Computer Modeling System Research Articles

Coupled Enzyme Reactions Performed in Heterogeneous Reaction Media: Experiments and Modeling for Glucose Oxidase and Horseradish Peroxidase in a PEG/Citrate Aqueous Two-Phase System

The intracellular environment in which biological reactions occur is crowded with macromolecules and subdivided into microenvironments that differ in both physical properties and chemical composition. The work described here combines experimental and computational model systems to help understand the consequences of this heterogeneous reaction media on the outcome of coupled enzyme reactions. Our experimental model system for solution heterogeneity is a biphasic polyethylene glycol (PEG)/sodium citrate aqueous mixture that provides coexisting PEG-rich and citrate-rich phases. Reaction kinetics for the coupled enzyme reaction between glucose oxidase (GOX) and horseradish peroxidase (HRP) were measured in the PEG/citrate aqueous two-phase system (ATPS). Enzyme kinetics differed between the two phases, particularly for the HRP. Both enzymes, as well as the substrates glucose and H2O2, partitioned to the citrate-rich phase; however, the Amplex Red substrate necessary to complete the sequential reaction partitioned strongly to the PEG-rich phase. Reactions in ATPS were quantitatively described by a mathematical model that incorporated measured partitioning and kinetic parameters. The model was then extended to new reaction conditions, i.e., higher enzyme concentration. Both experimental and computational results suggest mass transfer across the interface is vital to maintain the observed rate of product formation, which may be a means of metabolic regulation in vivo. Although outcomes for a specific system will depend on the particulars of the enzyme reactions and the microenvironments, this work demonstrates how coupled enzymatic reactions in complex, heterogeneous media can be understood in terms of a mathematical model.

Calculation of Gasoline Octane Numbers Taking into Account the Reaction Interaction of Blend Components

A new approach for calculation of gasoline octane numbers was described taking into account the reaction interaction of blend components and the interaction mechanism of antiknock additives with hydrocarbons. It was determined that for octane numbers of alkylates and isomerizates, synergistic effect is observed, and for octane numbers of reformates, antagonistic effect is observed. The computer modeling system «Compounding» for calculation of gasoline octane numbers was designed.

Review of the socket design and interface pressure measurement for transtibial prosthesis.

Socket is an important part of every prosthetic limb as an interface between the residual limb and prosthetic components. Biomechanics of socket-residual limb interface, especially the pressure and force distribution, have effect on patient satisfaction and function. This paper aimed to review and evaluate studies conducted in the last decades on the design of socket, in-socket interface pressure measurement, and socket biomechanics. Literature was searched to find related keywords with transtibial amputation, socket-residual limb interface, socket measurement, socket design, modeling, computational modeling, and suspension system. In accordance with the selection criteria, 19 articles were selected for further analysis. It was revealed that pressure and stress have been studied in the last decaeds, but quantitative evaluations remain inapplicable in clinical settings. This study also illustrates prevailing systems, which may facilitate improvements in socket design for improved quality of life for individuals ambulating with transtibial prosthesis. It is hoped that the review will better facilitate the understanding and determine the clinical relevance of quantitative evaluations.

Modeling radionuclide migration in complex nonuniform water bodies using the POMRad model system

The POMRad system of computer models is developed using the Princeton Ocean Model (POM) program code. The system enables modeling the radionuclide migration in large nonuniform water bodies (seas, bays, large rivers, and lakes) taking account of the migration of radioactive substances in the water mass-bottom system associated with the migration of radionuclides sorbed on suspended sediments and in solutes. In order to take account of radionucide transport with sediments the POM program code is supplemented with the models describing transport, settling, and resuspension of suspended sediments. The verification was carried out through comparing analytical solutions of simplified problems concerning the content of radionuclides in water, and modeling results. A potential of the POMRad application is demonstrated by an example of simulating the radioactivity transport in marine environment in the case of hypothetical accidents in the Saida and Kola bays.

