE PETROLOGY AND PETROGRAPHY OF THE VOLCANIC SEQUENCE ASSOCIATED WITH THE SUPERSTITION CALDERA, SUPERSTITION MOUNTAINS, ARIZONA
A DISSERTATION SUBMITTED TO THE DEPARTMENT OF GEOLOGY AND THE COMMITTEE ON THE GRADUATE DIVISION OF STANFORD UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF |
DOCTOR OF PHILOSOPHY
By Sohn S. Stuckless
June 1971
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.


|
Paris HiltonWhat do you get the socialite hotel chain heiress who has everything?   The entire feature weighs in at a scant two minutes and fifty-sex seconds, operating in near dismal conformity with Lars von Trier's Dogma treatise on moment-by-moment filmmaking. The handheld camera is unmistakably "on location," there is no superficial action or geographical alienation, all sound effects are produced in real-time collaboration with the images, and the primary director disavowed any immediate accreditation. The tape has been seen, screened, and lampooned on The Daily Show and Saturday Night Live -- but even to this day, more people have actually sat down to watch her insipid Fox series The Simple Life than the sex tape itself. The actual reasons for this upsidedown ratio are beyond the scope of this article, and must remain unexplored. But here's a girl who's chosen to spend her allowance on ways that don't benefit mankind, that don't create appealing business ventures or accomplish anything constructive. Gone are the days where being a student of the "upper class" meant facilitating a lifestyle meant to be envied or emulated by others. Instead, the world is watching Paris insinuate her noisy, shopworn caboose into just about every unnecessary public venue conceivable: modeling, acting, singing, television, fashion, jewelry, and amateur pornography. While she spreads herself thinner than the flimsy premise of her television program ("let's laugh at the poor people by pretending they're too icky to touch") Paris's porno bid contains no more extracurricular puss-puss than what she flashes at the paparazzi on a regular basis. The only thing unusual about the Paris Hilton sex tape is that looks like it was shot at the Motel 6 in Shitsville, New Mexico. It's a straight-to-video public relations ploy which raises neither controversial questions nor spontaneous erections. Paris appears sober and compliant throughout, although her family claims she may have been drugged. When the "scandal" broke, it quickly came to light that Paris's porn director and co-star was none other than Richard Salomon, an independent movie producer and online gambling entrepreneur. He's also the ex-boyfriend of Devon Aoki (model and heiress to the Benihana restaurant fortune) and estranged husband of Charmed actress Shannen Doherty. At first glance, the Sony Digicam infrared nightvision green makes Salomon look as though he wields an ample, larger-than-life dick, until you realize Paris's hands are abnormally waifish in size and shape, like those of Cruella DeVille. Salomon's cock has since been described as "nothing to write home about." When rumors of the tape first surfaced, Hilton denied its existence, calling Salomon "a complete liar and scumbag" in New York magazine, but she was later forced to backpedal after it become obvious the video was real. As suddenly as the tape begins, it screeches to a close. Paris dispenses less than twenty seconds of below-average blowjobbery, much of which is technically incompetent and more artistically bankrupt than Pamela Anderson's half-hearted performance upon Tommy Lee.   There is no happy finish, no climax, no splashy ejaculatory parade against her face, into her hair or down her neck.
Richard Salomon has filed a $10 million slander lawsuit against Hilton, asserting that she was in fact an active participant in making the video, alleging that the Hilton family has waged a "cold, calculated and malicious campaign to portray Salomon as a rapist." Hilton's lawyers are threatening legal action against anyone who distributes the tape or fails to destroy their copy of it, but purported snippets have been offered on eBay. Meanwhile, at high-class parties in New York, Las Vegas and Los Angeles, Paris Hilton remains the target of a very specific socialite indulgence. It's a game called Dump Your Drink On Paris, the object of which is to spot Paris at a party, "trip" next to her and splash the full contents of your Cape Cod across her expensive evening gown. The lighter the color of her fabric, and the darker the indelible fruit juice of your drink, the better.  "The Hilton family is greatly saddened at how low human beings will stoop to exploit their daughter, Paris, who is sweet-natured, for their own self-promotion as well as profit motives," read a statement released by the family. Funny how Paris Hilton's sister Nicky no longer seems interested in courting the public. Where'd she get off to, anyway? Shot by shot: here's a distilled, tastefully blacked-out breakdown of the video, partially censored by only the finest Rotten Dot Com stickers being manufactured to date. We start from frame 00:00:00:00 and end with frame 00:02:56:00. The following display is meant merely to edutain, infotate, and encourage the avoidance of unpleasant legal action items. There are two other central characters in this video: cellular telephone caller "Fred," and a pay-per-view television program which remains audible throughout the entire romp.  This is what E! Entertainment News calls a scandal?
|


