Search results for: molecular modelling

Authors: Claudia Matassa, Matthias Hohne, Dominic Ormerod, Yamini Satyawali

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Chiral amines integrate the backbone of several active pharmaceutical ingredients (APIs) used in modern medicine for the treatment of a vast range of diseases. Despite the demand, their synthesis remains challenging. Besides a range of chemicals and enzymatical methods, chiral amine synthesis using transaminases (EC 2.6.1.W) represents a useful alternative to access this important class of compounds. Even though transaminases exhibit excellent stereo and regioselectivity and the potential for high yield, the reaction suffers from a number of challenges, including the thermodynamic equilibrium, product inhibition, and low substrate solubility. In this work, we demonstrate a membrane assisted strategy for addressing these challenges. It involves the use of high molecular weight (HMW) amine donors for the transaminase-catalyzed synthesis of 4-phenyl-2-butylamine in both aqueous and organic solvent media. In contrast to common amine donors such as alanine or isopropylamine, these large molecules, provided in excess for thermodynamic equilibrium shifting, are easily retained by commercial nanofiltration membranes; thus a selective permeation of the desired smaller product amine is possible. The enzymatic transamination in aqueous media, combined with selective product removal shifted the equilibrium enhancing substrate conversion by an additional 25% compared to the control reaction. Along with very efficient amine product removal, there was undesirable loss of ketone substrate and low product concentration was achieved. The system was therefore further improved by performing the reaction in organic solvent (n-heptane). Coupling the reaction system with membrane-assisted product removal resulted in a highly concentrated and relatively pure ( > 97%) product solution. Moreover, a product yield of 60% was reached, compared to 15% without product removal.

Keywords: amine donor, chiral amines, in situ product removal, transamination

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Authors: Clive L. Morley

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Gravity models and panel data modelling of tourism flows are receiving renewed attention, after decades of general neglect. Such models have quite different underpinnings from conventional demand models derived from micro-economic theory. They operate at a different level of data and with different theoretical bases. These differences have important consequences for the interpretation of the results and their policy and managerial implications. This review compares and contrasts the two model forms, clarifying the distinguishing features and the estimation requirements of each. In general, gravity models are not recommended for use to address specific management and marketing purposes.

Keywords: gravity models, micro-economics, demand models, marketing

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Authors: Irmak Karaduman, Tugba Corlu, Sezin Galioglu, Burcu Akata, M. Ali Yildirim, Aytunç Ateş, Selim Acar

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Breath analysis represents a promising non-invasive, fast and cost-effective alternative to well-established diagnostic and monitoring techniques such as blood analysis, endoscopy, ultrasonic and tomographic monitoring. Portable, non-invasive, and low-cost breath analysis devices are becoming increasingly desirable for monitoring different diseases, especially asthma. Beacuse of this, NO gas sensing at low concentrations has attracted progressive attention for clinical analysis in asthma. Recently, nanomaterials based sensors are considered to be a promising clinical and laboratory diagnostic tool, because its large surface–to–volume ratio, controllable structure, easily tailored chemical and physical properties, which bring high sensitivity, fast dynamic processand even the increasing specificity. Among various nanomaterials, semiconducting metal oxides are extensively studied gas-sensing materials and are potential sensing elements for breathanalyzer due to their high sensitivity, simple design, low cost and good stability.The sensitivities of metal oxide semiconductor gas sensors can be enhanced by adding noble metals. Doping contents, distribution, and size of metallic or metal oxide catalysts are key parameters for enhancing gas selectivity as well as sensitivity. By manufacturing doping MOS structures, it is possible to develop more efficient sensor sensing layers. Zeolites are perhaps the most widely employed group of silicon-based nanoporous solids. Their well-defined pores of sub nanometric size have earned them the name of molecular sieves, meaning that operation in the size exclusion regime is possible by selecting, among over 170 structures available, the zeolite whose pores allow the pass of the desired molecule, while keeping larger molecules outside.In fact it is selective adsorption, rather than molecular sieving, the mechanism that explains most of the successful gas separations achieved with zeolite membranes. In view of their molecular sieving and selective adsorption properties, it is not surprising that zeolites have found use in a number of works dealing with gas sensing devices. In this study, the Cu doped ZnO nanostructure film was produced by SILAR method and investigated the NO gas sensing properties. To obtain the selectivity of the sample, the gases including CO,NH3,H2 and CH4 were detected to compare with NO. The maximum response is obtained at 85 C for 20 ppb NO gas. The sensor shows high response to NO gas. However, acceptable responses are calculated for CO and NH3 gases. Therefore, there are no responses obtain for H2 and CH4 gases. Enhanced to selectivity, Cu doped ZnO nanostructure film was coated with zeolite A thin film. It is found that the sample possess an acceptable response towards NO hardly respond to CO, NH3, H2 and CH4 at room temperature. This difference in the response can be expressed in terms of differences in the molecular structure, the dipole moment, strength of the electrostatic interaction and the dielectric constant. The as-synthesized thin film is considered to be one of the extremely promising candidate materials in electronic nose applications. This work is supported by The Scientific and Technological Research Council of Turkey (TUBİTAK) under Project No, 115M658 and Gazi University Scientific Research Fund under project no 05/2016-21.

Keywords: Cu doped ZnO, electrical characterization, gas sensing, zeolite

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Authors: Mohamed Abdel-Hamid, Olfat Gamil Shaker, Doha El-Sayed Ellakwa, Eman Fathy Abdel-Maksoud

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Introduction: Despite advances in the knowledge of the molecular virology of hepatitis C virus (HCV), the mechanisms of hepatocellular injury in HCV infection are not completely understood. Hepatitis C viral infection (HCV) influences the susceptibility to apoptosis. This could lead to insufficient antiviral immune response and persistent viral infection. Aim of this study: was to examine whether BCL-2 gene polymorphism at codon 43 (+127G/A or Ala43Thr) has an impact on development of hepatocellular carcinoma caused by chronic hepatitis C Egyptian patients. Subjects and Methods: The study included three groups; group 1: composing of 30 patients with hepatocellular carcinoma (HCC), group 2 composing of 30 patients with HCV, group 3 composing of 30 healthy subjects matching the same age and socioeconomic status were taken as a control group. Gene polymorphism of BCL2 (Ala43Thr) were evaluated by PCR-RFLP technique and measured for all patients and controls. Results: The summed 43Thr genotype was more frequent and statistically significant in HCC patients as compared to control group. This genotype of BCL2 gene may inhibit the programmed cell death which leads to disturbance in tissue and cells homeostasis and reduction in immune regulation. This result leads to viral replication and HCV persistence. Moreover, virus produces variety of mechanisms to block genes participated in apoptosis. This mechanism proves that HCV patients who have 43Thr genotype are more susceptible to HCC. Conclusion: The data suggest for the first time that the BCL2 polymorphism is associated with the susceptibility to HCC in Egyptian populations and might be used as molecular markers for evaluating HCC risk. This study clearly demonstrated that Chronic HCV exhibit a deregulation of apoptosis with the disease progression. This provides an insight into the pathogenesis of chronic HCV infection, and may contribute to the therapy.