Computer Modelling System Application for Catalytic Reforming Unit Work Optimisation

Catalytic reforming of naphtha is one of the most important processes for high octane gasoline manufacture and aromatic hydrocarbons production. The application of computer modelling system “Catalyst's Control” for monitoring of catalytic reforming unit of Achinsk oil-refinery is stated. The mathematical model-based system takes into account the physical and chemical mechanisms of hydrocarbon mixture conversion reaction as well as the catalyst deactivation. The models created can be used for optimization and prediction of operating parameters (octane number, reactors outlet temperature and yield) of the reforming process. It is shown, that the work on the optimal activity allows increasing product output with a constant level of production costs, and get the information about Pt-Re catalyst work efficiency.

Evaluation of the AnnAGNPS model for predicting runoff and sediment yield in a small Mediterranean agricultural watershed in Navarre (Spain)

AnnAGNPS (Annualized Agricultural Non-Point Source Pollution Model) is a computer model developed to predict non-point source pollutant loadings within agricultural watersheds. It contains a daily time step distributed parameter continuous simulation surface runoff model designed to assist with determining Best Management Practices (BMPs), the setting of Total Maximum Daily Loads (TMDLs), and for risk and cost/benefit analyses. The purpose of this study was to evaluate the capabilities of the model to simulate runoff and sediment loads in a small Mediterranean agricultural watershed (207ha) located in the region of Navarre (Spain) using nine years of continuous data monitoring. Data for the first five years (2003–2007) were used for calibration and the remaining four years (2008–2011) for validation. No significant channel erosion nor in-stream structures were identified within this small and homogeneous watershed. Thus the set of models for analysing stream networks and corridors were not considered in this study. Firstly, AnnAGNPS was calibrated for runoff by modifying Curve Number values for different stages of the main crops. Results showed that the model satisfactory simulated surface runoff at monthly, seasonal and annual scales both in calibration and in validation processes. A Differential Sensitivity Analysis (DSA) was carried out to evaluate the sensitivity of eight input parameters for sediment load prediction. Based on DSA results, the AnnAGNPS model was calibrated for sediment load simulation. The model was capable of simulating the sediment load at an annual scale with a difference of less than 1% for calibration and 7% for validation. However, the results at monthly and seasonal scale were less precise. The use of stream networks and corridors models, already inserted in the system of computer models that make up AnnAGNPS, seem to be necessary for a more precise explanation of sediment yields and loads at monthly and seasonal scales, even for small watersheds.

Functional verification of computationally predicted qnr genes

BackgroundThe quinolone resistance (qnr) genes are widely distributed among bacteria. We recently developed and applied probabilistic models to identify tentative novel qnr genes in large public collections of DNA sequence data including fragmented metagenomes.FindingsBy using inducible recombinant expressions systems the functionality of four identified qnr candidates were evaluated in Escherichia coli. Expression of several known qnr genes as well as two novel candidates provided fluoroquinolone resistance that increased with elevated inducer concentrations. The two novel, functionally verified qnr genes are termed Vfuqnr and assembled qnr 1. Co-expression of two qnr genes suggested non-synergistic action.ConclusionThe combination of a computational model and recombinant expression systems provides opportunities to explore and identify novel antibiotic resistance genes in both genomic and metagenomic datasets.

Computational Modeling of Inflammation and Wound Healing

Inflammation is both central to proper wound healing and a key driver of chronic tissue injury via a positive-feedback loop incited by incidental cell damage. We seek to derive actionable insights into the role of inflammation in wound healing in order to improve outcomes for individual patients. To date, dynamic computational models have been used to study the time evolution of inflammation in wound healing. Emerging clinical data on histo-pathological and macroscopic images of evolving wounds, as well as noninvasive measures of blood flow, suggested the need for tissue-realistic, agent-based, and hybrid mechanistic computational simulations of inflammation and wound healing. We developed a computational modeling system, Simple Platform for Agent-based Representation of Knowledge, to facilitate the construction of tissue-realistic models. A hybrid equation-agent-based model (ABM) of pressure ulcer formation in both spinal cord-injured and -uninjured patients was used to identify control points that reduce stress caused by tissue ischemia/reperfusion. An ABM of arterial restenosis revealed new dynamics of cell migration during neointimal hyperplasia that match histological features, but contradict the currently prevailing mechanistic hypothesis. ABMs of vocal fold inflammation were used to predict inflammatory trajectories in individuals, possibly allowing for personalized treatment. The intertwined inflammatory and wound healing responses can be modeled computationally to make predictions in individuals, simulate therapies, and gain mechanistic insights.

