A Plea for More Theory in Molecular Biology

The integrationist principles of systems theory have proven hugely successful in the physical sciences and engineering. It is an underlying assumption made in the systems approach to biology that they can also be used to understand biological phenomena at the level of an entire organism or organ. Within this holistic vision, the vastmajority of systems biology research projects investigate phenomena at the level of the cell, with the belief that unifying principles established at the most basic level can establish a framework within which we may understand phenomena at higher levels of organization. In this spirit, and to use a celestial analogy, if a disease effecting an organ or entire body is our universe of discourse, then the cell is the star we gaze at. In building an understanding of disease and the effect of drugs, systems biology makes an implicit assumption about direct causal entailment between cell function and physiology. A skeptic might argue that this is about the same as trying to predict the world economy from observations made at a local supermarket. However, assuming for the moment that the money and hope we are investing inmolecular biology, genomics, and systems biology is justified, how should this amazing 118 O. Wolkenhauer, M. Mesarovi´c, P. Wellstead intellectual achievement be possible? In this chapter we argue that an essential tool to progress is a systems theory that allows biological objects and their operational characteristics to be captured in a succinct yet general form. Armed with this conceptual framework, we construct mathematical representations of standard cellular and intercellular functions which can be integrated to describe more general processes of cell complexes, and potentially entire organ

Effects of crack tip geometry on dislocation emission and cleavage: A possible path to enhanced ductility

We present a systematic study of the effect of crack blunting on subsequent crack propagation and dislocation emission. We show that the stress intensity factor required to propagate the crack is increased as the crack is blunted by up to thirteen atomic layers, but only by a relatively modest amount for a crack with a sharp 60$^\circ$ corner. The effect of the blunting is far less than would be expected from a smoothly blunted crack; the sharp corners preserve the stress concentration, reducing the effect of the blunting. However, for some material parameters blunting changes the preferred deformation mode from brittle cleavage to dislocation emission. In such materials, the absorption of preexisting dislocations by the crack tip can cause the crack tip to be locally arrested, causing a significant increase in the microscopic toughness of the crack tip. Continuum plasticity models have shown that even a moderate increase in the microscopic toughness can lead to an increase in the macroscopic fracture toughness of the material by several orders of magnitude. We thus propose an atomic-scale mechanism at the crack tip, that ultimately may lead to a high fracture toughness in some materials where a sharp crack would seem to be able to propagate in a brittle manner. Results for blunt cracks loaded in mode II are also presented.Comment: 12 pages, REVTeX using epsfig.sty. 13 PostScript figures. Final version to appear in Phys. Rev. B. Main changes: Discussion slightly shortened, one figure remove

Environmental consciousness in the Netherlands

Contains fulltext : 3328.pdf (publisher's version ) (Open Access

A model structure-driven hierarchical decentralized stabilizing control structure for process networks

Based on the structure of process models a hierarchically structured state-space model has been proposed for process networks with controlled mass convection and constant physico-chemical properties. Using the theory of cascade-connected nonlinear systems and the properties of Metzler and Hurwitz matrices it is shown that process systems with controlled mass convection and without sources or with stabilizing linear source terms are globally asymptotically stable. The hierarchically structured model gives rise to a distributed controller structure that is in agreement with the traditional hierarchical process control system structure where local controllers are used for mass inventory control and coordinating controllers are used for optimizing the system dynamics. The proposed distributed controller is illustrated on a simple non-isotherm jacketed chemical reactor

Responsive Production in Manufacturing: A Modular Architecture

[EN] This paper proposes an architecture aiming at promoting the convergence of the physical and digital worlds, through CPS and IoT technologies, to accommodate more customized and higher quality products following Industry 4.0 concepts. The architecture combines concepts such as cyber-physical systems, decentralization, modularity and scalability aiming at responsive production. Combining these aspects with virtualization, contextualization, modeling and simulation capabilities it will enable self-adaptation, situational awareness and decentralized decision-making to answer dynamic market demands and support the design and reconfiguration of the manufacturing enterprise.The research leading to these results has received funding from the European Union H2020 project C2 NET (FoF-01-2014) nr 636909.Marques, M.; Agostinho, C.; Zacharewicz, G.; Poler, R.; Jardim-Goncalves, R. (2018). Responsive Production in Manufacturing: A Modular Architecture. 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McGraw-Hill, New York, USA (1980

Relating industrial symbiosis and circular economy to the sustainable development debate