Keywords: BCL2 gene, Hepatitis C Virus, Hepatocellular carcinoma, sensitivity, specificity, apoptosis

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Authors: Sakshi Piplani, Ajit Kumar

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Valproic acid (VPA) is the first synthetic therapeutic agent used to treat epileptic disorders, which account for affecting nearly 1% world population. Teratogenicity caused by VPA has prompted the search for next generation drug with better efficacy and lower side effects. Recent studies have posed HDAC8 as direct target of VPA that causes the teratogenic effect in foetus. We have employed molecular dynamics (MD) and docking simulations to understand the binding mode of VPA and their analogues onto HDAC8. A total of twenty 3D-structures of human HDAC8 isoforms were selected using BLAST-P search against PDB. Multiple sequence alignment was carried out using ClustalW and PDB-3F07 having least missing and mutated regions was selected for study. The missing residues of loop region were constructed using MODELLER and energy was minimized. A set of 216 structural analogues (>90% identity) of VPA were obtained from Pubchem and ZINC database and their energy was optimized with Chemsketch software using 3-D CHARMM-type force field. Four major neurotransmitters (GABAt, SSADH, α-KGDH, GAD) involved in anticonvulsant activity were docked with VPA and its analogues. Out of 216 analogues, 75 were selected on the basis of lower binding energy and inhibition constant as compared to VPA, thus predicted to have anti-convulsant activity. Selected hHDAC8 structure was then subjected to MD Simulation using licenced version YASARA with AMBER99SB force field. The structure was solvated in rectangular box of TIP3P. The simulation was carried out with periodic boundary conditions and electrostatic interactions and treated with Particle mesh Ewald algorithm. pH of system was set to 7.4, temperature 323K and pressure 1atm respectively. Simulation snapshots were stored every 25ps. The MD simulation was carried out for 20ns and pdb file of HDAC8 structure was saved every 2ns. The structures were analysed using castP and UCSF Chimera and most stabilized structure (20ns) was used for docking study. Molecular docking of 75 selected VPA-analogues with PDB-3F07 was performed using AUTODOCK4.2.6. Lamarckian Genetic Algorithm was used to generate conformations of docked ligand and structure. The docking study revealed that VPA and its analogues have more affinity towards ‘hydrophobic active site channel’, due to its hydrophobic properties and allows VPA and their analogues to take part in van der Waal interactions with TYR24, HIS42, VAL41, TYR20, SER138, TRP137 while TRP137 and SER138 showed hydrogen bonding interaction with VPA-analogues. 14 analogues showed better binding affinity than VPA. ADMET SAR server was used to predict the ADMET properties of selected VPA analogues for predicting their druggability. On the basis of ADMET screening, 09 molecules were selected and are being used for in-vivo evaluation using Danio rerio model.

Keywords: HDAC8, docking, molecular dynamics simulation, valproic acid

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Authors: Bello Abdullahi, Yahaya M. Ibrahim, Ahmed D. Ibrahim, Kabir Bala

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Public sector tendering has traditionally been conducted using manual paper-based processes which are known to be inefficient, less transparent and more prone to manipulations and errors. The advent of the Internet and the World Wide Web has led to the development of numerous e-Tendering systems that addressed some of the problems associated with the manual paper-based tendering system. However, most of these systems rarely support the evaluation of tenders and where they do it is mostly based on the single decision maker which is not suitable in public sector tendering, where for the sake of objectivity, transparency, and fairness, it is required that the evaluation is conducted through a tender evaluation committee. Currently, in Nigeria, the public tendering process in general and the evaluation of tenders, in particular, are largely conducted using manual paper-based processes. Automating these manual-based processes to digital-based processes can help in enhancing the proficiency of public sector tendering in Nigeria. This paper is part of a larger study to develop an electronic tendering system that supports the whole tendering lifecycle based on Nigerian procurement law. Specifically, this paper presents the design and implementation of part of the system that supports group evaluation of tenders based on a technique called fuzzy multi-attributes group decision making. The system was developed using Object-Oriented methodologies and Unified Modelling Language and hypothetically applied in the evaluation of technical and financial proposals submitted by bidders. The system was validated by professionals with extensive experiences in public sector procurement. The results of the validation showed that the system called NPS-eTender has an average rating of 74% with respect to correct and accurate modelling of the existing manual tendering domain and an average rating of 67.6% with respect to its potential to enhance the proficiency of public sector tendering in Nigeria. Thus, based on the results of the validation, the automation of the evaluation process to support tender evaluation committee is achievable and can lead to a more proficient public sector tendering system.

Keywords: e-Tendering, e-Procurement, group decision making, tender evaluation, tender evaluation committee, UML, object-oriented methodologies, system development

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Authors: Emilienne Lardy, Eric Ballot, Mariam Lafkihi

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Efficient urban logistics requires a comprehensive understanding of traffic dynamics, particularly as it pertains to kinetic parameters influencing energy consumption and trip duration estimations. While real-time traffic information is increasingly accessible, current high-precision forecasting services embedded in route planning often function as opaque 'black boxes' for users. These services, typically relying on AI-processed counting data, fall short in accommodating open design parameters essential for management studies, notably within Supply Chain Management. This work revisits the modelling of traffic conditions in the context of city logistics, emphasizing its significance from the user’s point of view, with two focuses. Firstly, the focus is not on the vehicle flow but on the vehicles themselves and the impact of the traffic conditions on their driving behaviour. This means opening the range of studied indicators beyond vehicle speed, to describe extensively the kinetic and dynamic aspects of the driving behaviour. To achieve this, we leverage the Art. Kinema parameters are designed to characterize driving cycles. Secondly, this study examines how the driving context (i.e., exogenous factors to the traffic flow) determines the mentioned driving behaviour. Specifically, we explore how accurately the kinetic behaviour of a vehicle can be predicted based on a limited set of exogenous factors, such as time, day, road type, orientation, slope, and weather conditions. To answer this question, statistical analysis was conducted on real-world driving data, which includes high-frequency measurements of vehicle speed. A Factor Analysis and a Generalized Linear Model have been established to link kinetic parameters with independent categorical contextual variables. The results include an assessment of the adjustment quality and the robustness of the models, as well as an overview of the model’s outputs.