Outcomes of Choroidal Melanomas Treated With Eye Physics

The University of Southern California Eye Physics plaques compare favorably with the Collaborative Ocular Melanoma Study plaques in terms of late adverse effects from radiation, metastasis, and local tumor recurrence. To review the University of Southern California experience using Eye Physics plaques and Plaque Simulator software to treat choroidal melanomas and compare the outcomes with published results of the Collaborative Ocular Melanoma Study. A retrospective case series of 82 patients treated for medium-sized choroidal melanoma from January 1, 1990, through December 30, 2010, using iodine 125 plaques and treatment simulation software developed at the University of Southern California. The dosimetric goal was 85 Gy in 7 days to a conformal volume enclosing the apex and a 2-mm margin surrounding the tumor base. Plaque localization was guided by the Plaque Simulator computer modeling system using preoperative imaging studies. Primary outcome measures were local tumor control, globe preservation, and metastases. Secondary outcome measures were late radiation adverse effects including postoperative vision changes, optic neuropathy, radiation retinopathy, and cataract. The median follow-up for 82 patients was 46.8 months (range, 1-171 months). Globe preservation was achieved in 80 patients (97.6%); 2 patients underwent enucleation for local recurrence. Metastatic disease developed in 9 patients (11.0%). Retinopathy was seen in 31 patients (37.8%), optic neuropathy in 12 (14.6%), and cataracts in 26 (31.7%). Postoperatively, 21 patients (25.6%) lost more than 6 lines of Snellen visual acuity. When considering rates of local recurrence, metastases, and late radiation adverse effects, the University of Southern California results for medium-sized choroidal melanomas using Eye Physics plaques compared favorably with Collaborative Ocular Melanoma Study data. The Plaque Simulator 3-dimensional tumor-modeling program developed at the University of Southern California is a reliable method for determining plaque positioning preoperatively and for treating this cohort of patients.

Patient-Centered Research Happens in Practice-based Research Networks

<h3>Introduction</h3> Flow diversion is an effective treatment option for cerebral aneurysms (CAs). Appropriately sizing flow diverters (FDs) is critical for treatment success.¹ However, FDs can be difficult to size. They can elongate by more than 50% of their nominal length after deployment and vessel diameters may vary considerably along the trajectory of the vessel.² Current convention does not address these challenges well. Here we present our preliminary evaluation of a computer modeling system that uses real-time FD deployment simulations and the three-dimensional (3D) model of the patient’s vessel to size FDs. <h3>Materials and methods</h3> The computational modeling system was evaluated for a series of 7 CAs that were planned for treatment with the Pipeline Flex (Medtronic, USA) FD. Evaluation was performed retrospectively in 2 CAs and prospectively in 5 CAs. In each case, rotational angiography image data were first uploaded to the SurgicalPreview® (EndoVantage, USA) computational modeling software. The image data were then segmented by the software and used to reconstruct a 3D model of the vessel. Next, FD sizes that were being considered for treatment were virtually deployed into the vessel model in real-time and the appropriate FD size for each vessel was selected. Simulated and clinical FD deployments were then compared using post-treatment angiography images. <h3>Results</h3> Good qualitative agreement was observed between simulated and clinical FD deployments based on device length and aneurysmal neck-coverage, as shown in figure 1. In the prospective cases, the simulations helped narrow the list of device sizes being considered and improved confidence in device selection. <h3>Conclusion</h3> Our early experience with the computational modeling system suggests that the technology can potentially accurately predict FD behavior and facilitate the selection of the optimal FD size for a vessel. The technology has great potential to reduce technical complications during FD treatment and improve treatment outcomes. <h3>References</h3> Aquarius R, et al. ‘The Importance of Wall Apposition in Flow Diverters. <i>Neurosurgery</i>April 2018. Narata AP, et al. ‘Early Results in Flow Diverter Sizing by Computational Simulation: Quantification of Size Change and Simulation Error Assessment’.<i> Oper Neurosurg</i> 2018: 9. <h3>Disclosures</h3> <b>C. Baccin:</b> None. <b>H. Babiker:</b> 4; C; EndoVantage. 5; C; EndoVantage.

