Kinetic Modeling Software Research Articles

Perspective on automated predictive kinetics using estimates derived from large datasets

AbstractA longstanding project of the chemical kinetics community is to predict reaction rates and the behavior of reacting systems, even for systems where there are no experimental data. Many important reacting systems (atmosphere, combustion, pyrolysis, partial oxidations) involve a large number of reactions occurring simultaneously, and reaction intermediates that have never been observed, making this goal even more challenging. Improvements in our ability to compute rate coefficients and other important parameters accurately from first principles, and improvements in automated kinetic modeling software, have partially overcome many challenges. Indeed, in some cases quite complicated kinetic models have been constructed which accurately predicted the results of independent experiments. However, the process of constructing the models, and deciding which reactions to measure or compute ab initio, relies on accurate estimates (and indeed most of the numerical rate parameters in most large kinetic models are estimates.) Machine‐learned models trained on large datasets can improve the accuracy of these estimates, and allow a better integration of quantum chemistry and experimental data. The need for continued development of shared (perhaps open‐source) software and databases, and some directions for improvement, are highlighted. As we model more complicated systems, many of the weaknesses of the traditional ways of doing chemical kinetic modeling, and of testing kinetic models, have been exposed, identifying several challenges for future research by the community.

PHYSICAL-CHEMICAL MODELING AND INVESTIGATION OF THE “HIGH-ENTROPY METAL MATRIX / TiC” SYSTEM COMPONENTS INTERACTION

The research carried out is aimed at developing the scientific basis for obtaining new composite materials based on high-entropy alloys, as well as developing the basic principles of processing and operation of such materials. It was necessary to conduct a theoretical and experimental study of the physical-chemical processes occurring during the interaction of high-entropy alloys with reinforcing TiC particles, as well as to study the effect of temperature and composition of interacting phases on the interaction process and its results. Thermodynamic and kinetic modeling of the interaction processes of the matrix components of high-entropy alloys based on the Cantor alloy (FeCoCrNiMn), including titanium and carbon with the formation of titanium carbide was carried out. Modern modeling approaches were used, which makes it possible to implement modern software. In particular, thermodynamic modeling using methods developed within the framework of the Calphad approach was carried out. Thermo-Calc software (includingTC-PRISMA kinetic modeling software) and FactSage software were used in the research process. An experimental study of the composition and structure of samples of TiC-reinforced metal matrix materials (using electron microscopy, X-ray spectral microanalysis and XRD) was also carried out. The distribution of various elements in the microstructure of materials and their phase composition were investigated. Comparison of the simulation results with experimental data allowed to make conclusions about the qualitative adequacy of thermodynamic and kinetic models of phase equilibria and phase transformations occurring during the formation, possible heat treatment and operation of TiC-reinforced metal matrix materials at high temperatures to the observed experimental data.

Determining the effect of cardiac blood volume on accuracy of uptake rate constants by simulation

Objective. There is great interest in better understanding coronary microvascular disease using mouse models. Typical quantification requires dynamic imaging to estimate the rate constant K 1 of the tracer moving from the blood into the myocardium. In addition to K 1, it is also desirable to determine blood volume fraction V, which if known allows for more accurate fitting of K 1. Our previously published kinetic modeling software did not consider the effect of V. To ensure a better fit of experimental data to the model for myocardial SPECT imaging, in this work we updated our kinetic modeling software to include a blood volume fraction V, which adds a fraction of the arterial activity concentration into the tissue concentration. Approach. The tissue and blood time-activity curves (TACs) used for fit input were generated using ideal equations with known values in MATLAB. This allowed post-fit results to be compared to known values to determine fit errors. Parameters that were varied in generating the TACs included blood volume fraction (0, 0.05, 0.1, 0.2 and 0.3), K 1 (0.5, 1.5, 2.5 ml min−1 g−1), frame length (1, 2, 5, 10, 15, 20 s), FWHM of the input Gaussian (10, 20, 40 s), and time of the injection peak relative to frame duration. Blood volume-fraction results have low error when blood volume is lowest, but results worsen as frame length and K 1 increase. Main results. We demonstrated that blood volume can be accurately determined, and also show how fit accuracy varies across TACs with different input properties. Significance. This information allows for robust use of the fitting algorithm and aids in understanding fit performance when used in animal studies.