Keywords: factor analysis, generalised linear model, real world driving data, traffic congestion, urban logistics, vehicle kinematics

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Authors: Foteini Zagklavara, Peter Jimack, Nikil Kapur, Ozz Querin, Harvey Thompson

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The invention and development of the Polymerase Chain Reaction (PCR) technology have revolutionised molecular biology and molecular diagnostics. There is an urgent need to optimise their performance of those devices while reducing the total construction and operation costs. The present study proposes a CFD-enabled optimisation methodology for continuous flow (CF) PCR devices with serpentine-channel structure, which enables the trade-offs between competing objectives of DNA amplification efficiency and pressure drop to be explored. This is achieved by using a surrogate-enabled optimisation approach accounting for the geometrical features of a CF μPCR device by performing a series of simulations at a relatively small number of Design of Experiments (DoE) points, with the use of COMSOL Multiphysics 5.4. The values of the objectives are extracted from the CFD solutions, and response surfaces created using the polyharmonic splines and neural networks. After creating the respective response surfaces, genetic algorithm, and a multi-level coordinate search optimisation function are used to locate the optimum design parameters. Both optimisation methods produced similar results for both the neural network and the polyharmonic spline response surfaces. The results indicate that there is the possibility of improving the DNA efficiency by ∼2% in one PCR cycle when doubling the width of the microchannel to 400 μm while maintaining the height at the value of the original design (50μm). Moreover, the increase in the width of the serpentine microchannel is combined with a decrease in its total length in order to obtain the same residence times in all the simulations, resulting in a smaller total substrate volume (32.94% decrease). A multi-objective optimisation is also performed with the use of a Pareto Front plot. Such knowledge will enable designers to maximise the amount of DNA amplified or to minimise the time taken throughout thermal cycling in such devices.

Keywords: PCR, optimisation, microfluidics, COMSOL

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Authors: Hossein Bazmara, Kaamran Raahemifar, Mostafa Sefidgar, Madjid Soltani

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Angiogenesis is formation of new blood vessels from existing vessels. Due to flow of blood in vessels, during angiogenesis, blood flow plays an important role in regulating the angiogenesis process. Multiple mathematical models of angiogenesis have been proposed to simulate the formation of the complicated network of capillaries around a tumor. In this work, a multi-scale model of angiogenesis is developed to show the effect of blood flow on capillaries and network formation. This model spans multiple temporal and spatial scales, i.e. intracellular (molecular), cellular, and extracellular (tissue) scales. In intracellular or molecular scale, the signaling cascade of endothelial cells is obtained. Two main stages in development of a vessel are considered. In the first stage, single sprouts are extended toward the tumor. In this stage, the main regulator of endothelial cells behavior is the signals from extracellular matrix. After anastomosis and formation of closed loops, blood flow starts in the capillaries. In this stage, blood flow induced signals regulate endothelial cells behaviors. In cellular scale, growth and migration of endothelial cells is modeled with a discrete lattice Monte Carlo method called cellular Pott's model (CPM). In extracellular (tissue) scale, diffusion of tumor angiogenic factors in the extracellular matrix, formation of closed loops (anastomosis), and shear stress induced by blood flow is considered. The model is able to simulate the formation of a closed loop and its extension. The results are validated against experimental data. The results show that, without blood flow, the capillaries are not able to maintain their integrity.

Keywords: angiogenesis, endothelial cells, multi-scale model, cellular Pott's model, signaling cascade

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Authors: Shikha Rani, Neeta Sehgal, Vipin Kumar Verma, Om Prakash

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Introduction: Fish is an important protein source for humans and has great economic value. Fish cultures are affected due to various anthropogenic activities that lead to bacterial and viral infections. Aeromonas hydrophila is a fish pathogenic bacterium that causes several aquaculture outbreaks throughout the world and leads to huge mortalities. In this study, plants of no commercial value were used to investigate their immunostimulatory, antioxidant, anti-inflammatory, anti-bacterial, and disease resistance potential in fish against Aeromonas hydrophila, through fish feed fortification. Methods: The plant was dried at room temperature in the shade, dissolved in methanol, and analysed for biological compounds through GC-MS/MS. DPPH, FRAP, Phenolic, and flavonoids were estimated following standardized protocols. In silico molecular docking was also performed to validate its broad-spectrum activities based on binding affinity with specific proteins. Fish were divided into four groups (n=6; total 30 in a group): Group 1, non-challenged fish (fed on a non-supplemented diet); Group 2, fish challenged with bacteria (fed on a non-supplemented diet); Group 3 and 4, fish challenged with bacteria (A. hydrophila) and fed on plant supplemented feed at 2.5% and 5%. Blood was collected from the fish on 0, 7th, 14th, 21st, and 28th days. Serum was separated for glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase assay (ALP), lysozyme activity assay, superoxide dismutase assay (SOD), lipid peroxidation assay (LPO) and molecular parameters (including cytokine levels) were estimated through ELISA. The phagocytic activity of macrophages from the spleen and head kidney, along with quantitative analysis of immune-related genes, were analysed in different tissue samples. The digestive enzymes (Pepsin, Trypsin, and Chymotrypsin) were also measured to evaluate the effect of plant-supplemented feed on freshwater fish. Results and Discussion: GC-MS/MS analysis of a methanolic extract of plant validated the presence of key compounds having antioxidant, anti-inflammatory, anti-bacterial, anti-inflammatory, and immunomodulatory activities along with disease resistance properties. From biochemical investigations like ABTS, DPPH, and FRAP, the amount of total flavonoids, phenols, and promising binding affinities towards different proteins in molecular docking analysis helped us to realize the potential of this plant that can be used for investigation in the supplemented feed of fish. Measurement liver function tests, ALPs, oxidation-antioxidant enzyme concentrations, and immunoglobulin concentrations in the experimental groups (3 and 4) showed significant improvement as compared to the positive control group. The histopathological evaluation of the liver, spleen, and head kidney supports the biochemical findings. The isolated macrophages from the group fed on supplemented feed showed a higher percentage of phagocytosis and a phagocytic index, indicating an enhanced cell-mediated immune response. Significant improvements in digestive enzymes were also observed in fish fed on supplemented feed, even after weekly challenges with bacteria. Hence, the plant-fortified feed can be recommended as a regular feed to enhance fish immunity and disease resistance against the Aeromonas hydrophila infection after confirmation from the field trial.