The importance of understanding computer analyses in civil engineering

Sophisticated computer modelling systems are widely used in civil engineering analysis. This paper takes examples from structural engineering, environmental engineering, flood management and geotechnical engineering to illustrate the need for civil engineers to be competent in the use of computer tools. An understanding of a model's scientific basis, appropriateness, numerical limitations, validation, verification and propagation of uncertainty is required before applying its results. A review of education and training is also suggested to ensure engineers are competent at using computer modelling systems, particularly in the context of risk management. 1. Introduction

A comparison of emission calculations using different modeled indicators with 1-year online measurements

The overall measurement of farm level greenhouse gas (GHG) emissions in dairy production is not feasible, from either an engineering or administrative point of view. Instead, computational model systems are used to generate emission inventories, demanding a validation by measurement data. This paper tests the GHG calculation of the dairy farm-level optimization model DAIRYDYN, including methane (CH₄) from enteric fermentation and managed manure. The model involves four emission calculation procedures (indicators), differing in the aggregation level of relevant input variables. The corresponding emission factors used by the indicators range from default per cow (activity level) emissions up to emission factors based on feed intake, manure amount, and milk production intensity. For validation of the CH₄ accounting of the model, 1-year CH₄ measurements of an experimental free-stall dairy farm in Germany are compared to model simulation results. An advantage of this interdisciplinary study is given by the correspondence of the model parameterization and simulation horizon with the experimental farm's characteristics and measurement period. The results clarify that modeled emission inventories (2,898, 4,637, 4,247, and 3,600 kg CO₂-eq. cow(-1) year(-1)) lead to more or less good approximations of online measurements (average 3,845 kg CO₂-eq. cow(-1) year(-1) (±275 owing to manure management)) depending on the indicator utilized. The more farm-specific characteristics are used by the GHG indicator; the lower is the bias of the modeled emissions. Results underline that an accurate emission calculation procedure should capture differences in energy intake, owing to milk production intensity as well as manure storage time. Despite the differences between indicator estimates, the deviation of modeled GHGs using detailed indicators in DAIRYDYN from on-farm measurements is relatively low (between -6.4% and 10.5%), compared with findings from the literature.

Abstract 2104: In vitro validation of rationally designed therapeutic based on drug repositioning and combinations.

Abstract Background: Drug repositioning - the application of marketed drugs to new diseases - is a time and cost effective alternative to de novo drug development. Thalidomide is a hallmark example of drug repositioning success. Withdrawn from the market in 1961 after causing thousands of severe birth defects, its newly discovered anti-angiogenic and immunomodulatory properties cleared the way for Food and Drug Administration (FDA) approval in 2006 for multiple myeloma (MM). Although thalidomide has demonstrated remarkable success in the treatment of MM, responses are typically short-lived with the emergence of resistance. For complex diseases like cancer, multi-target therapeutics are well suited to address efficacy and drug resistance challenges. Here we have designed a novel therapeutic combination of drugs for MM that impacts all disease phenotypes. Methods: Using a computer modeling system from Cellworks that mimics and simulates cancer disease physiology to predict clinical outcomes, we identified AT101 (Bcl2 antagonoist) and tesaglitazar (PPAR α/γ agonist) as a potentially effective drug combination for MM. This combination was shortlisted from over two hundred pharmacodynamic dose-response simulation studies using criteria of efficacy and synergy. Computer modeling predicted that this drug combination mechanistically targets apoptotic pathways and the combination of the agents provides greater than additive activity. These predictive findings were assessed in vitro using OPM2 and U266 human MM cell lines. AT101 and tesaglitazar growth inhibition was evaluated using the MTT assay and analysis of synergy was determined using the Bliss Independence model. Apoptotic induction was analyzed by immunoblotting for cleaved forms of caspases and PARP. Results: 10 μM tesaglitazar and 2 μM AT101 display minimal and moderate growth inhibition respectively as single agents in OPM2 and U266 MM cell lines. Growth inhibition in these cell lines is dramatically enhanced when the drugs are used in combination, reducing cellular viability by 88% and 77% in OPM2 and U266 cells, respectively. Based upon the Bliss Independence model, the relationship between tesaglitazar and AT-101 is synergistic in both cell lines. Combination treatment in both cell lines results in increased apoptosis as indicated by enhanced cleavage of PARP and caspase 3 and 9. Conclusions: Not only do these experiments identify AT101 and tesaglitazar as a potentially effective drug combination for the treatment of MM, these results also validate the use of rationally based, computer modeling to design effective therapeutics and predict clinical outcomes. Future studies will evaluate the mechanism of action for the synergistic interaction between tesaglitazar and AT101 in MM. Citation Format: Nicole A. Doudican, Shireen Vali, Shweta Kapoor, Anay Talawdekar, Zeba Sultana, Taher Abbasi, Gautam Sethi, Seth J. Orlow, Amitabha Mazumder. In vitro validation of rationally designed therapeutic based on drug repositioning and combinations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2104. doi:10.1158/1538-7445.AM2013-2104