Framing protocol optimization in oncological Patlak parametric imaging with uKinetics

PurposeTotal-body PET imaging with ultra-high sensitivity makes high-temporal-resolution framing protocols possible for the first time, which allows to capture rapid tracer dynamic changes. However, whether protocols with higher number of temporal frames can justify the efficacy with substantially added computation burden for clinical application remains unclear. We have developed a kinetic modeling software package (uKinetics) with the advantage of practical, fast, and automatic workflow for dynamic total-body studies. The aim of this work is to verify the uKinetics with PMOD and to perform framing protocol optimization for the oncological Patlak parametric imaging.MethodsSix different protocols with 100, 61, 48, 29, 19 and 12 temporal frames were applied to analyze 60-min dynamic 18F-FDG PET scans of 10 patients, respectively. Voxel-based Patlak analysis coupled with automatically extracted image-derived input function was applied to generate parametric images. Normal tissues and lesions were segmented manually or automatically to perform correlation analysis and Bland–Altman plots. Different protocols were compared with the protocol of 100 frames as reference.ResultsMinor differences were found between uKinetics and PMOD in the Patlak parametric imaging. Compared with the protocol with 100 frames, the relative difference of the input function and quantitative kinetic parameters remained low for protocols with at least 29 frames, but increased for the protocols with 19 and 12 frames. Significant difference of lesion Ki values was found between the protocols with 100 frames and 12 frames.ConclusionuKinetics was proved providing equivalent oncological Patlak parametric imaging comparing to PMOD. Minor differences were found between protocols with 100 and 29 frames, which indicated that 29-frame protocol is sufficient and efficient for the oncological 18F-FDG Patlak applications, and the protocols with more frames are not needed. The protocol with 19 frames yielded acceptable results, while that with 12 frames is not recommended.

A Python Multiscale Thermochemistry Toolbox (pMuTT) for thermochemical and kinetic parameter estimation

Estimating the thermochemical properties of systems is important in many fields such as material science and catalysis. The Python multiscale thermochemistry toolbox (pMuTT) is a Python software library developed to streamline the conversion of ab-initio data to thermochemical properties using statistical mechanics, to perform thermodynamic analysis, and to create input files for kinetic modeling software. Its open-source implementation in Python leverages existing scientific codes, encourages users to write scripts for their needs, and allows the code to be expanded easily. The core classes developed include a statistical mechanical model in which energy modes can be included or excluded to suit the application, empirical models for rapid thermodynamic property estimation, and a reaction model to calculate kinetic parameters or changes in thermodynamic properties. In addition, pMuTT supports other features, such as Brønsted–Evans–Polanyi (BEP) relationships, coverage effects, and ab-initio phase diagrams. Program summaryProgram title: pMuTTProgram files doi: http://dx.doi.org/10.17632/b7f7d28ynd.1Licensing provisions: MIT license (MIT)Programming language: PythonExternal routines: ASE, NumPy, Pandas, SciPy, Matplotlib, Pygal, PyMongo, dnspythonNature of problem: Conversion of ab-initio properties to thermochemical properties and rate constants is time consuming and error-prone.Solution method: Python package with a modular approach to statistical thermodynamics and rate constant estimation.

MON-145 THE RELATIONSHIP BETWEEN OSTEOPOROSIS AND THE NUTRITIONAL STATUS REPRESENTED BY NORMALIZED PROTEIN CATABOLIC RATE (nPCR) IN HEMODIALYSIS PATIENTS