Keywords: immunostimulation, antipathogen, plant fortified feed, macrophages, GC-MS/MS, in silico molecular docking

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Authors: Ella Tyuryumina, Alexey Neznanov

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This paper is devoted to mathematical modelling of the progression and stages of breast cancer. We propose Consolidated mathematical growth model of primary tumor and secondary distant metastases growth in patients with lymph nodes metastases (CoM-III) as a new research tool. We are interested in: 1) modelling the whole natural history of primary tumor and secondary distant metastases growth in patients with lymph nodes metastases; 2) developing adequate and precise CoM-III which reflects relations between primary tumor and secondary distant metastases; 3) analyzing the CoM-III scope of application; 4) implementing the model as a software tool. Firstly, the CoM-III includes exponential tumor growth model as a system of determinate nonlinear and linear equations. Secondly, mathematical model corresponds to TNM classification. It allows to calculate different growth periods of primary tumor and secondary distant metastases growth in patients with lymph nodes metastases: 1) ‘non-visible period’ for primary tumor; 2) ‘non-visible period’ for secondary distant metastases growth in patients with lymph nodes metastases; 3) ‘visible period’ for secondary distant metastases growth in patients with lymph nodes metastases. The new predictive tool: 1) is a solid foundation to develop future studies of breast cancer models; 2) does not require any expensive diagnostic tests; 3) is the first predictor which makes forecast using only current patient data, the others are based on the additional statistical data. Thus, the CoM-III model and predictive software: a) detect different growth periods of primary tumor and secondary distant metastases growth in patients with lymph nodes metastases; b) make forecast of the period of the distant metastases appearance in patients with lymph nodes metastases; c) have higher average prediction accuracy than the other tools; d) can improve forecasts on survival of breast cancer and facilitate optimization of diagnostic tests. The following are calculated by CoM-III: the number of doublings for ‘non-visible’ and ‘visible’ growth period of secondary distant metastases; tumor volume doubling time (days) for ‘non-visible’ and ‘visible’ growth period of secondary distant metastases. The CoM-III enables, for the first time, to predict the whole natural history of primary tumor and secondary distant metastases growth on each stage (pT1, pT2, pT3, pT4) relying only on primary tumor sizes. Summarizing: a) CoM-III describes correctly primary tumor and secondary distant metastases growth of IA, IIA, IIB, IIIB (T1-4N1-3M0) stages in patients with lymph nodes metastases (N1-3); b) facilitates the understanding of the appearance period and inception of secondary distant metastases.

Keywords: breast cancer, exponential growth model, mathematical model, primary tumor, secondary metastases, survival

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Authors: Mohammad Faheem, M. Tabish Rehman, Mohd Danishuddin, Asad U. Khan

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The worldwide dissemination of CTX-M type β-lactamases is a threat to human health. Previously, we have reported the spread of blaCTX-M-15 gene in different clinical strains of Enterobacteriaceae from the hospital settings of Aligarh in north India. In view of the varying resistance pattern against cephalosporins and other β-lactam antibiotics, we intended to understand the correlation between MICs and catalytic activity of CTX-M-15. In this study, steady-state kinetic parameters and MICs were determined on E. coli DH5α transformed with blaCTX-M-15 gene that was cloned from Enterobacter cloacae (EC-15) strain of clinical background. The effect of conventional β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) on CTX-M-15 was also studied. We have found that tazobactam is the best among these inhibitors against CTX-M-15. The inhibition characteristic of tazobactam is defined by its very low IC50 value (6 nM), high affinity (Ki = 0.017 µM) and better acylation efficiency (k+2/K9 = 0.44 µM-1s-1). It forms an acyl-enzyme covalent complex, which is quite stable (k+3 = 0.0057 s-1). Since increasing resistance has been reported against conventional b-lactam antibiotic-inhibitor combinations, we aspire to design a non-b-lactam core containing b-lactamase inhibitor. For this, we screened ZINC database and performed molecular docking to identify a potential non-β-lactam based inhibitor (ZINC03787097). The MICs of cephalosporin antibiotics in combination with this inhibitor gave promising results. Steady-state kinetics and molecular docking studies showed that ZINC03787097 is a reversible inhibitor which binds non-covalently to the active site of the enzyme through hydrogen bonds and hydrophobic interactions. Though, it’s IC50 (180 nM) is much higher than tazobactam, it has good affinity for CTX-M-15 (Ki = 0.388 µM). This study concludes that ZINC03787097 compound can be used as seed molecule to design more efficient non-b-lactam containing b-lactamase inhibitor that could evade pre-existing bacterial resistance mechanisms.

Keywords: ESBL, non-b-lactam-b-lactamase inhibitor, bioinformatics, biomedicine

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Authors: Tahani Hallek, Dhaou Akrout, Riadh Ahmadi, Mabrouk Montacer

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The present work is an organic geochemical study of the Fahdene Formation outcrops at the Mahjouba region belonging to the Eastern part of the Kalaat Senan structure in northwestern Tunisia (the Kef-Tedjerouine area). The analytical study of the organic content of the samples collected, allowed us to point out that the Formation in question is characterized by an average to good oil potential. This fossilized organic matter has a mixed origin (type II and III), as indicated by the relatively high values of hydrogen index. This origin is confirmed by the C29 Steranes abundance and also by tricyclic terpanes C19/(C19+C23) and tetracyclic terpanes C24/(C24+C23) ratios, that suggest a marine environment of deposit with high plants contribution. We have demonstrated that the heterogeneity of organic matter between the marine aspect, confirmed by the presence of foraminifera, and the continental contribution, is the result of an episodic anomaly in relation to the sequential stratigraphy. Given that the study area is defined as an outer platform forming a transition zone between a stable continental domain to the south and a deep basin to the north, we have explained the continental contribution by successive forced regressions, having blocked the albian transgression, allowing the installation of the lowstand system tracts. This aspect is represented by the incised valleys filling, in direct contact with the pelagic and deep sea facies. Consequently, the Fahdene Formation, in the Kef-Tedjerouine area, consists of transgressive system tracts (TST) brutally truncated by extras of continental progradation; resulting in a mixed influence deposition having retained a heterogeneous organic material.

Keywords: molecular geochemistry, biomarkers, forced regression, deposit environment, mixed origin, Northern Tunisia

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Authors: Sami Ayad, Mengshan Lee

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The Sustainable Development Goals (SDGs) were designed to be the best possible blueprint to achieve peace, prosperity, and overall, a better and more sustainable future for the Earth and all its people, and such a blueprint is needed more than ever. The SDGs face many hurdles that will prevent them from becoming a reality, one of such hurdles, arguably, is the chemical pollution and unintended chemical impacts generated through the production of various goods and resources that we consume. Chemical Alternatives Assessment has proven to be a viable solution for chemical pollution management in terms of filtering out hazardous chemicals for a greener alternative. However, the current substitution practice lacks crucial quantitative datasets (exposures and life cycle impacts) to ensure no unintended trade-offs occur in the substitution process. A Chemical Life Cycle Alternative Assessment (CLiCAA) framework is proposed as a reliable and replicable alternative to Life Cycle Based Alternative Assessment (LCAA) as it integrates chemical molecular structure analysis and Chemical Life Cycle Collaborative (CLiCC) web-based tool to fill in data gaps that the former frameworks suffer from. The CLiCAA framework consists of a four filtering layers, the first two being mandatory, with the final two being optional assessment and data extrapolation steps. Each layer includes relevant impact categories of each chemical, ranging from human to environmental impacts, that will be assessed and aggregated into unique scores for overall comparable results, with little to no data. A feasibility study will demonstrate the efficiency and accuracy of CLiCAA whilst bridging both cancer potency and exposure limit data, hoping to provide the necessary categorical impact information for every firm possible, especially those disadvantaged in terms of research and resource management.

