An integrated approach for remanufacturing job shop scheduling with routing alternatives.

Remanufacturing is a practice of growing importance due to increasing environmental awareness and regulations. However, the stochastic natures inherent in the remanufacturing processes complicate its scheduling. This paper undertakes the challenge and presents a remanufacturing job shop scheduling approach by integrating alternative routing assignment and machine resource dispatching. A colored timed Petri net is introduced to model the dynamics of remanufacturing process, such as various process routings, uncertain operation times for cores, and machine resource conflicts. With the color attributes in Petri nets, two types of decision points, recovery routing selection and resource dispatching, are introduced and linked with places in CTPN model. With time attributes in Petri nets, the temporal aspect of recovery operations for cores as well as the evolution dynamics in cores\u27 operational stages is mathematically analyzed. A hybrid meta-heuristic algorithm embedded scheduling strategy over CTPN is proposed to search for the optimal recovery routings for worn cores and their recovery operation sequences on workstations, in minimizing the total production cost. The approach is demonstrated through the remanufacturing of used machine tool and its effectiveness is compared against another two cases: baseline case with fixed recovery process routings and case 2 using standard SA/MST

Event structures for Petri nets with persistence

Event structures are a well-accepted model of concurrency. In a seminal paper by Nielsen, Plotkin and Winskel, they are used to establish a bridge between the theory of domains and the approach to concurrency proposed by Petri. A basic role is played by an unfolding construction that maps (safe) Petri nets into a subclass of event structures, called prime event structures, where each event has a uniquely determined set of causes. Prime event structures, in turn, can be identified with their domain of configurations. At a categorical level, this is nicely formalised by Winskel as a chain of coreflections. Contrary to prime event structures, general event structures allow for the presence of disjunctive causes, i.e., events can be enabled by distinct minimal sets of events. In this paper, we extend the connection between Petri nets and event structures in order to include disjunctive causes. In particular, we show that, at the level of nets, disjunctive causes are well accounted for by persistent places. These are places where tokens, once generated, can be used several times without being consumed and where multiple tokens are interpreted collectively, i.e., their histories are inessential. Generalising the work on ordinary nets, Petri nets with persistence are related to a new subclass of general event structures, called locally connected, by means of a chain of coreflections relying on an unfolding construction

Combination of Genome-Scale Models and Bioreactor Dynamics to Optimize the Production of Commodity Chemicals

The current production of a number of commodity chemicals relies on the exploitation of fossil fuels and hence has an irreversible impact on the environment. Biotechnological processes offer an attractive alternative by enabling the manufacturing of chemicals by genetically modified microorganisms. However, this alternative approach poses some important technical challenges that must be tackled to make it competitive. On the one hand, the design of biotechnological processes is based on trial-and-error approaches, which are not only costly in terms of time and money, but also result in suboptimal designs. On the other hand, the manufacturing of chemicals by biological processes is almost exclusively carried out by batch or fed-batch cultures. Given that batch cultures are expensive and not easy to scale, technical means must be developed to make continuous cultures feasible and efficient. In order to address these challenges, we have developed a mathematical model able to integrate in a single model both the genome-scale metabolic model for the organism synthesizing the chemical of interest and the dynamics of the bioreactor in which the organism is cultured. Such a model is based on the use of Flexible Nets, a modeling formalism for dynamical systems. The integration of a microscopic (organism) and a macroscopic (bioreactor) model in a single net provides an overall view of the whole system and opens the door to global optimizations. As a case study, the production of citramalate with respect to the substrate consumed by E. coli is modeled, simulated and optimized in order to find the maximum productivity in a steady-state continuous culture. The predicted computational results were consistent with the wet lab experiments

On the Interpretation of Delays in Delay Stochastic Simulation of Biological Systems

Delays in biological systems may be used to model events for which the underlying dynamics cannot be precisely observed. Mathematical modeling of biological systems with delays is usually based on Delay Differential Equations (DDEs), a kind of differential equations in which the derivative of the unknown function at a certain time is given in terms of the values of the function at previous times. In the literature, delay stochastic simulation algorithms have been proposed. These algorithms follow a "delay as duration" approach, namely they are based on an interpretation of a delay as the elapsing time between the start and the termination of a chemical reaction. This interpretation is not suitable for some classes of biological systems in which species involved in a delayed interaction can be involved at the same time in other interactions. We show on a DDE model of tumor growth that the delay as duration approach for stochastic simulation is not precise, and we propose a simulation algorithm based on a ``purely delayed'' interpretation of delays which provides better results on the considered model

Process Calculi Abstractions for Biology

Several approaches have been proposed to model biological systems by means of the formal techniques and tools available in computer science. To mention just a few of them, some representations are inspired by Petri Nets theory, and some other by stochastic processes. A most recent approach consists in interpreting the living entities as terms of process calculi where the behavior of the represented systems can be inferred by applying syntax-driven rules. A comprehensive picture of the state of the art of the process calculi approach to biological modeling is still missing. This paper goes in the direction of providing such a picture by presenting a comparative survey of the process calculi that have been used and proposed to describe the behavior of living entities. This is the preliminary version of a paper that was published in Algorithmic Bioprocesses. The original publication is available at http://www.springer.com/computer/foundations/book/978-3-540-88868-

