An integrative top-down and bottom-up qualitative model construction framework for exploration of biochemical systems

The authors would like to thank the support on this research by the CRISP project (Combinatorial Responses In Stress Pathways) funded by the BBSRC (BB/F00513X/1) under the Systems Approaches to Biological Research (SABR) Initiative.Peer reviewedPublisher PD

Design and Implementation of a Stand-Alone Tool for Metabolic Simulations

In this thesis, we present the design and implementation of a stand-alone tool for metabolic simulations. This system is able to integrate custom-built SBML models along with external user’s input information and produces the estimation of any reactants participating in the chain of the reactions in the provided model, e.g., ATP, Glucose, Insulin, for the given duration using numerical analysis and simulations. This tool offers the food intake arguments in the calculations to consider the personalized metabolic characteristics in the simulations. The tool has also been generalized to take into consideration of temporal genomic information and be flexible for simulation of any given biochemical model. After implementation, experimental results have demonstrated the numerical effectiveness of optimization for model selection and the feasibility of the proposed tool for the given metabolic simulation. The proof of concept analysis on the energy metabolism and insulin-glucose metabolism revealed this tool can be promising for a variety of healthcare applications

BioSilicoSystems - A Multipronged Approach Towards Analysis and Representation of Biological Data (PhD Thesis)

The rising field of integrative bioinformatics provides the vital methods to integrate, manage and also to analyze the diverse data and allows gaining new and deeper insights and a clear understanding of the intricate biological systems. The difficulty is not only to facilitate the study of heterogeneous data within the biological context, but it also more fundamental, how to represent and make the available knowledge accessible. Moreover, adding valuable information and functions that persuade the user to discover the interesting relations hidden within the data is, in itself, a great challenge. Also, the cumulative information can provide greater biological insight than is possible with individual information sources. Furthermore, the rapidly growing number of databases and data types poses the challenge of integrating the heterogeneous data types, especially in biology. This rapid increase in the volume and number of data resources drive for providing polymorphic views of the same data and often overlap in multiple resources. 

In this thesis a multi-pronged approach is proposed that deals with various methods for the analysis and representation of the diverse biological data which are present in different data sources. This is an effort to explain and emphasize on different concepts which are developed for the analysis of molecular data and also to explain its biological significance. The hypotheses proposed are in context with various other results and findings published in the past. The approach demonstrated also explains different ways to integrate the molecular data from various sources along with the need for a comprehensive understanding and clear projection of the concept or the algorithm and its results, but with simple means and methods. The multifarious approach proposed in this work comprises of different tools or methods spanning significant areas of bioinformatics research such as data integration, data visualization, biological network construction / reconstruction and alignment of biological pathways. Each tool deals with a unique approach to utilize the molecular data for different areas of biological research and is built based on the kernel of the thesis. Furthermore these methods are combined with graphical representation that make things simple and comprehensible and also helps to understand with ease the underlying biological complexity. Moreover the human eye is often used to and it is more comfortable with the visual representation of the facts

Applied orthogonal design for filtrating conditions of ultrasonic-assisted extraction from plant-chicory

The objective of the current study is to achieve global optimization of ultrasound-assisted extraction from chicory roots using a mixed orthogonal array design. Eight conditional factors were examined in the mixed orthogonal array (L16 (43×26)). The results showed that the importance of the eight factors, in decreasing order, was ethanol content, impregnation repetitions, ultrasonic input power, sonication temperature, sonication repetitions, solvent-to-solid ratio, impregnation time and sonication time. The optimum extraction conditions included a frequency of 40 kHz, an impregnation time of 24 h with two rounds of impregnation, a sonication period of 30 min and an ultrasonic input power of 400 W with two rounds of sonication. Importantly, these conditions were independent of alcohol content, solvent-tosolid ratio and sonication temperature. At frequency of 40 kHz, the alcohol content, solvent-to-solid ratio and sonication temperature were optimized in the range of 50 to 75% (v/v), 32:1 and 50°C, respectively.Key words: Chicory roots, ultrasound-assisted extraction, mixed orthogonal design, select factors, global optimization

