Simplified Mechanistic Model Research Articles

Translational modelling to predict human pharmacokinetics and pharmacodynamics of a Bruton's tyrosine kinase-targeted protein degrader BGB-16673.

Bifunctional small molecule degraders, which link the target protein with E3 ubiquitin ligase, could lead to the efficient degradation of the target protein. BGB-16673 is a Bruton's tyrosine kinase (BTK) degrader. A translational PK/PD modelling approach was used to predict the human BTK degradation of BGB-16673 from preclinical in vitro and in vivo data. A simplified mechanistic PK/PD model was used to establish the correlation between the in vitro and in vivo BTK degradation by BGB-16673 in a mouse model. Human and mouse species differences were compared using the parameters generated from in vitro human or mouse blood, and human or mouse serum spiked TMD-8 cells. Human PD was then predicted using the simplified mechanistic PK/PD model. BGB-16673 showed potent BTK degradation in mouse whole blood, human whole blood, and TMD-8 tumour cells in vitro. Furthermore, BGB-16673 showed BTK degradation in a murine TMD-8 xenograft model in vivo. The PK/PD model predicted human PD and the observed BTK degradation in clinical studies both showed robust BTK degradation in blood and tumour at clinical dose range. The presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage.

Abstract 3497: The polyclonal path to malignant transformation in familial adenomatous polyposis

Abstract Familial adenomatous polyposis (FAP) patients develop hundreds of premalignant polyps that progress to colorectal cancer due to a germline mutation in the APC tumor suppressor. Polyps from FAP patients uniquely facilitate interrogation of the continuum of malignant transformation from histologically normal mucosa to benign and dysplastic polyps and eventual adenocarcinomas. As part of the Human Tumor Atlas Network (HTAN), we performed multi-omic profiling, including whole genome sequencing, on 135 samples from six FAP patients across the pre-malignant continuum spanning all physical regions of the large intestine, and serving as the most comprehensive FAP dataset available. Through a comparative analysis with a published FAP cohort (58 multi-region samples across 5 patients) and sporadic colorectal cancer cohort (n=57), each including benign and malignant samples, we evaluate the timing of driver acquisitions at each stage of malignant progression. Despite being separated by vast regions of histologically normal mucosa, independently evolving polyps show extensive mutation sharing, suggesting FAP polyps are polyclonal in origin. Finally, we leverage a simplified mechanistic model of embryonic colonic development demonstrating that the path to malignant transformation in FAP is consistent with polyclonal origins attributable to early mixing, perhaps as early as in-utero. Taken together, the HTAN FAP Atlas provides a novel window into the earliest stages of cancer formation and may illuminate barriers to malignant transformation and opportunities for earlier intervention. Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Emma Monte, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Neves, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Jeannie Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Basil Michael, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri A. Longacre, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path to malignant transformation in familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3497.

Temperature dependence of volatile organic compound emissions from surface coatings: Inter-species difference observed in real indoor environments and mechanistic understanding

Coatings often cover two-thirds of the surfaces in indoor environments and represent important sources of indoor volatile organic compounds (VOCs). Temperature is known to affect VOC emission rates from coatings, yet inter-species difference in the temperature dependence still needs to be understood. Based on time-resolved VOC measurements in an indoor air campaign conducted in residences in Beijing, China, we identified dibasic ester (DBE), a solvent mixture often used in coatings, and found that the concentration ratios of DBE components exhibited strong temperature dependence in an apartment when the indoor temperature declined stepwise over a multiweek period. To interpret the observational results, we developed a simplified mechanistic model relating the temperature dependence of VOC emission rates from coated surfaces to the temperature dependence of the diffusion coefficient of the emitted VOCs in the coating layer and further to a predicable molecular property of the emitted VOCs, molar volumes at 0 K, based on the free-volume theory. This correlation was quantitatively verified using the DBE data as well as using the data of alkanes, another set of VOCs that might be emitted from coatings, observed in two apartments in the same campaign. Given that indoor temperature varies considerably over seasons and across regions, the correlation proposed herein may help better predict indoor VOC emissions from coatings.