The risk of osteoporosis in hemodialysis patients is high. If such osteoporosis occurs, it will cause various complications. Various indicators are available for predicting the occurrence of osteoporosis. And the preventive method is suggested. However, there is a lack of predictable indicators of the risk of osteoporosis associated with the nutritional status of hemodialysis patients. The purpose of this study is to investigate the relationship between nutritional status and the incidence of osteoporosis. We studied 145 patients who underwent bone mineral density (BMD) test among hemodialysis patients. BMD was measured by dual-energy X-ray absorptiometry. The diagnosis of osteoporosis followed the WHO criteria according to the values of the femoral neck T-scores. Nutritional status of patients was assessed using nPCR values calculated using urea kinetic modeling software programs. nPCR reflects the overall nutritional status and malnutrition of hemodialysis patients, reflecting the amount of protein metabolized in excess of the amount of synthesized protein. Among patients with residual renal function, total urea lost in the urine was also considered. The mean age was 65.12 ± 11.04 years. There are 76 men and 69 women. A total of 60 patients were diagnosed with osteoporosis (41.4%), of whom 12 (20%) were male and 48 (80%) were female. There was no difference in dialysis duration between two groups according to osteoporosis diagnosis (49.8 ± 31.9 months vs. 59.8 ± 46.4 months, p = 0.151). However, age was higher in the group diagnosed with osteoporosis (63.2 ± 11.9 years vs 67.8 ± 9.2 years, p = 0.010). Patients’ nPCR was compared according to the presence or absence of osteoporosis diagnosis. The nPCR in the group not diagnosed with osteoporosis was 1.2 ± 0.3 g/㎏ per day. On the other hand, nPCR in the group diagnosed with osteoporosis was 0.9 ± 0.2 g/kg per day and showed statistical difference (p = 0.016). The nPCR values observed in the non-osteoporotic group are consistent with the target nPCR provided by the American Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines and the European Best Practice Guidelines. It has been confirmed that maintaining adequate nutritional status in hemodialysis patients has a low risk of developing osteoporosis. Because of the high risk of osteoporosis in inappropriate nutritional status, continuous nutritional assessment and treatment of hemodialysis patients is important.

Teaching Chemical Kinetics with Dynamic Simulations

Teaching chemical kinetics is often challenging because quantifying multistep reactions typically requires mathematically nontrivial analyses. Here, we describe the use of ‘KinTek Explorer’ kinetic modeling software to fit kinetic data from a common two-step reaction [i.e., reduction of chromium(VI) by glutathione], thereby facilitating students’ intuitive understanding of chemical kinetics.

Homogenizing Advanced Alloys: Thermodynamic and Kinetic Simulations Followed by Experimental Results

Segregation of solute elements occurs in nearly all metal alloys during solidification. The resultant elemental partitioning can severely degrade as-cast material properties and lead to difficulties during post-processing (e.g., hot shorts and incipient melting). Many cast articles are subjected to a homogenization heat treatment in order to minimize segregation and improve their performance. Traditionally, homogenization heat treatments are based upon past practice or time-consuming trial and error experiments. Through the use of thermodynamic and kinetic modeling software, NETL has designed a systematic method to optimize homogenization heat treatments. Use of the method allows engineers and researchers to homogenize casting chemistries to levels appropriate for a given application. The method also allows for the adjustment of heat treatment schedules to fit limitations on in-house equipment (capability, reliability, etc.) while maintaining clear numeric targets for segregation reduction. In this approach, the Scheil module within Thermo-Calc is used to predict the as-cast segregation present within an alloy, and then diffusion controlled transformations is used to model homogenization kinetics as a function of time and temperature. Examples of computationally designed heat treatments and verification of their effects on segregation and properties of real castings are presented.

Microstructural Evolution and Mechanical Properties of Simulated Heat-Affected Zones in Cast Precipitation-Hardened Stainless Steels 17-4 and 13-8+Mo

Cast precipitation-hardened (PH) stainless steels 17-4 and 13-8+Mo are used in applications that require a combination of high strength and moderate corrosion resistance. Many such applications require fabrication and/or casting repair by fusion welding. The purpose of this work is to develop an understanding of microstructural evolution and resultant mechanical properties of these materials when subjected to weld thermal cycles. Samples of each material were subjected to heat-affected zone (HAZ) thermal cycles in the solution-treated and aged condition (S-A-W condition) and solution-treated condition with a postweld thermal cycle age (S-W-A condition). Dilatometry was used to establish the onset of various phase transformation temperatures. Light optical microscopy (LOM), scanning electron microscopy (SEM), and energy dispersive spectrometry (EDS) were used to characterize the microstructures, and comparisons were made to gas metal arc welds that were heat treated in the same conditions. Tensile testing was also performed. MatCalc thermodynamic and kinetic modeling software was used to predict the evolution of copper (Cu)-rich body center cubic precipitates in 17-4 and β-NiAl precipitates in 13-8+Mo. The yield strength was lower in the simulated HAZ samples of both materials prepared in the S-A-W condition when compared to their respective base metals. Samples prepared in the S-W-A condition had higher and more uniform yield strengths for both materials. Significant changes were observed in the matrix microstructure of various HAZ regions depending on the peak temperature, and these microstructural changes were interpreted with the aid of dilatometry results, LOM, SEM, and EDS. Despite these significant changes to the matrix microstructure, the changes in mechanical properties appear to be governed primarily by the precipitation behavior. The decrease in strength in the HAZ samples prepared in the S-A-W condition was attributed to the dissolution of precipitates, which was supported by the MatCalc modeling results. MatCalc modeling results for samples in the S-W-A condition predicted uniform size of precipitates across all regions of the HAZ, and these predictions were supported by the observed trends in mechanical properties. Cross-weld tensile tests performed on GMA welds showed the same trends in mechanical behavior as the simulated HAZ samples. Welding in the S-W-A condition resulted in over 90 pct retention in yield strength when compared to base metal strengths. These findings indicate that welding these PH stainless steels in the solution-treated condition and using a postweld age will provide better and more uniform mechanical properties in the HAZ that are more consistent with the base metal properties.

