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PubMed1990

Smooth muscle energetics: testing theories of crossbridge regulation.

Our results indicate that the kinetic "latch" model of Hai & Murphy is not very sensitive to the proportion of ATP assigned to crossbridges relative to that ascribed to MLC phosphorylation/dephosphorylation. Thus the basis for the relatively low efficiency of smooth muscle, attributed to high MLC phosphorylation/dephosphorylation in this model, remains open to question. Moreover, this model, or any model with mixed populations of crossbridges with differing cycle rates and/or high MLC phosphorylation/dephosphorylation rates is unlikely to account for the observed linearity of JATP and stress reported for many smooth muscles. Our studies comparing the heat production of intact and skinned smooth muscle indicate that the ATPase associated with myosin phosphorylation/dephosphorylation is unlikely to be a major factor in the tension cost of intact smooth muscle. Thus it would appear that energetics places considerable constraints on current theories of crossbridge regulation. Our modelling (Paul, 1989) suggests that it may be time to reevaluate Bozler's original hypothesis that a high attachment:detachment rate ratio for smooth muscle actin-myosin interaction may be sufficient to explain the energetics of smooth muscle.

Adenosine Triphosphate↗
PubMed2005

Population balance modeling of aggregation kinetics of recombinant human interleukin-1 receptor antagonist.

The kinetics of benzyl alcohol-induced nonnative aggregation of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) were investigated using a population balance model. Steady-state size distributions of rhIL-1ra aggregates formed in a continuous mixed suspension, mixed product removal (MSMPR) reactor were measured and used to extrapolate aggregate nucleation and growth rates parameters. Aggregate growth rate was size-dependent and a linear growth rate model was used to derive a population density function. Addition of 0.9 wt/v% benzyl alcohol increased the nucleation rate by approximately four orders of magnitude. The growth rate for aggregates, however, changed little as a function of benzyl alcohol concentration in the range of 0-0.9%. The addition of sucrose to buffer containing 0.9% benzyl alcohol decreased rhIL1-ra nucleation rate by orders of magnitude and had little impact on growth rate kinetics. The simplicity of the population balance model and the physical relevance of the information obtained from this model render it a useful tool to study protein aggregation kinetics and the effects of excipients on this process.

Benzyl Alcohol↗
PubMed2001

Patterns of sperm precedence and predictors of paternity in the Trinidadian guppy.

Despite its widespread occurrence in animals, sperm competition has been studied in a limited range of taxa. Among the most neglected groups in this respect are internally fertilizing fish in which virtually nothing is known about the dynamics of sperm competition. In this study, we examined the outcome of sperm competition when virgin female guppies mated with two males. Behavioural cues were used to ensure that each male mated once (with female cooperation) and that sperm were successfully inseminated at copulation. Two polymorphic microsatellite loci were used to estimate the proportion of offspring sired by the second male (P2) and the results revealed a bimodal distribution with either first or (more often) second male priority The observed P2 distribution differed from that expected under the 'fair raffle' model of sperm competition. Random sperm mixing is therefore unlikely to account for the observed variance in P2 in this study. A further aim of our study was to identify predictors of male reproductive success. Using logistic linear modelling, we found that the best predictors of paternity were time to remating and the difference in courtship display rate between first and second males. Males that mated quickly and performed relatively high numbers of sigmoid displays obtained greater parentage than their slower and less vigorous counterparts. Since females are attracted to high-displaying males, our results suggest that female choice may facilitate sperm competition and/or sperm choice in guppies.

Animals↗
PubMed2004

No acute changes in postural control after soccer heading.