Dynamics of di-2-ethylhexyl phthalate (DEHP) in the indoor air of an office

Largely limited by measurement technique, dynamics of semivolatile organic compounds (SVOCs) in the indoor air is not well understood. This study reports time-resolved measurements of airborne concentration of di-2-ethylhexyl phthalate (DEHP) in an office, using semivolatile thermal desorption aerosol gas chromatography (SV-TAG). The measurements were conducted in two separate periods during the summer-to-fall transition in 2020, each for more than 10 days. The indoor gas-plus-particle DEHP concentration varied by more than one order of magnitude in each observation period, and the temporal pattern exhibited possible influences of the indoor temperature, particle mass concentration, and outdoor DEHP concentrations. Further analysis focusing on window-closed conditions (i.e., with less outdoor contribution) reveals that the DEHP dynamics was primarily driven by variations in the indoor temperature ( R 2 = 0.85) during the first, warmer period (24–29 °C), and by variations in the particle mass concentration ( R 2 = 0.83) during the subsequent cooler period (20–23 °C). The unexpected transition of the key driving factor with change of the temperature was qualitatively justified by a simplified mechanistic model. Moreover, the particle fraction of DEHP was measured during the latter, cooler period, and it exhibited strong dependence on particle concentration, which can be fitted assuming gas-particle equilibrium partitioning, with a best-fit apparent partitioning coefficient of 0.053 ± 0.006 m 3 /μg at 20 ± 1 °C. Overall, these results improve our understanding of real-world SVOC dynamics. • In a warmer period variation in temperature drove DEHP dynamics in an office. • In a cooler period variation in particle concentration drove DEHP dynamics in the office. • Transition of the key driving factor with change in temperature was justified by mechanistic model. • Observed gas/particle partitioning of DEHP can be fitted assuming equilibrium state.

Online temperature estimation of Shell coal gasification process based on extended Kalman filter

Obtaining the temperature inside the gasifier of a Shell coal gasification process (SCGP) in real-time is very important for safe process operation. However, this temperature cannot be measured directly due to the harsh operating condition. Estimating this temperature using the extended Kalman filter (EKF) based on a simplified mechanistic model is proposed in this paper. The gasifier is partitioned into three zones. The quench pipe and the transfer duct are seen as two additional zones. A simplified mechanistic model is developed in each zone and formulated as a state-space representation. The temperature in each zone is estimated by the EKF in real-time. The proposed method is applied to an industrial SCGP and the effectiveness of the estimated temperatures is verified by a process variable both qualitatively and quantitatively. The prediction capability of the simplified mechanistic model is validated. The effectiveness of the proposed method is further verified by comparing it to a Kalman filter-based single-zone temperature estimation method.

Thermal evolution of chemical structure and mechanism of oil sands bitumen

Oil sands bitumen (OSB) is the key component of extracted oil sands, thus further investigation of the mechanism of OSB pyrolysis reaction would be helpful for the development and application of oil sands pyrolysis process. First, chemical structure parameters and thermogravimetric (TG) behavior of OSB were experimentally investigated by 13C NMR spectroscopy and TG analysis, respectively, to initially evaluate the correlation between chemical structure parameters and pyrolytic behavior. Further, the ATR–FTIR spectroscopy technology was used to experimentally characterize and calculate the structural parameters of OSB at different pyrolysis final temperatures, and the main thermal evolution rules of different functional groups during the pyrolysis reaction were obtained. Based on this result and by using the model fitting method, the pyrolysis of OSB was found to be a parallel reaction. Moreover, the kinetic calculation results obtained by Straink method and distributed activated energy model method also supported this result. The correlation between chemical structure parameters and activation energy was analyzed, and it was found that the degree of aromatization Y-factor could be used to characterize the pyrolysis reaction activity. Finally, this study proposed a simplified mechanistic model of chemical structure evolution during OSB pyrolysis.

Operation optimization of Shell coal gasification process based on convolutional neural network models

Coal gasification technology has gained increasing popularity in recent years, but the optimization of operating conditions remains inefficient. The operation optimization of the Shell coal gasification process (SCGP) is investigated in this paper using an operation optimization model integrating data analytics and mechanism analysis. The objective function contains two important indicators. One is effective syngas productivity and the other one is specific oxygen consumption. The optimization is subject to constraints on gasifier temperature and syngas yield. The objective function and the constraints can be calculated by six key operating parameters through three convolutional neural network (CNN) models, which can additionally utilize the correlations between process variables. Prior physical knowledge and a simplified mechanistic model of SCGP are integrated with the development of CNN models. The effectiveness of the proposed model is validated by an industrial case study. After the operation optimization, the objective function decreases by 28.3306% compared with its minimum value on historical process operation data, which outperforms the operation optimization model developed by artificial neural network models. The sensitivities of the objective function and effective syngas yield are analyzed. The operating condition of SCGP can be optimized by the proposed model.

Can metabolites at harvest be used as physiological markers for modelling the softening behaviour of Chilean “Hass” avocados destined to local and distant markets?

