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An improved 3-D Look--Locker imaging method for T(1) parameter estimation.

The 3-D Look-Locker (LL) imaging method has been shown to be a highly efficient and accurate method for the volumetric mapping of the spin lattice relaxation time T(1). However, conventional 3-D LL imaging schemes are typically limited to small tip angle RF pulses ( 5 degrees ), thereby improving the SNR and the accuracy of the method. In phantom studies, a mean T(1) measurement accuracy of less than 2% (0.2-3.1%) using a tip angle of 10 degrees was obtained for a range of T(1) from approximately 300 to 1,700 ms with a measurement time increase of only 15%. This accuracy compares favorably with the conventional 3-D LL method that provided an accuracy between 2.2% and 7.3% using a 5 degrees flip angle.

Contrast Media↗

Accounting for nonlinear BOLD effects in fMRI: parameter estimates and a model for prediction in rapid event-related studies.

Nonlinear effects in fMRI BOLD data may substantially influence estimates of task-related activations, particularly in rapid event-related designs. If the BOLD response to each stimulus is assumed to be independent of the stimulation history, nonlinear interactions create a prediction error that may reduce sensitivity. When stimulus density differs among conditions, nonlinear effects can cause artifactual differences in activation. This situation can occur in rapid event-related designs or when comparing blocks of unequal lengths. We present data showing substantial nonlinear history effects for stimuli 1 s apart and use estimates of nonlinearities in response magnitude, onset time, and time to peak to form a low-dimensional parameterization of these nonlinear effects. Our estimates of nonlinearity appear relatively consistent throughout the brain, and these estimates can be used to form adjusted linear predictors for future rapid event-related fMRI studies. Adjusting the linear model for these known nonlinear effects results in a substantially better model fit. The biggest advantages to using predictors adjusted for known nonlinear effects are (1) higher sensitivity at the individual subject level of analysis, (2) better control of confounds related to nonlinear effects, and (3) more accurate estimates of design efficiency in experimental fMRI design.

Adolescent↗

Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malariatherapy data.

Plasmodium falciparum malaria is one of mankind's main killers. Part of the parasite's life-cycle is spent in human blood, mainly as asexual stages. A fraction of the asexual parasites develops into gametocytes (gamete precursors) while sequestered in deep tissues. After re-entering the circulation, gametocytes can be picked up by a mosquito to continue the parasite's life-cycle. We present estimates of the conversion probability from asexual parasites to circulating gametocytes and of the gametocytes' sequestration and circulation times, obtained for the first time by fitting a dynamic model to individual patients' histories (daily records of 113 neurosyphilitic patients undergoing malariatherapy). The model assumes that the conversion probability can vary among the successive waves of asexual parasitaemia of a patient, and that gametocytes die at an age-dependent rate which increases under high asexual parasite densities. On average, 1 gametocyte per 156 asexual parasites (range 7.4-3700) is produced. The most remarkable findings are the large individual variation of conversion probabilities and circulation times, the average gametocyte circulation time of 6.4 days (range 1.3-22.2 days) which is more than twice the currently accepted value, and the large variation of conversion probabilities among successive waves of asexual parasitaemia without any particular time pattern. The latter finding could be explained by an association between conversion probability and variation of PfEMP1.

Animals↗

Multi-step analysis as a tool for kinetic parameter estimation and mechanism discrimination in the reaction between tight-binding fasciculin 2 and electric eel acetylcholinesterase.

The mechanism of action of a potent peptidic inhibitor fasciculin 2 (Fas2) on electric eel acetylcholinesterase (eleelAChE) has been examined in a three-level analysis. Classical steps included equilibration experiments for the evaluation of high affinity binding constant and the existence of residual hydrolytic activity in a solution of completely Fas2 saturated enzyme. The two rate constants for the association (k(on)) and the dissociation (k(off)) of Fas2 with free enzyme were determined by the time course of residual enzyme activity measurements. In the third step, with a nonclassical progress curve analysis, we found that the Fas2-enzyme complex exhibited hydrolytic activity in a butyrylcholinesterase-like kinetics. The switch appears to be a consequence of steric obstruction, but also the consequence of subtle rapid conformational changes around catalytic site, upon slow single-step binding of large Fas2 molecule at the peripheral site. An unusual unilateral effect of bound Fas2 is reflected by acylation-independent association and dissociation rates and might indeed be due to inability of small acylation agent to influence the binding of a large opponent.