BACKGROUND: Soccer heading has been proposed as a potential cause of cerebral dysfunction. OBJECTIVE: To examine the acute effects of two types of soccer heading on postural control. METHODS: Collegiate soccer players were randomly assigned to one of four groups: control, linear heading, simulated rotational heading, or rotational heading. Each subject completed a baseline postural stability assessment on day 1. On day 2 the same assessment was completed for the control subjects. The simulated rotational heading group completed a simulated heading drill before postural stability testing. The linear and rotational heading groups performed a heading drill with 20 balls at 88.71 km/h (55 mph), before postural stability testing. Separate one between (group), three within (surface, eyes, and day), mixed model, repeated measures analyses of variance were conducted on values for total sway and mean centre of pressure. RESULTS: The mixed model analysis of variance of results showed no significant differences (p>0.05) for the interactions of interest for either variable. Results suggest no acute changes in measures of postural control in soccer players completing either a linear or rotational soccer heading drill of 20 balls at a fixed speed. CONCLUSION: Non-significant interactions between surface, eyes, day, and group indicate that sensory interaction of the balance mechanism components are not be compromised by the heading drill. This research supports previous studies suggesting that there are no acute risks associated with routine soccer heading. A direct comparison between these findings and those suggesting long term chronic deficits, however, cannot be made. Other studies that report chronic cerebral deficits in soccer players may have resulted from factors other than soccer heading and warrant further examination.

Adolescent↗
PubMed2002

Two-step and random regression analyses of weight gain of station-tested beef bulls.

Our objectives were to compare a two-step model and a joint procedure via random regression model for evaluating weight gain of beef bulls, weighed every 28 d on 140-d test, and to estimate genetic, environmental, and phenotypic parameters. Two-step analysis consisted of fitting fixed linear regressions to weights of each bull to determine weight gain on test. In the second step, gain on test was analyzed by a mixed model that included fixed effects of breed, test group, and starting age and random effects of weaning herd-year group and animal (additive genetic). The random regression model included the same effects as the two-step mixed-model analysis with an additional random animal permanent environment effect. Fourth-order Legendre polynomials of days on test were fitted for all fixed and random effects in the random regression model, except for breed. Breed effects and residual variances varied for each measurement period. Variance components and EBV for gain were obtained from the covariance function and estimates of random regression coefficients for weight, respectively. Random regression heritability estimates for gain on test increased over time, being maximum at end of test (0.38) and equal to two-step estimate. Permanent environment variance ratio estimates also increased over time and were greater than heritability estimates. Estimate of weaning herd-year variance ratio was approximately constant over time, being equal to 0.07 at end of test and similar to two-step estimate. Genetic correlations between gain through different periods on test given by random regression model were high (from 0.81, between 28 and 140-d gain on test, to 0.99, between 112 and 140-d gain on test). Genetic correlations between gain on discrete 28-d intervals were moderate to high (e.g., 0.49 and 0.99 between the last 28 d on test and the first and fourth 28 d, respectively). Rank correlations between EBV for 140-d gain by the two procedures were 0.98, 0.84, and 0.73 for all bulls and the 5% and 1% of bulls with highest random regression EBV, respectively. Results indicated that the two procedures rank top bulls quite differently for 140-d gain on test. Random regression model accounted for changes over time of genetic and environmental effects on the test weight gain curve of the bulls. Use of 112-d instead of a 140-d test provided similar ranking of bulls on the basis of EBV for gain on test.

Animals↗
PubMed2006

Combination tetrathiomolybdate and radiation therapy in a mouse model of head and neck squamous cell carcinoma.

OBJECTIVE: To assess the effect of combining tetrathiomolybdate therapy and radiation treatment (RT) on tumor growth in the mouse head and neck squamous cell carcinoma (HNSCC) model. DESIGN: One million HNSCC cells were injected subcutaneously into the flanks of C3H/HeJ mice and the tumors grown to an average of 301 mm3 (day 0). Mice were randomized into 4 groups: (a) no therapy, (b) tetrathiomolybdate alone, (c) RT alone, or (d) tetrathiomolybdate + RT. Data from 3 experiments with these 4 groups were analyzed. A gaussian mixed model was fit to the initialized logarithm of the tumor size counts between days 7 and 16 (linear component), and growth rates were compared. Assays using 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyltetrazolium bromide (MTT) were conducted on HNSCC cells in culture with varying doses of tetrathiomolybdate. INTERVENTIONS: Treated mice were given tetrathiomolybdate in their water and observed for clinical evidence of toxic effects associated with copper depletion as measured by ceruloplasmin assay. When tumor sizes reached an average of 535 mm(3), mice receiving RT were given a single fraction of 750 rad (7.5 Gy), a dose determined in previous experiments to slow but not cure tumor growth, permitting an examination of interaction of radiation with tetrathiomolybdate. RESULTS: Data from 3 separate experiments were analyzed. There were a total of 37 mice in the untreated group, 32 mice in the tetrathiomolybdate alone group, 38 mice in the RT alone group, and 46 mice in the tetrathiomolybdate + RT group. Ceruloplasmin assays showed that we had obtained adequate copper reduction throughout the experiments to inhibit angiogenesis with minimal toxic effects. The tetrathiomolybdate + RT combined therapy group of mice showed a statistically significant decrease in tumor growth compared with both the tetrathiomolybdate alone (P = .001) and RT alone groups (P<.001). CONCLUSION: The combination of the anti-angiogenic copper chelating agent tetrathiomolybdate with RT improved local control of HNSCC in an isogenic mouse model compared with either therapy alone.