The aim of this study was to model Chilean “Hass” avocado softening behaviour, destined to local and distant markets, taking into account the biological variation given by growing location and harvest stages. A total of 24 batches were obtained during the season 2018–2019 from different agro-climatic zones (coast, intermediate and interior) and two harvest stages (based on dry matter content). Fruit softening during either regular air (RA) or controlled atmosphere (CA) storage at 5 °C followed by shelf-life at 20 °C was modelled using a simplified mechanistic model. Most of the model parameters were treated as being generic for all fruit except for two fruit specific parameters, F0 (firmness at harvest) and E0 (amount of enzyme complex at harvest) that characterized the fruit at harvest and thus postharvest ripening behaviour. The model was able to describe 87.6 % of the observed variation of all 24 fruit batches studied from different agro-climatic zones at the batch averaged level, but 93.5 % of the observed variation at the fruit individual level. Since measured at harvest when most fruit are highly firm, initial fruit firmness by itself was not able to discriminate among the various batches as they all showed similar normal distributions among the different agro-climatic zones, in addition, the estimated E0 values for each individual fruit were correlated to key metabolites to identify potential metabolite biomarkers discriminating among the different regions and batches. The developed model can be utilized to predict the batch specific ripening behaviour of “Hass” avocado under different postharvest logistic chains given the distribution of E0 is known.

Performance of battery rack auxiliary power systems under FEMA 461 quasi-static seismic loading protocol

The performance of nonstructural components in nuclear power plants (NPPs), which is primarily based on experience and historical data, has been attracting increased interest from researchers following the Fukushima Daiichi nuclear disaster in 2011. This disaster demonstrated the importance of using batteries in NPPs as an auxiliary power system, where such systems can provide the necessary power to mitigate the risk of serious accidents. However, little research has been conducted on such nonstructural components (e.g., auxiliary battery power systems) to evaluate their performance following the post-Fukushima safety requirements, recommended by several nuclear regulators worldwide [e.g., Nuclear Regulatory Commission (NRC), and Nuclear Safety Commission (NSC)]. To address this research gap, the current study investigates the lateral performance of an auxiliary battery power system similar to those currently existing/operational in NPPs in Canada. The rack system was experimentally tested under displacement-controlled quasi-static cyclic fully-reversed loading that simulates lateral seismic demands, following the FEMA 461 guidelines “Interim testing protocol for determining the seismic performance characteristics of structural and nonstructural components”. Following a brief summary of the experimental program, the test results are presented in terms of the rack hysteretic response, damage sequence, stiffness degradation, ductility capacity, member strains, and local deformations. Subsequently, a simplified mechanistic model and a concentrated plasticity model in OpenSees have been developed and calibrated using the experimental results. The results show that without detailed modeling of the rack system connections (i.e., L-shaped connection and sliding nuts), incorrect performance prediction of such systems may result. The findings of the current study can be utilized, within the next generation of performance-based seismic design approaches, to enhance the robustness and improve the reliability of damage state predictions of auxiliary battery power systems in critical facilities.

Parametric and Rate Studies of Reduction of Cr(VI) in Slurry of Contaminated Soil with Hydrazine and Sonochemical Augmentation

ABSTRACT Reduction of Cr(VI) to Cr(III) in aqueous solution and also in suspension of contaminated soil with hydrazine has been investigated thoroughly. The effects of the major parameters such as concentrations of Cr(VI) and hydrazine and their mole ratio, the fraction of soil in suspension, pH and temperature on the rate of reduction have been studied. Suspended oil has a strong catalytic effect on the process, a phenomenon not hitherto reported in the literature. With 33.3% soil in suspension, complete reduction of Cr(VI) was achieved in 4 hr with 33% excess hydrazine. But the time reduces to 20 minutes if four times the stoichiometric quantity of hydrazine is used. A simplified mechanistic model for the reduction reaction rather than the phenomenological approach adopted by some of the earlier researchers has been developed on the basis of two-electron transfer pathway leading to a second-order rate form. Experimental rate data fitted satisfactorily in the equation and the rate constant could be evaluated using the integrated form of the equation. The rate constant depends linearly on soil concentration; the logarithm of the rate constant is linear in pH over the range 4–10. The activation energy for the reaction is 34 kJ/mol. Sonication of an aqueous solution of Cr(VI) significantly enhances the reaction, the rate constant being doubled at a sonication frequency of 30 kHz. Effect of sonication is also significant in presence of suspended soil. Complete reduction of Cr(VI) with stoichiometric dosing of hydrazine was achieved under sonication in a much smaller reaction time. Treatment with hydrazine in the slurry phase especially with sonication will prove to be a practically effective ex situ strategy of remediation of a large number of Cr(VI)-contaminated sites worldwide.