Acetylcholinesterase↗

State and parameter estimation of microalgal photobioreactor cultures based on local irradiance measurement.

Local photosynthetic photon flux fluence rate (PPFFR) determined by a submersible 4pi quantum micro-sensor was used in developing a versatile on-line state estimator for stirred-tank microalgal photobioreactor cultures. A marine micro-alga Dunaliella salina was used as a model organism in this study. On-line state estimation was realized using the extended Kalman filter (EKF), based on a state model of the photobioreactor and on-line local PPFFR measurement. The dynamic state model for the photobioreactor was derived based on mass-balance equations of the relevant states. The measurement equation was established based on an empirical correlation between the microalgal biomass concentration and the local PPFFR measured at a fixed point inside the photobioreactor. An internal model approach was used to estimate the specific growth rate without the need of state-based kinetic expression. The estimator was proven to be capable of estimating biomass concentration and specific growth rate, as well as phosphate and dissolved oxygen concentrations in a photobioreactor illuminated with either fixed or time-varying incident radiation. The quantum sensor was shown to be robust and able to quickly respond to dynamic changes in local PPFFR. In addition, the quantum sensor outputs were not affected by bubble aeration or agitation within the typical operating range. The strong filtering capacity of EKF gives the state estimator superior performance compared to direct calculation from the empirical biomass/local PPFFR correlation. This state estimation system makes use of inexpensive and reliable sensor hardware to report key process dynamics of microalgal photobioreactor cultures on-line, enabling improved operation of such a process.

Biomass↗

NADH-Regulated metabolic model for growth of Methylosinus trichosporium OB3b. Model presentation, parameter estimation, and model validation.

A biochemical model is presented that describes growth of Methylosinus trichosporium OB3b on methane. The model, which was developed to compare strategies to alleviate NADH limitation resulting from cometabolic contaminant conversion, includes (1) catabolism of methane via methanol, formaldehyde, and formate to carbon dioxide; (2) growth as formaldehyde assimilation; and (3) storage material (poly-beta-hydroxybutyric acid, PHB) metabolism. To integrate the three processes, the cofactor NADH is used as central intermediate and controlling factor-instead of the commonly applied energy carrier ATP. This way a stable and well-regulated growth model is obtained that gives a realistic description of a variety of steady-state and transient-state experimental data. An analysis of the cells' physiological properties is given to illustrate the applicability of the model. Steady-state model calculations showed that in strain OB3b flux control is located primarily at the first enzyme of the metabolic pathway. Since no adaptation in V(MAX) values is necessary to describe growth at different dilution rates, the organism seems to have a "rigid enzyme system", the activity of which is not regulated in response to continued growth at low rates. During transient periods of excess carbon and energy source availability, PHB is found to accumulate, serving as a sink for transiently available excess reducing power.

Biotechnology↗

Performance comparison of parameter estimation techniques for the quantitation of local cerebral blood flow by dynamic positron computed tomography.

Local CBF (LCBF) can be quantitated from positron computed tomographic (PCT) data and physiologically based mathematical models by several general methods. Those using a dynamic sequence of PCT scans allow the simultaneous estimation of both LCBF and p, the indicator's tissue-blood partition coefficient. This article presents a comparison of three rapid estimation techniques for use with inert diffusible radioindicators and serial PCT, each of which is based on the original Kety model. One method, developed in our laboratory, involves minimizing the mean squared discrepancy between measured data and model predictions, whereas the other two methods, recently reported in the literature, are weighted integration techniques that involve multiplying the measured data by time-dependent weighting functions. Simulation studies of noise propagation and other sources of error were performed under a variety of simulated conditions. Functional images of LCBF and p were calculated using each method for both phantom and human subject data. Errors can differ by as much as a factor of 2-3 between methods, with each having its own unique advantages and disadvantages.