Angiogenesis Inhibitors↗
PubMed1996

Concentration-effect relationship of the positive chronotropic and hypokalaemic effects of fenoterol in healthy women of childbearing age.

OBJECTIVE: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most frequent adverse effects of tocolytic therapy with beta 2-adrenoceptor agonists in females of childbearing age. METHODS: The study was performed as a double blind, randomised, placebo controlled, cross over trial. Seven healthy women aged 22-38 y, received intravenous infusions of fenoterol at 3 different rates within the therapeutic range for tocolysis (0.5,1.0, and 2.0 micrograms.min-1) and placebo. The time courses of the plasma concentrations of fenoterol and potassium, and the heart rate were analysed with mixed effects pharmacokinetic-pharmacodynamic (PKPD) modeling using NONMEM. RESULTS: The plasma concentration-time course followed a linear two compartment model. Fenoterol-induced tachycardia was described by a linear concentration-effect model with baseline. The estimated baseline and slope parameters were 78 beats.min-1 and 0.032 beats.min-1.microgram-1.1, respectively. Fenoterol-induced hypokalaemia could be described by a physiological indirect response model including feedback; the Estimated basal plasma potassium concentration was 3.93 mmol.1-1 and the slope factor for the fenoterol-induced relative increase in the efflux of potassium from the extracellular space was 6.22*10(-4) ng.1(-1). CONCLUSION: The estimated population parameters permitted calculation of the expected time course of tachycardia and hypokalaemia in women after the initiation of tocolysis with fenoterol over the clinically relevant concentration range, and prediction of its variability. Based on simulation, our model predicted that a continuous infusion of 2.0 micrograms.min-1 (highest rate examined) would increase heart rate to 113 beats.min-1 at steady state and lower the plasma potassium concentration to 2.77 mmol.1(-1) 1.5 h after beginning the infusion. Thereafter, the plasma potassium concentration would slowly return to normal.

Adrenergic beta-Agonists↗
PubMed1989

ADP release is rate limiting in steady-state turnover by the dynein adenosinetriphosphatase.

The kinetics of the product release steps in the pathway of ATP hydrolysis by dynein were investigated by examining the rate and partition coefficient of phosphate-water 18O exchange under equilibrium and steady-state conditions. Dynein catalyzed both medium and intermediate phosphate-water oxygen exchange with a partition coefficient of 0.30. The dependence of the rate of loss of the fully labeled phosphate species on the concentration of ADP was hyperbolic, with an apparent Kd for the binding of ADP to dynein of 0.085 mM. The apparent second-order rate constant for phosphate binding to the dynein-ADP complex was 8000 M-1 s-1. The time course of medium phosphate-water oxygen exchange during net ATP hydrolysis was examined in the presence of an ATP regeneration system. The observed rate of loss of P18O4 was comparable to the rate observed at saturating ADP which implies that ADP release is rate limiting for dynein in the steady state. Product inhibition of the dynein ATPase was also examined. ADP inhibited the enzyme competitively with a Ki of 0.4 mM. Phosphate was a linear noncompetitive mixed-type inhibitor with a Ki of 11 mM. These data were fit to a model in which phosphate release is fast and is followed by rate-limiting release of ADP, allowing us to define each rate constant in the pathway. A discrepancy between the total free energy calculated compared to the known free energy of ATP hydrolysis suggests that there is an additional step in the pathway, perhaps involving a change in conformation of the enzyme-ADP state preceding ADP release.

Adenosine Diphosphate↗
PubMed2006

Association of a single nucleotide polymorphism in the calpastatin gene with carcass and meat quality traits of beef cattle.