Industrial Symbiosis (IS) is a business-focused collaborative approach oriented towards resource efficiency that has been theorised and studied mainly over the last twenty-five years. Recently, IS seems to have found a renewed impetus in the framework of the Circular Economy (CE), a novel approach to sustainability and Sustainable Development (SD) that has been rapidly gaining momentum world-wide. This opening chapter of the book provides an introduction to the concepts of IS, CE and SD, and summarizes their complex evolutionary paths, recalling the rel-evant developments and implementation challenges. In addition, the authors point out the divergences and interrelations of these concepts, both among themselves and with other related concepts and research fields, such as industrial ecology, eco-logical modernization and the green economy. Furthermore, the potential contribu-tion of IS and the CE to SD is briefly discussed, also highlighting critical issues and trade-offs, as well as gaps in research and application, especially relating to the so-cial component of sustainability. Particular attention is given to the potential role of IS in the achievement of targets connected to the Sustainable Development Goals set in the UN Agenda 2030. The recent advances in the IS and CE discussion in the context of the SD research community are further explored, with particular empha-sis on the contribution of the International Sustainable Development Research So-ciety (ISDRS) and its 24th annual conference organised in Messina, Italy, in 2018. The programme of that conference, indeed, included specific tracks on the above-mentioned themes, the contents of which are briefly commented on here, after an overview on the whole conference and the main cross-cutting concepts emerged. In the last part of the chapter, a brief description of the chapters collected in the book is presented. These contributions describe and discuss theoretical frameworks, methodological approaches and/or experiences and case studies where IS and the principles of CE are applied in different geographical context and at different scales to ultimately improve the sustainability of the current production patterns

Metabolic flux understanding of Pichia pastoris grown on heterogenous culture media

[EN] Within the emergent field of Systems Biology, mathematical models obtained from physical chemical laws (the so-called first principles-based models) of microbial systems are employed to discern the principles that govern cellular behaviour and achieve a predictive understanding of cellular functions. The reliance on this biochemical knowledge has the drawback that some of the assumptions (specific kinetics of the reaction system, unknown dynamics and values of the model parameters) may not be valid for all the metabolic possible states of the network. In this uncertainty context, the combined use of fundamental knowledge and data measured in the fermentation that describe the behaviour of the microorganism in the manufacturing process is paramount to overcome this problem. In this paper, a grey modelling approach is presented combining data-driven and first principles information at different scales, developed for Pichia pastoris cultures grown on different carbon sources. This approach will allow us to relate patterns of recombinant protein production to intracellular metabolic states and correlate intra and extracellular reactions in order to understand how the internal state of the cells determines the observed behaviour in P. pastoris cultivations.Research in this study was partially supported by the Spanish Ministry of Science and Innovation and FEDER funds from the European Union through grants DPI2011-28112-C04-01 and DPI2011-28112-C04-02. The authors are also grateful to Biopolis SL for supporting this research. We also gratefully acknowledge Associate Professor Jose Camacho for providing the Exploratory Data Analysis Toolbox.González Martínez, JM.; Folch-Fortuny, A.; Llaneras Estrada, F.; Tortajada Serra, M.; Picó Marco, JA.; Ferrer, A. (2014). Metabolic flux understanding of Pichia pastoris grown on heterogenous culture media. Chemometrics and Intelligent Laboratory Systems. 134:89-99. https://doi.org/10.1016/j.chemolab.2014.02.003S899913

MCR-ALS on metabolic networks: Obtaining more meaningful pathways

[EN] With the aim of understanding the flux distributions across a metabolic network, i.e. within living cells, Principal Component Analysis (PCA) has been proposed to obtain a set of orthogonal components (pathways) capturing most of the variance in the flux data. The problems with this method are (i) that no additional information can be included in the model, and (ii) that orthogonality imposes a hard constraint, not always reasonably. To overcome these drawbacks, here we propose to use a more flexible approach such as Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to obtain this set of biological pathways through the network. By using this method, different constraints can be included in the model, and the same source of variability can be present in different pathways, which is reasonable from a biological standpoint. This work follows a methodology developed for Pichia pastoris cultures grown on different carbon sources, lately presented in González-Martínez et al. (2014). In this paper a different grey modelling approach, which aims to incorporate a priori knowledge through constraints on the modelling algorithms, is applied to the same case of study. The results of both models are compared to show their strengths and weaknesses.Research in this study was partially supported by the Spanish Ministry of Science and Innovation and FEDER funds from the European Union through grants DPI2011-28112-C04-01 and DPI2011-28112-C04-02. The authors are also grateful to Biopolis SL for supporting this research.Folch-Fortuny, A.; Tortajada Serra, M.; Prats-Montalbán, JM.; Llaneras Estrada, F.; Picó Marco, JA.; Ferrer Riquelme, AJ. (2015). MCR-ALS on metabolic networks: Obtaining more meaningful pathways. Chemometrics and Intelligent Laboratory Systems. 142:293-303. https://doi.org/10.1016/j.chemolab.2014.10.004S29330314