Reduced dose measurement of absolute myocardial blood flow using dynamic SPECT imaging in a porcine model.

Absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) measurements provide important additional information over traditional relative perfusion imaging. Recent advances in camera technology have made this possible with single-photon emission tomography (SPECT). Low dose protocols are desirable to reduce the patient radiation risk; however, increased noise may reduce the accuracy of MBF measurements. The authors studied the effect of reducing dose on the accuracy of dynamic SPECT MBF measurements. Nineteen 30-40 kg pigs were injected with 370 + 1110 MBq of Tc-99m sestamibi or tetrofosmin or 37 + 111 MBq of Tl-201 at rest + stress. Microspheres were injected simultaneously to measure MBF. The pigs were imaged in list-mode for 11 min starting at the time of injection using a Discovery NM 530c camera (GE Healthcare). Each list file was modified so that 3/4, 1/2, 1/4, 1/8, 1/16, and 1/32 of the original counts were included in the projections. Modified projections were reconstructed with CT-based attenuation correction and an energy window-based scatter correction and analyzed with FlowQuant kinetic modeling software using a 1-compartment model. A modified Renkin-Crone extraction function was used to convert the tracer uptake rate K1 to MBF values. The SPECT results were compared to those from microspheres. Correlation between SPECT and microsphere MBF values for the full injected activity was r ≥ 0.75 for all 3 tracers and did not significantly degrade over all count levels. The mean MBF and MFR and the standard errors in the estimates were not significantly worse than the full-count data at 1/4-counts (Tc99m-tracers) and 1/2-counts (Tl-201). Dynamic SPECT measurement of MBF and MFR in pigs can be performed with 1/4 (Tc99m-tracers) or 1/2 (Tl-201) of the standard injected activity without significantly reducing accuracy and precision.

Experimental and mathematical analysis of in vitro Pitavastatin hepatic uptake across species

1. To investigate the non-linear kinetics of in vitro hepatocyte uptake across species, the OATP substrate Pitavastatin was used as a probe.2. Experiments were conducted at AstraZeneca (Alderley Park, Macclesfield) using freshly isolated rat, dog and human hepatocytes, utilising the “oil spin” methodology described by Hassen et al. (1996). Very few mechanistic models have previously been used to characterise the uptake process.3. Here two candidate pharmacokinetic non-linear compartmental models are proposed. Both models have been shown to be structurally identifiable and distinghishable previously, which establishes that all unknown parameters could be identified from the experimental observations available and that input/output relationships for both the candidate models were structurally different.4. A kinetic modelling software package, FACSIMILE (MCPA Software, Faringdon, UK), was used to obtain numerical solutions for the system equations and for parameter estimation. Model fits gave good agreement with the in vitro data and suggest the current widely accepted assumption that the rate of diffusion across the hepatocyte cell membrane is the same at both 4 °C and 37 °C is not valid, at least for Pitavastatin. Although this finding has already been proposed, this is the first time it is comprehensively debunked using statistical testing.

Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein

A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios.

Selection of modalities, prescription, and technical issues in children on peritoneal dialysis.

Peritoneal dialysis (PD) is widely employed as a dialytic therapy for uraemic children, especially in its automated form (APD), that is associated with less burden of care on patient and family than continuous ambulatory PD. Since APD offers a wide range of treatment options, based on intermittent and continuous regimens, prescription can be individualized according to patient’s age, body size, residual renal function, nutritional intake, and growth-related metabolic needs. Transport capacity of the peritoneal membrane of each individual patient should be assessed, and regularly monitored, by means of standardized peritoneal function tests validated in pediatric patients. To ensure maximum recruitment of peritoneal exchange area, fill volume should be scaled to body surface area and adapted to each patient, according to clinical tolerance and intraperitoneal pressure. PD solutions should be employed according to their biocompatibility and potential ultrafiltration capacity; new pH-neutral, glucose-free solutions can be used in an integrated way in separate dwells, or by appropriately mixing during the same dialytic session. Kinetic modelling software programs may help in the tailoring of PD prescription to individual patients’ characteristics and needs. Owing to advances in the technology of new APD machines, greater programming flexibility, memorized delivery control, and tele-dialysis are currently possible.