Calpastatin (CAST) is a naturally occurring protein that inhibits the normal tenderization of meat as it ages postmortem. A SNP was identified in the CAST gene (a G to C substitution) and genotyped on crossbred commercially fed heifers (n = 163), steers (n = 226), and bulls (n = 61) from beef feedlots, and steers (n = 178) from a University of Guelph feeding trial. The association of the CAST SNP with carcass and meat quality traits was studied. Carcass traits included fat, lean, and bone yield; grade fat; LM area; and HCW. Meat quality traits included marbling grade; i.m. fat content of LM; tenderness evaluation of LM (Warner-Bratzler shear force) at 2, 7, 14, and 21 d of postmortem aging; and tenderness evaluation of semitendinosus muscle at 7 d of postmortem aging. The mixed model used in the analyses included fixed effects of CAST genotype, sex, slaughter group, and breed composition (linear covariate); sire was a random effect. For the analysis of shear force, i.m. fat content of LM was also included in the model as a linear covariate. Shear force measures were analyzed within days of postmortem aging and by repeated measures analysis. The CAST SNP allele C was more frequent (63%) in the crossbred population than allele G. The CAST SNP was associated with shear force across days of postmortem aging (P = 0.005); genotype CC yielded beef that was more tender than GG (-0.32 kg +/- 0.13), and CG had intermediate tenderness. The corresponding average allele substitution effect (G to C substitution) was also highly significant (-0.15 +/- 0.05 kg, P = 0.002). A lower percentage of unacceptably tough steaks (shear force > 5.7 kg) at 2 and 7 d postmortem was associated with an increasing number of C alleles (P < or = 0.05). At 7 d postmortem, the percentage of unacceptably tough steaks decreased by 24 and 35%, respectively, for animals carrying 1 and 2 copies of the C allele relative to animals with no C alleles. However, genotype CC had a greater fat yield (+1.44 +/- 0.56%; P = 0.037) than genotype GG, with a corresponding allele substitution effect of 0.67 +/- 0.27% (P = 0.015). Therefore, the CAST SNP allele C was associated with increased LM tenderness across days of postmortem aging and, importantly for the beef industry, had a significant reduction in the percentage of steaks rated unacceptably tough by consumers based on an assumed threshold level.

Animals↗
PubMed1977

[Model building in pharmacokinetics/Part II: Generalized theoretical presentation of complete integration of linear compartment models of optional structure (author's transl)].

The method of Laplace transformation is used to obtain the integral of linear differential equations for pharmacokinetic models. A general solution uniform in structure for all types of models (mammillary, catenary, mixed) was established. Choice of one more application compartments, of kinetics describing the input procedure and of elimination pathways is free.

Kinetics↗
PubMed2003

General multilevel linear modeling for group analysis in FMRI.

This article discusses general modeling of multisubject and/or multisession FMRI data. In particular, we show that a two-level mixed-effects model (where parameters of interest at the group level are estimated from parameter and variance estimates from the single-session level) can be made equivalent to a single complete mixed-effects model (where parameters of interest at the group level are estimated directly from all of the original single sessions' time series data) if the (co-)variance at the second level is set equal to the sum of the (co-)variances in the single-level form, using the BLUE with known covariances. This result has significant implications for group studies in FMRI, since it shows that the group analysis requires only values of the parameter estimates and their (co-)variance from the first level, generalizing the well-established "summary statistics" approach in FMRI. The simple and generalized framework allows different prewhitening and different first-level regressors to be used for each subject. The framework incorporates multiple levels and cases such as repeated measures, paired or unpaired t tests and F tests at the group level; explicit examples of such models are given in the article. Using numerical simulations based on typical first-level covariance structures from real FMRI data we demonstrate that by taking into account lower-level covariances and heterogeneity a substantial increase in higher-level Z score is possible.

Algorithms↗
PubMed2003

Modeling of phosphorus dynamics in aquatic sediments: I--model development.