Measurement of cardiac function using dual catheterization in the Dahl SS rat on low salt

The assessment of cardiovascular function in both animal and human studies has traditionally focused on left ventricular pressure and volume measurements. However, quantifying the interaction of left ventricular function with the right ventricle and cardiovascular system as a whole extends this functional assessment to the systems level. Computational models of the heart and circulatory system incorporating left and right ventricular function have been developed but experimental data describing simultaneous function of both right and left side of the heart have not been previously measured. Here, we studied cardiac performance in rats by measuring left ventricular pressure‐volume and right ventricular pressure simultaneously using a pressure‐volume conductance catheter in the left ventricle and a pressure‐tip catheter in the right ventricle. This study focuses on development of the experimental protocol and using it to assess normal cardiovascular function in the Dahl SS rat (SS/JrHsdMcwiCrl) on low salt as a baseline for comparative studies. It was found that this dual catheterization measurement method sufficiently informs our computational model, defines cardiac and cardiovascular system function and provides an excellent platform for future comparison of cardiovascular system function between strains on different diets such as Dahl SS and SS.13BN on low and high salt.

Novel cancer drivers: mining the kinome

Large-scale cancer genome studies are unveiling significant complexity and heterogeneity even in histopathologically indistinguishable cancers. Differentiating 'driver' mutations that are functionally relevant from 'passenger' mutations is a major challenge in cancer genomics. While recurrent mutations in a gene provides supporting evidence of 'driver' status, novel computational methods and model systems are greatly improving our ability to identify genes important in carcinogenesis. Reimand and Bader have recently shown that driver gene discovery in discrete gene classes (in this case the kinome) is possible across multiple cancer types and has the potential to yield new druggable targets and clinically relevant leads.

Genomics and epigenomics of colorectal cancer

Colorectal cancer is one of the most common cancer types worldwide and accounts for approximately 600,000 deaths annually. Work over the last decades has uncovered a number of tumor-suppressor and oncogenes which are frequently mutated and might thus be responsible for the malignant transformation. However, only with the development of new high-throughput technologies systematic analyses of the genome and epigenomes became feasible. While data generation has increased exponential, we are now faced with new challenges to transform these data into useful models that help predicting the outcome of genomic aberrations and to develop novel diagnostic and therapeutic strategies. As a basis for the modeling it is essential to understand and integrate current knowledge. We review previous and current ideas in colorectal cancer development and focus on a pathway oriented view. We show that colorectal cancer is a multilayer complex disease affecting the genome as well as the epigenome with direct consequences on the gene and microRNA (miRNA) expression signatures. The goal is to illustrate the current principles of colorectal cancer pathogenesis and to illustrate the need for elaborate computer modeling systems.

Ensemble and ligand effects on the acetylene adsorption on ordered PdxAg1−x/Pd(100) surface alloys investigated by periodic DFT study

The interactions of acetylene with structurally ordered PdxAg1-x/Pd(100) (x = 1, 0.75, 0.5, 0.25) surface alloys, in which Ag is presented only in the first layer as the computational model system, were investigated by gradient corrected periodic density functional calculations to unravel and understand contributions from electronic strain, electronic ligand and geometric ensemble effects. The calculated adsorption energies indicate that the hollow sites are always found to be more stable than any others and more sensitive to the Ag atoms because of the strong ensemble effect. However, the ligand effect plays a significant role in both the top and bridge adsorption sites. The electrons transferred to the acetylene molecules from the surface increase with increasing concentration of the surface atomic Ag.