Keywords: chemical alternative assessment, LCA, LCAA, CLiCC, CLiCAA, chemical substitution framework, cancer potency data, chemical molecular structure analysis

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Authors: Gelareh Changizi, Mahsa Khajavi, Ladan Shahhosseini

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Corporate-level strategy, or simply ‘parent strategy’, is a topic that has received much attention since the very early days of the strategic planning field. Since the multi level enterprises have different sub enterprises which deal with different business environments, we cannot define the same strategic perspective for all of them. Therefore, the determination of a perspective to manage and deal with affiliates of such enterprises is the main challenge. The parent strategy in mother enterprises' level has been analyzed in this research. A case study has been carried to comprehensively describe the proposed model.

Keywords: parent strategy, multi-business companies, performance evaluation, lifecycle

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Authors: Merouane Salhi, Mohamed Roudane, Abdelkader Kirad

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In this work, we present a new form of characteristics method, which is a technique for solving partial differential equations. Typically, it applies to first-order equations; the aim of this method is to reduce a partial differential equation to a family of ordinary differential equations along which the solution can be integrated from some initial data. This latter developed under the real gas theory, because when the thermal and the caloric imperfections of a gas increases, the specific heat and their ratio do not remain constant anymore and start to vary with the gas parameters. The gas doesn’t stay perfect. Its state equation change and it becomes for a real gas. The presented equations of the characteristics remain valid whatever area or field of study. Here we need have inserted the developed Prandtl Meyer function in the mathematical system to find a new model when the effect of stagnation pressure is taken into account. In this case, the effects of molecular size and intermolecular attraction forces intervene to correct the state equation, the thermodynamic parameters and the value of Prandtl Meyer function. However, with the assumptions that Berthelot’s state equation accounts for molecular size and intermolecular force effects, expressions are developed for analyzing the supersonic flow for thermally and calorically imperfect gas. The supersonic parameters depend directly on the stagnation parameters of the combustion chamber. The resolution has been made by the finite differences method using the corrector predictor algorithm. As results, the developed mathematical model used to design 2D minimum length nozzles under effect of the stagnation parameters of fluid flow. A comparison for air with the perfect gas PG and high temperature models on the one hand and our results by the real gas theory on the other of nozzles shapes and characteristics are made.

Keywords: numerical methods, nozzles design, real gas, stagnation parameters, supersonic expansion, the characteristics method

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Authors: Rupesh S. Gundewar, Kanchan C. Khare

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Runoff contribution from urban areas is generally from manmade structures and few natural contributors. The manmade structures are buildings; roads and other paved areas whereas natural contributors are groundwater and overland flows etc. Runoff alleviation is done by manmade as well as natural storages. Manmade storages are storage tanks or other storage structures such as soakways or soak pits which are more common in western and European countries. Natural storages are catchment slope, infiltration, catchment length, channel rerouting, drainage density, depression storage etc. A literature survey on the manmade and natural storages/inflow has presented percentage contribution of each individually. Sanders et.al. in their research have reported that a vegetation canopy reduces runoff by 7% to 12%. Nassif et el in their research have reported that catchment slope has an impact of 16% on bare standard soil and 24% on grassed soil on rainfall runoff. Infiltration being a pervious/impervious ratio dependent parameter is catchment specific. But a literature survey has presented a range of 15% to 30% loss of rainfall runoff in various catchment study areas. Catchment length and channel rerouting too play a considerable role in reduction of rainfall runoff. Ground infiltration inflow adds to the runoff where the groundwater table is very shallow and soil saturates even in a lower intensity storm. An approximate percent contribution through this inflow and surface inflow contributes to about 2% of total runoff volume. Considering the various contributing factors in runoff it has been observed during a literature survey that integrated modelling approach needs to be considered. The traditional storm water network models are able to predict to a fair/acceptable degree of accuracy provided no interaction with receiving water (river, sea, canal etc), ground infiltration, treatment works etc. are assumed. When such interactions are significant then it becomes difficult to reproduce the actual flood extent using the traditional discrete modelling approach. As a result the correct flooding situation is very rarely addressed accurately. Since the development of spatially distributed hydrologic model the predictions have become more accurate at the cost of requiring more accurate spatial information.The integrated approach provides a greater understanding of performance of the entire catchment. It enables to identify the source of flow in the system, understand how it is conveyed and also its impact on the receiving body. It also confirms important pain points, hydraulic controls and the source of flooding which could not be easily understood with discrete modelling approach. This also enables the decision makers to identify solutions which can be spread throughout the catchment rather than being concentrated at single point where the problem exists. Thus it can be concluded from the literature survey that the representation of urban details can be a key differentiator to the successful understanding of flooding issue. The intent of this study is to accurately predict the runoff from impermeable areas from urban area in India. A representative area has been selected for which data was available and predictions have been made which are corroborated with the actual measured data.

Keywords: runoff, urbanization, impermeable response, flooding

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Authors: Audrey Ngambia, Ondrej Masek, Valentina Erastova

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Biochar is an amorphous carbon-rich material generated from the pyrolysis of biomass with multifarious properties and functionality. Biochar has shown proven applications in the treatment of flue gas and organic and inorganic pollutants in soil and water/wastewater as a result of its multiple surface functional groups and porous structures. These properties have also shown potential in energy storage and carbon capture. The availability of diverse sources of biomass to produce biochar has increased interest in it as a sustainable and environmentally friendly material. The properties and porous structures of biochar vary depending on the type of biomass and high heat treatment temperature (HHT). Biochars produced at HHT between 400°C – 800°C generally have lower H/C and O/C ratios, higher porosities, larger pore sizes and higher surface areas with temperature. While all is known experimentally, there is little knowledge on the porous role structure and functional groups play on processes occurring at the atomistic scale, which are extremely important for the optimization of biochar for application, especially in the adsorption of gases. Atomistic simulations methods have shown the potential to generate such amorphous materials; however, most of the models available are composed of only carbon atoms or graphitic sheets, which are very dense or with simple slit pores, all of which ignore the important role of heteroatoms such as O, N, S and pore morphologies. Hence, developing realistic models that integrate these parameters are important to understand their role in governing adsorption mechanisms that will aid in guiding the design and optimization of biochar materials for target applications. In this work, molecular dynamics simulations in the isobaric ensemble are used to generate realistic biochar models taking into account experimentally determined H/C, O/C, N/C, aromaticity, micropore size range, micropore volumes and true densities of biochars. A pore generation approach was developed using virtual atoms, which is a Lennard-Jones sphere of varying van der Waals radius and softness. Its interaction via a soft-core potential with the biochar matrix allows the creation of pores with rough surfaces while varying the van der Waals radius parameters gives control to the pore-size distribution. We focused on microporosity, creating average pore sizes of 0.5 - 2 nm in diameter and pore volumes in the range of 0.05 – 1 cm3/g, which corresponds to experimental gas adsorption micropore sizes of amorphous porous biochars. Realistic biochar models with surface functionalities, micropore size distribution and pore morphologies were developed, and they could aid in the study of adsorption processes in confined micropores.