30 pictures of Aspley from over the last 100 years
Aspley library which opened in the late 1930s is featured throughout the decades in this gallery. We also have a great picture of a steam train making its way over the railway bridge on Broxtowe Lane. Do you remember the Forum Cinema on Aspley lane? Did you attend William Crane School which closed in 2003 and was subsequently demolished?  The pricelists on the wall show that a gentleman's haircut would have cost 2/6, a boys was 1/9 and old age pensioners were charges 1/3.(Image: PICTURE NOTTINGHAM/J Orton)
1931 Mineral Railway Bridge, Broxtowe Lane, Aspley. The old bridge (right) with the new bridge under construction. The Mineral Railway used to run to the west of Nuthall Road, crossing Aspley Lane and Broxtowe Lane, before this was a residential area.(Image: PICTURE NOTTINGHAM)
1968 Napoleon Square, Aspley.(Image: Picture Nottingham/George L Roberts)
1968 Napoleon Square, Aspley. 54 Terraced Colliery Houses built by Thomas North in the 1840's to house workers at his nearby Cinderhill Colliery.(Image: Picture Nottingham/George L Roberts)
1937 Branch Library Interior, Nuthall Road, Aspley. The Aspley branch library was opened on 25th November 1937 by Principal Wortley of University College.(Image: PICTURE NOTTINGHAM)
1936 Dining Room at William Crane School, Minver Crescent, Aspley.(Image: PICTURE NOTTINGHAM)
1983 Children's summer activities, Branch Library Interior, Nuthall Road, Aspley.(Image: PICTURE NOTTINGHAM)
1985 Aspley Library, Nuthall Road, Aspley.(Image: PICTURE NOTTINGHAM)
1973 Aspley Library, Nuthall Road, Aspley.(Image: PICTURE NOTTINGHAM/Mr K Harris)
1957 Aspley Library, Nuthall Road, Aspley.(Image: PICTURE NOTTINGHAM)
1973 Broxtowe Lane, Aspley. Picture was taken just before the junction with Sherborne Road.(Image: Picture Nottingham/Reg Baker)
1953 Aspley Boys club float join in the coronation procession, Albert Street Nottingham.(Image: NOTTINGHAM POST)
1973 Nuthall Road, Aspley. These pre-fabricated houses were built in 1946, to re-house bombed-out victims.(Image: Picture Nottingham/Reg Baker)
1932 Junction of Amersham Rise and Allendale Avenue, Aspley. New council housing on the Aspley Estate, seen looking north from Amersham Rise with Allendale Avenue going off to the left.(Image: PICTURE NOTTINGHAM)
c1930 William Crane School, Minver Crescent, Aspley.(Image: PICTURE NOTTINGHAM)
c2000 St. Margaret's Church, Aspley Lane, Aspley.(Image: Picture Nottingham/G Oldfield)
c2000 Bluecoat School, Aspley Lane, Aspley.(Image: Picture Nottingham/G Oldfield)
Late 1980s-Early 1990s Forum Cinema, Aspley lane, Aspley.(Image: Picture Nottingham/A Sheldon)
c1930 aerial view of Minver Crescent , Aspley.(Image: PICTURE NOTTINGHAM)
c1930 Aerial view of Minver Crescent , Aspley.(Image: PICTURE NOTTINGHAM)
1925 Aspley Hall.(Image: PICTURE NOTTINGHAM)
1973 Amersham Rise, Aspley, part of Aspley Council Housing Estate.(Image: Picture Nottingham/Reg Baker)
1973 Melbourne Road looking from Aspley Lane.(Image: Picture Nottingham/Reg Baker)
1973 The southern entrance to William Crane School, Minver Crescent, Aspley.(Image: Picture Nottingham/Reg Baker)
Date unknown - Dulverton Vale Road or Munford Circus, Aspley.(Image: PICTURE NOTTINGHAM)
1973 Junction of Broxtowe lane and Aspley Lane.(Image: Picture Nottingham/Reg Baker)
1973 Junction of Aspley Lane, Broxtowe Lane.(Image: Picture Nottingham/Reg Baker)
1930 Looking from Melbourne Road. Aspley Lane. Property on left in City of Nottingham. Corporation Estate on the right is in the parish of Bilborough. City Engineer's Department(Image: PICTURE NOTTINGHAM)
1936 Mixed Girls and Boys Infant Class at William Crane School, Minver Crescent, Aspley.(Image: PICTURE NOTTINGHAM)