A model is developed to study the phosphorus dynamics in aquatic sediments and to conduct dynamic predictions of phosphorus release across a sediment-water interface. The model focuses on the sediment active layer below the sediment-water interface and is based on primary mechanisms regulating phosphorus behavior in sediments, including effective diffusion, bioturbation mixing and burial processes (transport), organic decomposition, sorption kinetic processes and non-linear partitioning (mobilization). The effects of environmental factors such as dissolved oxygen and temperature are taken into account. The model is solved by numerical integration. The primary difference from models in the literature is that the model directly describes the dynamic behavior of dissolved, particulate exchangeable ortho-phosphorus and organic phosphorus in sediments, and incorporates dynamic sorption and non-linear partitioning processes. These improve model mechanisms and allow regulation of phosphorus flux through the sediment reservoir that acts as both a source and sink of phosphorus.

Biological Availability↗
PubMed1999

Myocardial kinetics of 99m technetium-Q agents: studies in isolated cardiac myocyte, isolated perfused rat heart, and canine regional myocardial ischemia models.

OBJECTIVE: Based on reports of high cellular uptake and low plasma binding of nonreducible mixed ligand Tc(III) cations (Q complexes) and high linear uptake versus blood flow of 99mTc-Q3 in canine hearts, the authors hypothesized that the two Q complexes, 99mTc-Q63 and 99mTc-Q64, would have high cell uptake and better differentiation between ischemic and nonischemic myocardium compared with other 99mTc-based compounds. METHODS: Uptake and retention kinetics of 99mTc-Q63 and 99mTc-Q64 were measured in isolated rat cardiac myocytes, isolated perfused rat hearts, and intact canines and compared with previously reported Q-based compounds, a clinically available 99mTc perfusion agent (sestamibi), and 201Tl. RESULTS: Uptake of Q63, Q64, and sestamibi by isolated cardiac myocytes was similar. Maximum extraction (Emax) of Q64 by isolated perfused rat hearts was greatest among the 99mTc agents (P < 0.02), but net extraction (Enet) of Q64 was not different from Q63 or sestamibi 3 minutes after tracer injection. By 15 minutes, 201Tl Enet was lower than Q63, Q64, and sestamibi (P < 0.05). Among 99mTc agents, the uptake versus flow of Q3, Q63, and Q64 by canine heart was superior to Q12 and sestamibi (P < 0.05). CONCLUSIONS: The activity of Q63 and Q64 in the myocardium is related to actual myocardial blood flow over a broad, clinically relevant range of flows. The ischemic-to-normal zone activity distributions of Q63 and Q64 approximate actual flow in a manner more like that of 201Tl than sestamibi or Q12. These results provide a rational foundation in support of further evaluation of Q63 and Q64 in humans.

Acute Disease↗
PubMed2005

Responder cell frequency estimation and binomial three-level nonlinear mixed effects model in limiting dilution assays.

Responder cell frequencies (RCF), which describe vaccine-boosted immune responses in herpes zoster (HZ) prevention studies, have been estimated by using limiting dilution assays (LDA). The theoretical linearity assumption between the logarithm of the proportion of nonresponding wells (s) and the cell concentration (N) (or dilution level) in LDA, based on the single-hit Poisson model, is often violated with observed data resulting in biased estimates of RCF. In this article, the Poisson assumption is modified by applying a mixture of Poisson and gamma distributions, resulting in a negative binomial assumption, which presents a better fit between s and N. In LDA for HZ prevention studies, binary responses (responder or non-responder wells) are measured repeatedly at different cell concentrations and over time. To account for the correlation between responses to varying dilution levels from individuals, and the correlation between repeated assays of individuals over time simultaneously, a binomial three-level nonlinear mixed-effects model is proposed. For parameter estimation, a maximum likelihood method is applied via adaptive Gaussian quadrature. There is a lack of non-Gaussian multilevel nonlinear mixed-effects software, which can execute such a complicated fit. In this article, an algorithm for the three-level nonlinear mixed-effects model, which can be inserted into the code in the SAS procedure NLMIXED, is suggested.

Cell Count↗
PubMed2004

[Study on the calculation methods of confidence intervals of genetic parameter estimates by method R and number of repeating estimations].