Homogenizing a Nickel-Based Superalloy: Thermodynamic and Kinetic Simulation and Experimental Results

If the chemical inhomogeneity profile is known a priori, kinetic modeling software such as diffusion-controlled transformations (DICTRA) can be used to model the homogenization kinetics of an alloy. In this study, the Scheil module within the Thermo-Calc software was used to predict the as-cast segregation present within the Ni-based superalloy Nimonic 105. The segregation profiles were read into DICTRA to refine the homogenization heat treatment of this alloy. The thermodynamic and kinetic modeling of the computationally predicted heat treatment and microstructure, and subsequent experimental verification on a real casting of Nimonic 105, are presented.

Compartmental Modelling of the Pharmacokinetics of a Breast Cancer Resistance Protein

A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent inhibitor, Fumitremorgin C (FTC), present is described. This non-linear compartmental model has seven macroscopic sub-units, with fourteen rate parameters. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used to obtain numerical solutions for the system equations and for parameter fitting. Model fits gave good agreement with in-vitro data provided by AstraZeneca.

Kinetic Data by Nonisothermal Reaction Calorimetry: A Model-Assisted Calorimetric Evaluation

The use of a reaction calorimeter in combination with kinetic modeling software to obtain nonisothermal kinetic data is presented. The Diels−Alder reaction of maleic anhydride and isoprene in DMF was used as a model to demonstrate the feasibility of the method. The Arrhenius A factor and the activation energy could be achieved from a single experiment with a reaction calorimeter (Mettler RC1) by fitting the experimental heat generation curve to a second-order kinetic model using commercially available software packages. The use of fitting software revealed a discrepancy between the experimental reaction heat and the heat calculated from the rate parameters. This discrepancy could be resolved by reintegration of the heat generation curve using an adjusted baseline derived from the rate data. The methodology was applied by varying reaction conditions (starting concentrations, heat rate, temperature range), and the results appeared to be independent of these variations within the experimental errors (Ea = 58...

Degradation of carbendazim by UV/H 2 O 2 investigated by kinetic modelling

The transformation of the fungicide carbendazim (methyl-2 benzimidazole carbamate) induced by hydroxyl radical generated by the UV photolysis of H2O2 has been studied in dilute aqueous solution. The efficient reaction of hydroxyl radicals with carbendazim led to the rapid degradation of carbendazim. The study of reaction kinetics yielded a second order rate constant of 2.2±0.3 109 M−1 s−1 for HO· radicals with carbendazim. This value is in agreement with a high reactivity of HO· radicals with carbendazim. Most degradation products were identified by high performance liquid chromatography mass spectrometry (HPLC-MS). In the presence of hydrogenocarbonate and carbonate ions, hydroxyl radicals were quenched and in turn carbonate radicals CO3·− were formed. Carbonate radicals are indeed known to react efficiently with compounds containing electron-rich sites such as nitrogen or sulfur atoms. The use of a kinetic modelling software gave evidence for the occurrence of such reactions with carbendazim. The second order rate constant of carbonate radical with carbendazim was equal to 6±2 106 M−1 s−1.

Rearrangement of alkyl phenyl ethers over dealuminated HY zeolites under liquid-phase conditions

The rearrangement reaction of alkyl phenyl analogue ethers of anisole, such as ethoxybenzene, n-propoxybenzene and n-butoxybenzene, over a dealuminated HY zeolite (Si/Al=10) has been investigated. Phenol, alkoxyalkylbenzenes and alkylphenols are obtained as main products. From the systematic study of the rearrangement reaction of ethoxybenzene, chosen as a model substrate, a general scheme has been advanced for the dealkylation reaction. Such a scheme, which involves both intramolecular and intermolecular rearrangements, has been confirmed by the use of kinetic modelling software. The influence of the temperature on the rate constants of each step of the reactional process and on the product distribution has been studied, together with the isomer distribution in ethoxyethylbenzene and ethylphenol formation.