Dynamic Optimization of a Fed-Batch Nosiheptide Reactor

Nosiheptide is a sulfur-containing peptide antibiotic, showing exceptional activity against critical pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) with livestock applications that can be synthesized via fed-batch fermentation. A simplified mechanistic fed-batch fermentation model for nosiheptide production considers temperature- and pH-dependence of biomass growth, substrate consumption, nosiheptide production and oxygen mass transfer into the broth. Herein, we perform dynamic simulation over a broad range of possible feeding policies to understand and visualize the region of attainable reactor performances. We then formulate a dynamic optimization problem for maximization of nosiheptide production for different constraints of batch duration and operability limits. A direct method for dynamic optimization (simultaneous strategy) is performed in each case to compute the optimal control trajectories. Orthogonal polynomials on finite elements are used to approximate the control and state trajectories allowing the continuous problem to be converted to a nonlinear program (NLP). The resultant large-scale NLP is solved using IPOPT. Optimal operation requires feedrate to be manipulated in such a way that the inhibitory mechanism of the substrate can be avoided, with significant nosiheptide yield improvement realized.

Model-based analysis of biocatalytic processes and performance of microbioreactors with integrated optical sensors

Design and development of scale-down approaches, such as microbioreactor (μBR) technologies with integrated sensors, are an adequate solution for rapid, high-throughput and cost-effective screening of valuable reactions and/or production strains, with considerably reduced use of reagents and generation of waste. A significant challenge in the successful and widespread application of μBRs in biotechnology remains the lack of appropriate software and automated data interpretation of μBR experiments. Here, it is demonstrated how mathematical models can be usedas helpful tools, not only to exploit the capabilities of microfluidic platforms, but also to reveal the critical experimental conditions when monitoring cascade enzymatic reactions. A simplified mechanistic model was developed to describe the enzymatic reaction of glucose oxidase and glucose in the presence of catalase inside a commercial microfluidic platform with integrated oxygen sensor spots. The proposed model allowed an easy and rapid identification of the reaction mechanism, kinetics and limiting factors. The effect of fluid flow and enzyme adsorption inside the microfluidic chip on the optical sensor response and overall monitoring capabilities of the presented platform was evaluated via computational fluid dynamics (CFD) simulations. Remarkably, the model predictions were independently confirmed for μL- and mL- scale experiments. It is expected that the mechanistic models will significantly contribute to the further promotion of μBRs in biocatalysis research and that the overall study will create a framework for screening and evaluation of critical system parameters, including sensor response, operating conditions, experimental and microbioreactor designs.

378 Induced psoriasis-like inflammation in an air pouch mouse model

Human psoriasis is a complex autoimmune skin disease, affecting a significant number of the global population. The initiation pathway comprises the differentiation and infiltration of Th17 cells into the skin and is characterized by the production of IL-17A and IL-17F cytokines. This results in a downstream cascade of events, including an exacerbated inflammatory response. In order to establish a more simplified mechanistic mouse model of psoriasis inflammation, we utilized the 6-day air pouch mouse model and aimed for the induction of a psoriasis-like inflammation by injecting a cocktail of inflammatory triggers into the air pouch cavity. The combination of anti-CD3 and IL-23 with or without IL-1β resulted in significantly increased IL-17A and IL-17F intra-pouch levels, and triggered a downstream production of the CXCL1 chemokine. The produced cytokines were detectable even 72 hours post-induction. In addition, TCRβ was downregulated on the cell surface of CD4 and CD8 positive T cells, indicating intra-pouch T cell activation. The presence of anti-CD3 seemed to be important for the increased production of the IL-17 cytokines, even at low concentrations. Furthermore, anti-CD3 induced CD3 positive cell migration into the subcutis and the lining tissue surrounding the air pouch cavity. In conclusion, the induced air pouch mouse model can mirror the IL-23/IL-17 axis of psoriasis-like inflammation.