Lively Kernel Tutorial: (17) Miscellaneous UI Features
In addition to the features discussed in the earlier sections of this
tutorial, there are a number of additional features that have not been
mentioned yet. Such features include:
turn fisheye on/off: For every object in the system you can
enable a fisheye feature that will automatically enlarge and shrink
the object based on the proximity of the mouse cursor. Apart from changing
the size of the object, this feature has no other particular purpose.
reset rotation/scaling: These menu operations allow the rotation
and scaling factors to be easily reset back to their original values.
put me in a window/tab/in the open open: These experimental
features allow you to easily place any object inside a window, or remove
the window from around the contents of the window.
use debug background: This world menu operation makes the
background of the world transparent, allowing you to see the debug
console of the web browser. (Note: To enable the debug console, you
may have to tweak your browser settings or enable the debug console
explicitly from the HTML file that starts to the system.)
In addition to the features discussed above, there are many
other features that are still experimental at this point.
Try it yourself! Try applying the operations mentioned above
to the objects below.


{% extends 'base.html' %} {% load static %} {% block content%}
Finished
Not Finished
Created On {{task.createdOn}}
Create Task


This is an info window at {{ latitude | number:4 }}, {{ longitude | number:4 }}!
My marker will stay open when the window is popped up!
Dynamic Marker created via a delay!
This is an info window at {{ latitude | number:4 }}, {{ longitude | number:4 }}!
My marker will stay open when the window is popped up!


Auth0
Azure
Cognito
Okta
Redirect
Popup
New Tab
Iframe
id_token
id_token token
code
Single
Separate Login and Logout
Session Storage
Local Storage
Not Secured
Secure All Routes
Secure All Endpoints
Fully Secured
Login
Logout
Navigate


Before Change
@rule
async def determine_all_source_files(request: AllSourceFilesRequest) -> SourceFiles:
Merge all `Sources` fields into one Snapshot.
if request.strip_source_roots:
stripped_snapshots = await MultiGet(
Get(
SourceRootStrippedSources,
StripSourcesFieldRequest(
sources_field,
for_sources_types=request.for_sources_types,
enable_codegen=request.enable_codegen,
),
)
for sources_field in request.sources_fields
)
digests_to_merge = tuple(
stripped_snapshot.snapshot.digest for stripped_snapshot in stripped_snapshots
)
else:
all_hydrated_sources = await MultiGet(
Get(
HydratedSources,
HydrateSourcesRequest(
sources_field,
for_sources_types=request.for_sources_types,
enable_codegen=request.enable_codegen,
),
)
for sources_field in request.sources_fields
)
digests_to_merge = tuple(
hydrated_sources.snapshot.digest for hydrated_sources in all_hydrated_sources
)
result = await Get(Snapshot, MergeDigests(digests_to_merge))
return SourceFiles(result)
After Change
)
for hydrated_sources, sources_field in zip(all_hydrated_sources, request.sources_fields):
if isinstance(sources_field, FilesSources):
unrooted_files.update(hydrated_sources.snapshot.files)
digests_to_merge = tuple(
hydrated_sources.snapshot.digest for hydrated_sources in all_hydrated_sources
)
result = await Get(Snapshot, MergeDigests(digests_to_merge))