Keywords: biochar, heteroatoms, micropore size, molecular dynamics simulations, surface functional groups, virtual atoms

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Authors: Neha Thakur, Pravin S. More

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The interaction of CO, H2 and LPG with Cu-dosed SnO2 catalysts was studied by means of Fourier transform infrared spectroscopy (FTIR). With increasing Cu loading, pronounced and progressive red shifts of the C–O stretching frequency associated with molecular CO adsorbed on the Cu/SnO2 component were observed. This decrease in n(CO) correlates with enhancement of CO dissociation at higher temperatures on Cu promoted SnO2 catalysts under conditions, where clean Cu is almost ineffective. In the conclusion, the capability of our technique is discussed, and a technique for enhancing the sensitivity in our technique is proposed.

Keywords: FTIR, spectroscopic, dissociation, n(CO)

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Authors: Steffen Illig, Alexander S. Eggeman, Alessandro Troisi, Stephen G. Yeates, John E. Anthony, Henning Sirringhaus

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Large-amplitude intermolecular vibrations in combination with complex shaped transfer integrals generate a thermally fluctuating energetic landscape. The resulting dynamic disorder and its intrinsic presence in organic semiconductors is one of the most fundamental differences to their inorganic counterparts. Dynamic disorder is believed to govern many of the unique electrical and optical properties of organic systems. However, the low energy nature of these vibrations makes it difficult to access them experimentally and because of this we still lack clear molecular design rules to control and reduce dynamic disorder. Applying a novel technique based on electron diffraction we encountered strong intermolecular, thermal vibrations in every single organic material we studied (14 up to date), indicating that a large degree of dynamic disorder is a universal phenomenon in organic crystals. In this paper a new molecular design strategy will be presented to avoid dynamic disorder. We found that small molecules that have their side chains attached to the long axis of their conjugated core have been found to be less likely to suffer from dynamic disorder effects. In particular, we demonstrate that 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothio-phene (C8-BTBT) and 2,9-di-decyl-dinaphtho-[2,3-b:20,30-f]-thieno-[3,2-b]-thiophene (C10DNTT) exhibit strongly reduced thermal vibrations in comparison to other molecules and relate their outstanding performance to their lower dynamic disorder. We rationalize the low degree of dynamic disorder in C8-BTBT and C10-DNTT with a better encapsulation of the conjugated cores in the crystal structure which helps reduce large amplitude thermal motions. The work presented in this paper provides a general strategy for the design of new classes of very high mobility organic semiconductors with low dynamic disorder.

Keywords: charge transport, C8-BTBT, C10-DNTT, dynamic disorder, organic semiconductors, thermal vibrations

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Authors: A. C. Kumbharkhane

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Time domain dielectric relaxation microwave spectroscopy (TDRMS) is a term used to describe a technique of observing the time dependant response of a sample after application of time dependant electromagnetic field. A TDRMS probes the interaction of a macroscopic sample with a time dependent electrical field. The resulting complex permittivity spectrum, characterizes amplitude (voltage) and time scale of the charge-density fluctuations within the sample. These fluctuations may arise from the reorientation of the permanent dipole moments of individual molecules or from the rotation of dipolar moieties in flexible molecules, like polymers. The time scale of these fluctuations depends on the sample and its relative relaxation mechanism. Relaxation times range from some picoseconds in low viscosity liquids to hours in glasses, Therefore the TDRS technique covers an extensive dynamical process. The corresponding frequencies range from 10-4 Hz to 1012 Hz. This inherent ability to monitor the cooperative motion of molecular ensemble distinguishes dielectric relaxation from methods like NMR or Raman spectroscopy, which yield information on the motions of individual molecules. Recently, we have developed and established the TDR technique in laboratory that provides information regarding dielectric permittivity in the frequency range 10 MHz to 30 GHz. The TDR method involves the generation of step pulse with rise time of 20 pico-seconds in a coaxial line system and monitoring the change in pulse shape after reflection from the sample placed at the end of the coaxial line. There is a great interest to study the dielectric relaxation behaviour in liquid systems to understand the role of hydrogen bond in liquid system. The intermolecular interaction through hydrogen bonds in molecular liquids results in peculiar dynamical properties. The dynamics of hydrogen-bonded liquids have been studied. The theoretical model to explain the experimental results will be discussed.

Keywords: microwave, time domain reflectometry (TDR), dielectric measurement, relaxation time

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Authors: Mohd Ali Abbas Zaidi, Meenu Sachdeva, Jonaki Sen

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In the vertebrate embryo, the forebrain anlagen develops from the anterior-most region of the neural tube which is the precursor of the central nervous system (CNS). The roof plate located at the dorsal midline region of the forebrain anlagen, acts as a source of several secreted molecules involved in patterning and morphogenesis of the forebrain. One such key morphogenetic event is the invagination of the forebrain roof plate which results in separation of the single forebrain vesicle into two cerebral hemispheres. Retinoic acid (RA) signaling plays a key role in this process. Blocking RA signaling at the dorsal forebrain midline inhibits dorsal invagination and results in the absence of certain key features of this region, such as thinning of the neuroepithelium and a lowering of cell proliferation. At present we are investigating the possibility of other signaling pathways acting in concert with RA signaling to regulate this process. We have focused on BMP signaling, which we found to be active in a mutually exclusive domain to that of RA signaling within the roof plate. We have also observed that there is a change in BMP signaling activity on modulation of RA signaling indicating an antagonistic relationship between the two. Moreover, constitutive activation of BMP signaling seems to completely inhibit thinning and partially affect invagination, leaving the lowering of cell proliferation in the midline unaffected. We are employing in-silico modeling as well as molecular manipulations to investigate the relative contribution if any, of regional differences in rates of cell proliferation and thinning of the neuroepithelium towards the process of invagination. We have found expression of certain cell adhesion molecules in forebrain roof-plate whose mRNA localization across the thickness of neuroepithelium is influenced by Bmp and RA signaling, giving regional rigidity to roof plate and assisting invagination. We also found expression of certain cytoskeleton modifiers in a localized small domains in invaginating forebrain roof plate suggesting that midline invagination is under control of many factors.