A critical review on modelling formalisms and simulation tools in computational biosystems

Integration of different kinds of biological processes is an ultimate goal for whole-cell modelling. We briefly review modelling formalisms that have been used in Systems Biology and identify the criteria that must be addressed by an integrating framework capable of modelling, analysing and simulating different biological networks. Aware that no formalism can fit all purposes we realize Petri nets as a suitable model for Metabolic Engineering and take a deeper perspective on the role of this formalism as an integrating framework for regulatory and metabolic networks.Research supported by PhD grant SFRH/BD/35215/2007 from the Fundacao para a Ciencia e a Tecnologia (FCT) and the MIT-Portugal program

Multi-level dynamic modeling in biological systems : application of hybrid Petri nets to network simulation

The recent progress in the high-throughput experimental technologies allows the reconstruction of many biological networks and to evaluate changes in proteins, genes and metabolites levels in different conditions. On the other hand, computational models, when complemented with regulatory information, can be used to predict the phenotype of an organism under different genetic and environmental conditions. These computational methods can be used for example to identify molecular targets capable of inactivating a bacterium and to understand its virulence factors. This work proposes a hybrid metabolic-regulatory Petri net approach that is based on the combination of approximate enzyme-kinetic rate laws and Petri nets. A prototypic network model is used as a test-case to illustrate the application of these concepts in Systems Biology.This work was partially supported by post-doctoral grant by Fundacao para a Ciencia e a Tecnologia (FCT) (SFRH/BPD/80784/2011), project PneumoSyS - A Systems Biology approach to the role of pneumococcal carbon metabolism in colonization and invasive disease (FCT contract: PTDC/SAU-MII/100964/2008) and by FCT (INESC-ID multiannual funding) through the PIDDAC program funds

Simulation of a Petri net-based Model of the Terpenoid Biosynthesis Pathway

<p>Abstract</p> <p>Background</p> <p>The development and simulation of dynamic models of terpenoid biosynthesis has yielded a systems perspective that provides new insights into how the structure of this biochemical pathway affects compound synthesis. These insights may eventually help identify reactions that could be experimentally manipulated to amplify terpenoid production. In this study, a dynamic model of the terpenoid biosynthesis pathway was constructed based on the Hybrid Functional Petri Net (HFPN) technique. This technique is a fusion of three other extended Petri net techniques, namely Hybrid Petri Net (HPN), Dynamic Petri Net (HDN) and Functional Petri Net (FPN).</p> <p>Results</p> <p>The biological data needed to construct the terpenoid metabolic model were gathered from the literature and from biological databases. These data were used as building blocks to create an HFPNe model and to generate parameters that govern the global behaviour of the model. The dynamic model was simulated and validated against known experimental data obtained from extensive literature searches. The model successfully simulated metabolite concentration changes over time (pt) and the observations correlated with known data. Interactions between the intermediates that affect the production of terpenes could be observed through the introduction of inhibitors that established feedback loops within and crosstalk between the pathways.</p> <p>Conclusions</p> <p>Although this metabolic model is only preliminary, it will provide a platform for analysing various high-throughput data, and it should lead to a more holistic understanding of terpenoid biosynthesis.</p

A novel method for high-throughput detection and quantification of neutrophil extracellular traps reveals ROS-independent NET release with immune complexes

AbstractA newly-described first-line immune defence mechanism of neutrophils is the release of neutrophil extracellular traps (NETs). Immune complexes (ICxs) induce low level NET release. As such, the in vitro quantification of NETs is challenging with current methodologies. In order to investigate the role of NET release in ICx-mediated autoimmune diseases, we developed a highly sensitive and automated method for quantification of NETs. After labelling human neutrophils with PKH26 and extracellular DNA with Sytox green, cells are fixed and automatically imaged with 3-dimensional confocal laser scanning microscopy (3D-CLSM). NET release is then quantified with digital image analysis whereby the NET amount (Sytox green area) is corrected for the number of imaged neutrophils (PKH26 area). A high sensitivity of the assay is achieved by a) significantly augmenting the area of the well imaged (11%) as compared to conventional assays (0.5%) and b) using a 3D imaging technique for optimal capture of NETs, which are topologically superimposed on neutrophils. In this assay, we confirmed low levels of NET release upon human ICx stimulation which were positive for citrullinated histones and neutrophil elastase. In contrast to PMA-induced NET release, ICx-induced NET release was unchanged when co-incubated with diphenyleneiodonium (DPI). We were able to quantify NET release upon stimulation with serum from RA and SLE patients, which was not observed with normal human serum. To our knowledge, this is the first semi-automated assay capable of sensitive detection and quantification of NET release at a low threshold by using 3D CLSM. The assay is applicable in a high-throughput manner and allows the in vitro analysis of NET release in ICx-mediated autoimmune diseases