The objective of the study was to probe the calculation methods of confidence intervals of genetic parameter estimates by Method R and influences of number of repeating estimations (NORE). Four models were used to generate the datasets by simulation. The datasets originated from 200 sires and 2 000 dams and simulation progressed by BLUP( Best Linear Unbiased Prediction) selection for five overlapping generations. Variance components were estimated by using multivariate multiplicative iteration (MMI), combined with preconditioned conjugate gradient (PCG) to solve the mixed model equations. Parameter estimates and their standard errors and confidence intervals were computed by classical method, classical method after Box-Cox transformation and bootstrapping. The results showed that when NORE was larger, all three methods were feasible, but when NORE was fewer, bootstrapping was recommended. Fewer NORE was feasible under simple models, but more NORE was needed for complex models. Direct heritabilities were overestimated with the increase of number of random effects, but underestimation was found for many parameters with the increase of iteration numbers of PCG and MMI.

Animals↗
PubMed2005

Finite element modeling of coupled diffusion with partitioning in transdermal drug delivery.

The finite element method is employed to simulate two-dimensional (axisymmetric) drug diffusion from a finite drug reservoir into the skin. The numerical formulation is based on a general mathematical model for multicomponent nonlinear diffusion that takes into account the coupling effects between the different components. The presence of several diffusing components is crucial, as many transdermal drug delivery formulations contain one or more permeation enhancers in addition to the drug. The coupling between the drug and permeation enhancer(s) results in nonlinear diffusion with concentration-dependent diffusivities of the various components. The framework is suitable for modeling both linear and nonlinear, single- and multicomponent diffusions, however, as it reduces to the correct formulation simply by setting the relevant parameters to zero. In addition, we show that partitioning of the penetrants from the reservoir into the skin can be treated in a straightforward manner in this framework using the mixed method. Partitioning at interface boundaries poses some difficulty with the standard finite element method as it creates a discontinuity in the concentration variable at the interface. To our knowledge, nonlinear (concentration-dependent) partitioning in diffusion problems has not been treated numerically before, and we demonstrate that nonlinear partitioning may have an important role in the effect of permeation enhancers. The mixed method that we adopt includes the flux at the interface explicitly in the formulation, allowing the modeling of concentration-dependent partitioning of the permeants between the reservoir and the skin as well as constant (linear) partitioning. The result is a versatile finite element framework suitable for modeling both linear and nonlinear diffusions in heterogeneous media where the diffusivities and partition coefficients may vary in each subregion.

Administration, Cutaneous↗
PubMed1981

Plasmid transformation of Streptococcus sanguis (Challis) occurs by circular and linear molecules.

Transformation of Streptococcus sanguis (Challis) by antibiotic resistance plasmids has shown that (a) competence developed with identical kinetics for chromosomal and plasmid DNA; (b) dependence of transformant yield on plasmid DNA concentration was second order; (c) open circular plasmid DNA transformed Challis, although at reduced frequency, (d) linearization of plasmid DNA by restriction enzymes cutting at unique sites inactivated the transforming capacity; (e) transforming activity was restored when linear plasmid molecules generated by different restriction enzymes were mixed; (f) restoration of transforming activity depended on the distance between the linearizing cuts, i.e. on the presence of sufficiently long overlapping homologous sequences; (g) when linear deletion mutants were mixed with linear parental plasmids the smaller plasmid was restored with significantly higher frequency. Based on these data, a model for plasmid transformation of Challis is proposed according to which circular plasmid is linearized during binding and uptake. One DNA strand enters the cell and restoration of circular plasmids inside the cell occurs by annealing of complementary single strands from two different donor molecules. Implications of this model for recombinant DNA experiments in streptococci are discussed.

Chromosomes, Bacterial↗
PubMed2005

Linear programming to optimize performance in a department of surgery.

BACKGROUND: Linear programming is an analytic method that can be used to develop models for health care that optimize distribution of resources through mathematical means. STUDY DESIGN: The linear programming model contained objective, decision, and constraint elements. The objective was to optimize financial outcomes for both the hospital and physicians in the Department of Surgery. The decision concerns procedure mix or the number of each type of surgical procedure. Constraints apply to resources that are consumed during the course of the patient's surgical encounter. RESULTS: The optimal solution produced an increase in professional payments of 3.6% and an increase in hospital total margin of 16.1%. This solution favored surgical procedures that require inpatient care; these patients had greater comorbidity, reflected in a higher case-mix index of 3.74 compared to 2.97. Substantial differences were noted in use of general care and ICU days, and in consumption of preoperative, intraoperative, and recovery room time. CONCLUSIONS: Aligning quality surgical care with optimal financial performance may be assisted by mathematical models such as linear programming.

Comorbidity↗