Brain↗

Improved parameter estimation for systems with an experimentally located Hopf bifurcation.

When performing system identification, we have two sources of information: experimental data and prior knowledge. Many cell-biological systems are oscillating, and sometimes we know an input where the system reaches a Hopf bifurcation. This is the case, for example, for glycolysis in yeast cells and for the Belousov-Zhabotinsky reaction, and for both of these systems there exist significant numbers of quenching data, ideal for system identification. We present a method that includes prior knowledge of the location of a Hopf bifurcation in estimation based on time-series. The main contribution is a reformulation of the prior knowledge into the standard formulation of a constrained optimisation problem. This formulation allows for any of the standard methods to be applied, including all the theories regarding the method's properties. The reformulation is carried out through an over-parametrisation of the original problem. The over-parametrisation allows for extra constraints to be formed, and the net effect is a reduction of the search space. A method that can solve the new formulation of the problem is presented, and the advantage of adding the prior knowledge is demonstrated on the Brusselator.

Algorithms↗

EDTA leaching of copper from contaminated soils: experimental study and transport model application for parameters estimation.

EDTA column's extraction were performed on four artificially contaminated soils, followed by the percolation of pure water to ensure the removal of EDTA entrapped in soil. The investigated soils were characterized by a content of organic matter ranging from 1% to 25%. A mathematical model was developed for copper leaching from the soils. The correlation of experimental data shows that while the EDTA transport was not affected by the soil organic fraction, the simulated transport of Cu-EDTA complexes in solution exhibited a delay effect due to the chemical adsorption of such complexes onto the soil organic matter. The distribution coefficient (Kd), between the solid and liquid phases showed a logarithmic increase when the organic content of soil increased. The column's hydrodynamic characteristics (alphaL) and the kinetic coefficients (k) of chelant extraction were estimated independently for each soil. A correlation of kinetic coefficients data versus soil's organic content was also proposed: experimental data showed, in the investigated range, a logarithmic dependence of k on the organic content of soil.

Chelating Agents↗

Two-stage case-control studies: precision of parameter estimates and considerations in selecting sample size.

A two-stage case-control design, in which exposure and outcome are determined for a large sample but covariates are measured on only a subsample, may be much less expensive than a one-stage design of comparable power. However, the methods available to plan the sizes of the stage 1 and stage 2 samples, or to project the precision/power provided by a given configuration, are limited to the case of a binary exposure and a single binary confounder. The authors propose a rearrangement of the components in the variance of the estimator of the log-odds ratio. This formulation makes it possible to plan sample sizes/precision by including variance inflation factors to deal with several confounding factors. A practical variance bound is derived for two-stage case-control studies, where confounding variables are binary, while an empirical investigation is used to anticipate the additional sample size requirements when these variables are quantitative. Two methods are suggested for sample size planning based on a quantitative, rather than binary, exposure.

Case-Control Studies↗

Multiple comparisons distortions of parameter estimates.

In experiments involving many variables, investigators typically use multiple comparisons procedures to determine differences that are unlikely to be the result of chance. However, investigators rarely consider how the magnitude of the greatest observed effect sizes may have been subject to bias resulting from multiple testing. These questions of bias become important to the extent investigators focus on the magnitude of the observed effects. As an example, such bias can lead to problems in attempting to validate results, if a biased effect size is used to power a follow-up study. An associated important consequence is that confidence intervals constructed using standard distributions may be badly biased. A bootstrap approach is used to estimate and adjust for the bias in the effect sizes of those variables showing strongest differences. This bias is not always present; some principles showing what factors may lead to greater bias are given and a proof of the convergence of the bootstrap distribution is provided.

Bias↗