生物学的亜硝酸酸化における可逆的および非可逆的阻害の動力学モデルに関する研究

本研究は、生物学的排水処理プロセスにおける微生物の増殖阻害について、その応答を阻害物質の濃度や曝露時間と関連付けて数学的に表現することを目的としたものである。北九州市立大

Predicting Anatomical Therapeutic Chemical (ATC) Classification of Drugs by Integrating Chemical-Chemical Interactions and Similarities

The Anatomical Therapeutic Chemical (ATC) classification system, recommended by the World Health Organization, categories drugs into different classes according to their therapeutic and chemical characteristics. For a set of query compounds, how can we identify which ATC-class (or classes) they belong to? It is an important and challenging problem because the information thus obtained would be quite useful for drug development and utilization. By hybridizing the informations of chemical-chemical interactions and chemical-chemical similarities, a novel method was developed for such purpose. It was observed by the jackknife test on a benchmark dataset of 3,883 drug compounds that the overall success rate achieved by the prediction method was about 73% in identifying the drugs among the following 14 main ATC-classes: (1) alimentary tract and metabolism; (2) blood and blood forming organs; (3) cardiovascular system; (4) dermatologicals; (5) genitourinary system and sex hormones; (6) systemic hormonal preparations, excluding sex hormones and insulins; (7) anti-infectives for systemic use; (8) antineoplastic and immunomodulating agents; (9) musculoskeletal system; (10) nervous system; (11) antiparasitic products, insecticides and repellents; (12) respiratory system; (13) sensory organs; (14) various. Such a success rate is substantially higher than 7% by the random guess. It has not escaped our notice that the current method can be straightforwardly extended to identify the drugs for their 2nd-level, 3rd-level, 4th-level, and 5th-level ATC-classifications once the statistically significant benchmark data are available for these lower levels

Decoding Complexity in Metabolic Networks using Integrated Mechanistic and Machine Learning Approaches

How can we get living cells to do what we want? What do they actually ‘want’? What ‘rules’ do they observe? How can we better understand and manipulate them? Answers to fundamental research questions like these are critical to overcoming bottlenecks in metabolic engineering and optimizing heterologous pathways for synthetic biology applications. Unfortunately, biological systems are too complex to be completely described by physicochemical modeling alone. In this research, I developed and applied integrated mechanistic and data-driven frameworks to help uncover the mysteries of cellular regulation and control. These tools provide a computational framework for seeking answers to pertinent biological questions. Four major tasks were accomplished. First, I developed innovative tools for key areas in the genome-to-phenome mapping pipeline. An efficient gap filling algorithm (called BoostGAPFILL) that integrates mechanistic and machine learning techniques was developed for the refinement of genome-scale metabolic network reconstructions. Genome-scale metabolic network reconstructions are finding ever increasing applications in metabolic engineering for industrial, medical and environmental purposes. Second, I designed a thermodynamics-based framework (called REMEP) for mutant phenotype prediction (integrating metabolomics, fluxomics and thermodynamics data). These tools will go a long way in improving the fidelity of model predictions of microbial cell factories. Third, I designed a data-driven framework for characterizing and predicting the effectiveness of metabolic engineering strategies. This involved building a knowledgebase of historical microbial cell factory performance from published literature. Advanced machine learning concepts, such as ensemble learning and data augmentation, were employed in combination with standard mechanistic models to develop a predictive platform for important industrial biotechnology metrics such as yield, titer, and productivity. Fourth, my modeling tools and skills have been used for case studies on fungal lipid metabolism analyses, E. coli resource allocation balances, reconstruction of the genome-scale metabolic network for a non-model species, R. opacus, as well as the rapid prediction of bacterial heterotrophic fluxomics. In the long run, this integrated modeling approach will significantly shorten the “design-build-test-learn” cycle of metabolic engineering, as well as provide a platform for biological discovery