Keywords: bone morphogenetic signaling, cytoskeleton, cell adhesion molecules, forebrain roof plate, retinoic acid signaling

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Authors: Ekaterina A. Savchenko, Elena N. Velichko, Evgenii T. Aksenov

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The development of pathological processes, such as cardiovascular and oncological diseases, are accompanied by changes in molecular parameters in cells, tissues, and serum. The study of the behavior of protein molecules in solutions is of primarily importance for diagnosis of such diseases. Various physical and chemical methods are used to study molecular systems. With the advent of the laser and advances in electronics, optical methods, such as scanning electron microscopy, sedimentation analysis, nephelometry, static and dynamic light scattering, have become the most universal, informative and accurate tools for estimating the parameters of nanoscale objects. The electrophoretic light scattering is the most effective technique. It has a high potential in the study of biological solutions and their properties. This technique allows one to investigate the processes of aggregation and dissociation of different macromolecules and obtain information on their shapes, sizes and molecular weights. Electrophoretic light scattering is an analytical method for registration of the motion of microscopic particles under the influence of an electric field by means of quasi-elastic light scattering in a homogeneous solution with a subsequent registration of the spectral or correlation characteristics of the light scattered from a moving object. We modified the technique by using the regime of total internal reflection with the aim of increasing its sensitivity and reducing the volume of the sample to be investigated, which opens the prospects of automating simultaneous multiparameter measurements. In addition, the method of total internal reflection allows one to study biological fluids on the level of single molecules, which also makes it possible to increase the sensitivity and the informativeness of the results because the data obtained from an individual molecule is not averaged over an ensemble, which is important in the study of bimolecular fluids. To our best knowledge the study of electrophoretic light scattering in the regime of total internal reflection is proposed for the first time, latex microspheres 1 μm in size were used as test objects. In this study, the total internal reflection regime was realized on a quartz prism where the free electrophoresis regime was set. A semiconductor laser with a wavelength of 655 nm was used as a radiation source, and the light scattering signal was registered by a pin-diode. Then the signal from a photodetector was transmitted to a digital oscilloscope and to a computer. The autocorrelation functions and the fast Fourier transform in the regime of Brownian motion and under the action of the field were calculated to obtain the parameters of the object investigated. The main result of the study was the dependence of the autocorrelation function on the concentration of microspheres and the applied field magnitude. The effect of heating became more pronounced with increasing sample concentrations and electric field. The results obtained in our study demonstrated the applicability of the method for the examination of liquid solutions, including biological fluids.

Keywords: light scattering, electrophoretic light scattering, electrophoresis, total internal reflection

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Authors: E. Kaygan, A. Gatto

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An investigation of adaptable winglets for morphing aircraft control and performance is described in this paper. The concepts investigated consist of various winglet configurations fundamentally centred on a baseline swept wing. The impetus for the work was to identify and optimize winglets to enhance controllability and the aerodynamic efficiency of a small unmanned aerial vehicle. All computations were performed with Athena Vortex Lattice modelling with varying degrees of twist, swept, and dihedral angle considered. The results from this work indicate that if adaptable winglets were employed on small scale UAV’s improvements in both aircraft control and performance could be achieved.

Keywords: aircraft, rolling, wing, winglet

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Authors: Yong Chen

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To understand the detailed molecular mechanisms of memory formation in engram cells is one of the most fundamental questions in neuroscience. Recent single-cell RNA-seq (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq) techniques have allowed us to explore the sparsely activated engram ensembles, enabling access to the molecular mechanisms that underlie experience-dependent memory formation and consolidation. However, the absence of specific and powerful computational methods to detect memory-related genes (modules) and their regulatory relationships in the sc/snRNA-seq datasets has strictly limited the analysis of underlying mechanisms and memory coding principles in mammalian brains. Here, we present a deep-learning method named SCENTBOX, to detect memory-related gene modules and causal regulatory relationships among themfromsc/snRNA-seq datasets. SCENTBOX first constructs codifferential expression gene network (CEGN) from case versus control sc/snRNA-seq datasets. It then detects the highly correlated modules of differential expression genes (DEGs) in CEGN. The deep network embedding and attention-based convolutional neural network strategies are employed to precisely detect regulatory relationships among DEG genes in a module. We applied them on scRNA-seq datasets of TRAP; Ai14 mouse neurons with fear memory and detected not only known memory-related genes, but also the modules and potential causal regulations. Our results provided novel regulations within an interesting module, including Arc, Bdnf, Creb, Dusp1, Rgs4, and Btg2. Overall, our methods provide a general computational tool for processing sc/snRNA-seq data from case versus control studie and a systematic investigation of fear-memory-related gene modules.

Keywords: sc/snRNA-seq, memory formation, deep learning, gene module, causal inference

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Authors: Tz-Bang Du, Cheng-Han Hsieh, Li-Ping Ju, Hung-Jie Liou

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Polyether amines synthesize by secondary hydroxyl polyether diol play an important role in epoxy hardener. The low molecular weight product is used in low viscosity and high transparent polyamine product for the logo, ground cover, especially for wind turbine blade, while the high molecular weight products are used in advanced agricultures such as a high-speed railway. High-pressure reductive amination process is required for producing these amines. In the condition of higher than 150 atm pressure and 200 degrees Celsius temperature, supercritical ammonia is used as a reactant and also a solvent. It would be a great challenge to select a catalyst support for such high-temperature alkaline circumstance. In this study, we have established a six-autoclave-type (SAT) high-pressure reactor for amination catalyst screening, which six experiment conditions with different temperature and pressure could be examined at the same time. We synthesized copper-nickel catalyst on different shaped alumina catalyst support and evaluated the catalyst activity for high-pressure reductive amination of polypropylene glycol (PPG) by SAT reactor. Ball type gamma alumina, ball type activated alumina and pellet type gamma alumina catalyst supports are evaluated in this study. Gamma alumina supports have shown better activity on PPG reductive amination than activated alumina support. In addition, the catalysts are evaluated in fixed bed reactor. The diamine product was successfully synthesized via this catalyst and the strength of the catalysts is measured. The crush strength of blank supports is about 13.5 lb for both gamma alumina and activated alumina. The strength increases to 20.3 lb after synthesized to be copper-nickel catalyst. After test in the fixed bed high-pressure reductive amination process for 100 hours, the crush strength of the used catalyst is 3.7 lb for activated alumina support, 12.0 lb for gamma alumina support. The gamma alumina is better than activated alumina to use as catalyst support in high-pressure reductive amination process.

Keywords: high pressure reductive amination, copper nickel catalyst, polyether amine, alumina

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Authors: Nacira Mecheri, N. Boussid

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A new chemical mechanism designed to study the process of forming the first aromatic ring (benzene) and polycyclic aromatic hydrocarbons (PAH) from a flame of acetylene (C2H2) has been developed. The mechanism developed, contains 50 chemical species involved in 268 reversible elementary reactions. The comparison between the results from modelling and experimental measurements allowed us to test the validity of the postulated mechanism in specific experimental conditions. Kinetic analysis of the flame by calculating the maximum rates for each elementary reaction, allowed us to identify key reactions pathways of consumption and formation of main precursors of soot.