Lateral behavior of panelized CLT walls: A pushover analysis based on minimal resistance assumption

A new simplified mechanistic model was developed in this study to predict the rocking and sliding lateral response of a CLT panel wall under monotonic pushover with different boundary and gravity loading conditions based on an approximation of the principle of virtual work. Namely, for a given forced lateral displacement increment, the CLT wall will engage in a combination of rocking and sliding motion that will minimize the total work needed to go through that displacement increment. The proposed model was compared to the existing test results to illustrate its ability to capture the two types of wall behavior. Being a simplified mechanistic model, a number of material nonlinear characteristics such as the local crush of wood and the biaxial interaction of the connectors were not captured, resulting in a backbone characterization accuracy not as good as some existing well-calibrated models. However, the contribution of the study is to provide a mechanistic approach to address the switching between rocking and sliding behavior of CLT panelized walls under different boundary conditions. Using the model, a sensitivity analysis was conducted to investigate the effect of wall configurations and boundary conditions on the behavior of CLT shear walls.

Mechanistic Studies on the Nickel-Catalyzed Cyclopropanation with Lithiomethyltrimethylammonium Triflate

We report here our mechanistic study of the previously published nickel-catalyzed cyclopropanation reaction using lithiomethyltrimethylammonium triflate as methylene donor. The cyclopropane yield is highly dependent on the olefin substrate and correlates well with the binding affinity of the olefin to Ni(0) as established elsewhere. On the basis of this observation, we developed a simplified mechanistic model that can explain several odd observations we found in our initial report. Most importantly, a binding equilibrium between the olefin substrate and phosphine ligand appears to govern the ratio between product formation and unproductive ylide decomposition in a side reaction.

Simplified Mechanistic Model for Seismic Response Prediction of Coupled Cross-Laminated Timber Rocking Walls

AbstractA simplified mechanistic model is developed in this study to predict the lateral load resistance of coupled rocking walls made from cross-laminated timber (CLT) panels as an alternative to ...

Simplified Mechanistic Model of the Multiple Hearth Furnace for Control Development

Simplified Mechanistic Model of the Multiple Hearth Furnace for Control Development

A Simplified Mechanistic Model of Three-Component Surrogate Fuels for RP-3 Aviation Kerosene

In this study, a detailed chemical reaction kinetic model of a three-component surrogate fuel (73% n-dodecane, 14.7% 1,3,5–3-trimethylcyclohexane, and 12.3% n-propylbenzene) for RP-3 aviation kerosene was simplified, and a simplified mechanism for this fuel was obtained and validated. The detailed chemical reaction kinetic model included 257 components and 874 elementary reactions. In the first step, a mechanism consisting of 109 components and 423 elementary reactions was constructed from the detailed model using a directed relation graph (DRG). The second step, based on the first, was to construct an 84-component, 271-elementary-reaction mechanism using a DRG based on error propagation (DRGEP) and computational singular perturbation (CSP). In the third step, path analysis was applied to analyze the combustion paths under atmospheric pressure and high-temperature conditions; the results were compared with those of the detailed mechanism and the simplified mechanism of the second step to remove unimportan...

Numerical Simulation and Experimental Verification of an Alternative to Biomass Fuel

N-heptane was used as an alternative for biomass fuels research. A simplified mechanistic model of n-heptane oxidation has been studied in this paper. The calculation results reveal the relationship between ambience temperature and components. The environmental temperature acts on the chemical reaction mechanism, thus affecting the distribution of components. High temperature contributes to the formation of CO and C2H2, while low temperature contributes to the formation of CO2 and C2H2, and the influence of temperature on other components is not so obvious, such as C3H6 and so on. The experiment of biomass fuel combustion rate has a good agreement with that from the simulation of n-heptane, so we can conclude that this simplified n-heptane reaction mechanism model is a good alternative to biomass fuel study.

Permanent Deformation Characteristics of Coarse Grained Subgrade Soils under Train-Induced Repeated Load

This paper presents the results of a laboratory experiment that aimed to characterize the permanent deformation behavior of coarse grained soils. To evaluate the effects of the cyclic stress amplitude, initial mean stress, and initial stress ratio on the permanent axial deformation, six series of repeated load triaxial tests were performed. The results indicate that permanent deformation of coarse grained soils increased with increasing cyclic stress amplitude. In particular, for relative low cyclic stress levels, accumulation rate of permanent deformation decreased progressively with number of cycles and eventually reached an equilibrium state. The initial stress ratio was also found to obviously facilitate the buildup of axial deformation since it means higher deviatoric stress as the mean pressure kept constant. As the initial stress ratio was less than the slope of static failure line, the experimental results indicated that the increase of initial mean stress enhanced the capability of resisting deformation. A simplified mechanistic empirical prediction model was proposed, which predicted the permanent deformation as product of four independent functions about cyclic stress amplitude, initial mean stress, initial stress ratio, and number of load cycles. Satisfactory predictions of the permanent deformation behavior of coarse grained soils were obtained with the proposed model.