Development of approach to modelling and optimization of non-stationary catalytic processes in oil refining and petrochemistry

Abstract An approach to modelling of non-stationary catalytic processes of oil refining and petrochemistry is proposed. The computer modelling systems under development take into account the physical and chemical reaction laws, raw materials composition, and catalyst nature. This allows using the software for the optimization of process conditions and equipment design. The models created can be applied for solving complex problems of chemical reactors design; calculation of different variants of industrial plants reconstruction; refining and petrochemicals catalysts selection and testing; catalyst service life prolongation; determination of optimum water supply into the alkanes dehydrogenation reactor; optimization of products separation in the benzene alkylation process.

Evaluation of high resolution simulated and OMI retrieved tropospheric NO2 column densities over Southeastern Europe

High resolution model estimates (10×10km2) of tropospheric NO2 column amounts from the Comprehensive Air Quality Model (CAMx) for the Balkan Peninsula are compared with OMI/Aura measurements (13×24km2 at nadir) for the year April 2009 to March 2010. The Balkan area contributes significantly to the NO2 burden in European air and so numerous urban, industrial and rural regions are studied aiming to investigate the consistency of both satellite retrievals and model predictions at high spatial resolution. It has already been shown that OMI can detect the tropospheric column of NO2 over polluted Balkan cities due to its fine horizontal resolution and instrument sensitivity (Zyrichidou et al., 2009). In this study the improved OMI DOMINO v2.0 satellite retrievals showed that over South-Eastern Europe the monthly mean NO2 tropospheric column density fluctuated between 2.0 and 5.7±1.1×1015 molecules/cm2 over urban areas, 1.6–5.0±0.7×1015 molecules/cm2 over large industrial complexes and 1.1–2.2±0.4×1015 molecules/cm2 over rural areas for the year studied. The Comprehensive Air Quality Model with extensions (CAMx) version 4.40 is a publicly available open-source computer modeling system for the integrated assessment of gaseous and particulate air pollution. The anthropogenic emissions used in CAMx for the Greek domain being studied were compiled employing bottom-up approaches (road transport sector, off-road machinery, etc.) as well as other national registries and international databases. The rest of the Balkan domain has natural and anthropogenic emissions based on the TNO emission inventory of 2003. The high-resolution CAMx simulations reveal consistent spatial and temporal patterns with the OMI/Aura data. The annual spatial correlation coefficient between OMI and CAMx computed in this high spatial resolution analysis is of the order of 0.6, somewhat improved over those estimated in Zyrichidou et al. (2009) (R≈0.5). However, in such a validation study it is important to take into account the averaging kernel (AK) information in order to achieve the creation of comparable data sets. Minor differences are found for area-averaged model columns with and without applying the kernel, which shows that the impact of limiting the effect of the a priori profile on the comparison is on average small. The main aim of the paper, which was to evaluate OMI retrieved and high resolution simulated tropospheric NO2 column densities over South-Eastern Europe and to assess the use of the averaging kernels, is achieved and the two data sources are being employed further in an inverse emission inventory creation study (Zyrichidou et al., in preparation).

Automatic Arrangement Algorithm for Tower Cranes Used in High-rise Apartment Buildings

On most construction sites, the arrangement of tower cranes is decided by site engineers based on their own experience, which can cause cost overruns and delays in the lifting work. Although many researchers have conducted studies on tower crane arrangement using computer modeling and knowledge-based expert systems as well as mathematical models, no research has aimed to develop an algorithm to identify an optimum solution among several alternatives for installation areas of tower cranes satisfying the conditions of lifting work. The objective of this study is to develop an automatic arrangement algorithm for tower cranes used in high-rise apartment construction. First, as a new concept, a possible installation area of tower cranes was suggested. Second, after proposing several alternatives based on the installation points suggested in this study, an algorithm analyzing the economic feasibility of tower cranes was developed considering the rental, installation and removal costs. Third, a case study was conducted to prove the validity of the developed algorithm for selecting and installing an effective set of tower cranes at minimum cost.