Keywords: benzene, PAH, acetylene, modeling, flame, soot

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Authors: Mitsuhiro Hirai, Satoshi Ajito, Nobutaka Shimizu, Noriyuki Igarashi, Hiroki Iwase, Shinichi Takata

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Sugars and polyols are known to be bioprotectants preventing such as protein denaturation and enzyme deactivation and widely used as a nontoxic additive in various industrial and medical products. The mechanism of their protective actions has been explained by specific bindings between biological components and additives, changes in solvent viscosities, and surface tension and free energy changes upon transfer of those components into additive solutions. On the other hand, some organisms having tolerances against extreme environment produce stress proteins and/or accumulate sugars in cells, which is called cryptobiosis. In particular, trehalose has been drawing attention relevant to cryptobiosis under external stress such as high or low temperature, drying, osmotic pressure, and so on. The function of cryptobiosis by trehalose has been explained relevant to the restriction of the intra-and/or-inter-molecular movement by vitrification or from the replacement of water molecule by trehalose. Previous results suggest that the structure and interaction between sugar and water are a key determinant for understanding cryptobiosis. Recently, we have shown direct evidence that the protein hydration (solvation) and structural stability against chemical and thermal denaturation significantly depend on sugar species and glycerol. Sugar and glycerol molecules tend to be preferentially or weakly excluded from the protein surface and preserved the native protein hydration shell. Due to the protective action of the protein hydration shell by those molecules, the protein structure is stabilized against chemical (guanidinium chloride) and thermal denaturation. The protective action depends on sugar species. To understand the above trend and difference in detail, it is essentially important to clarify the characteristics of solutions containing those additives. In this study, by using wide-angle X-ray scattering technique covering a wide spatial region (~3-120 Å), we have clarified structures of sugar solutions with the concentration from 5% w/w to 65% w/w. The sugars measured in the present study were monosaccharides (glucose, fructose, mannose) and disaccharides (sucrose, trehalose, maltose). Due to observed scattering data with a wide spatial resolution, we have succeeded in obtaining information on the internal structure of individual sugar molecules and on the correlation between them. Every sugar gradually shortened the average inter-molecular distance as the concentration increased. The inter-molecular interaction between sugar molecules was essentially showed an exclusive tendency for every sugar, which appeared as the presence of a repulsive correlation hole. This trend was more weakly seen for trehalose compared to other sugars. The intermolecular distance and spread of individual molecule clearly showed the dependence of sugar species. We will discuss the relation between the characteristic of sugar solution and its protective action of biological materials.

Keywords: hydration, protein, sugar, X-ray scattering

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Authors: M. Cardenas-Garcia, P. P. Gonzalez-Perez

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Intercellular communication is a necessary condition for cellular functions and it allows a group of cells to survive as a population. Throughout this interaction, the cells work in a coordinated and collaborative way which facilitates their survival. In the case of cancerous cells, these take advantage of intercellular communication to preserve their malignancy, since through these physical unions they can send signs of malignancy. The Wnt/β-catenin signaling pathway plays an important role in the formation of intercellular communications, being also involved in a large number of cellular processes such as proliferation, differentiation, adhesion, cell survival, and cell death. The modeling and simulation of cellular signaling systems have found valuable support in a wide range of modeling approaches, which cover a wide spectrum ranging from mathematical models; e.g., ordinary differential equations, statistical methods, and numerical methods– to computational models; e.g., process algebra for modeling behavior and variation in molecular systems. Based on these models, different simulation tools have been developed from mathematical ones to computational ones. Regarding cellular and molecular processes in cancer, its study has also found a valuable support in different simulation tools that, covering a spectrum as mentioned above, have allowed the in silico experimentation of this phenomenon at the cellular and molecular level. In this work, we simulate and explore the complex interaction patterns of intercellular communication in cancer cells using the Cellulat bioinformatics tool, a computational simulation tool developed by us and motivated by two key elements: 1) a biochemically inspired model of self-organizing coordination in tuple spaces, and 2) the Gillespie’s algorithm, a stochastic simulation algorithm typically used to mimic systems of chemical/biochemical reactions in an efficient and accurate way. The main idea behind the Cellulat simulation tool is to provide an in silico experimentation environment that complements and guides in vitro experimentation in intra and intercellular signaling networks. Unlike most of the cell signaling simulation tools, such as E-Cell, BetaWB and Cell Illustrator which provides abstractions to model only intracellular behavior, Cellulat is appropriate for modeling both intracellular signaling and intercellular communication, providing the abstractions required to model –and as a result, simulate– the interaction mechanisms that involve two or more cells, that is essential in the scenario discussed in this work. During the development of this work we made evident the application of our computational simulation tool (Cellulat) for the modeling and simulation of intercellular communication between normal and cancerous cells, and in this way, propose key molecules that may prevent the arrival of malignant signals to the cells that surround the tumor cells. In this manner, we could identify the significant role that has the Wnt/β-catenin signaling pathway in cellular communication, and therefore, in the dissemination of cancer cells. We verified, using in silico experiments, how the inhibition of this signaling pathway prevents that the cells that surround a cancerous cell are transformed.

Keywords: cancer cells, in silico approach, intercellular communication, key molecules, modeling and simulation

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Authors: Eirini Konstanta, Cedric Gouedard, Aggeliki Delimitsou, Stefania Patera, Samuel Murray

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Introduction: Quality reference DNA standards (QRS) for molecular testing by next-generation sequencing (NGS) are essential for accurate quantitation of copy number variations (CNV) for germline and variant allelic frequencies (VAF) for somatic analyses. Objectives: Presently, several molecular analytics for oncology patients are reliant upon quantitative metrics. Test validation and standardisation are also reliant upon the availability of surrogate control materials allowing for understanding test LOD (limit of detection), sensitivity, specificity. We have developed a dual calibration platform allowing for QRS pairs to be included in analysed DNA samples, allowing for accurate quantitation of CNV and VAF metrics within and between patient samples. Methods: QRS™ blocks up to 500nt were designed for common NGS panel targets incorporating ≥ 2 identification tags (IDTDNA.com). These were analysed upon spiking into gDNA, somatic, and ctDNA using a proprietary CalSuite™ platform adaptable to common LIMS. Results: We demonstrate QRS™ calibration reproducibility spiked to 5–25% at ± 2.5% in gDNA and ctDNA. Furthermore, we demonstrate CNV and VAF within and between samples (gDNA and ctDNA) with the same reproducibility (± 2.5%) in a clinical sample of lung cancer and HBOC (EGFR and BRCA1, respectively). CNV analytics was performed with similar accuracy using a single pair of QRS calibrators when using multiple single targeted sequencing controls. Conclusion: Dual paired QRS™ calibrators allow for accurate and reproducible quantitative analyses of CNV, VAF, intrinsic sample allele measurement, inter and intra-sample measure not only simplifying NGS analytics but allowing for monitoring clinically relevant biomarker VAF across patient ctDNA samples with improved accuracy.

Keywords: calibrator, CNV, gene copy number, VAF

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