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Systematic Models for Biological Systems Engineering Training Network

Deliverables

Methodology for reverse engineering: model selection and parameter identification

A systematic methodology will be investigated for reverse engineering: model selection and parameter identification using systematic model-based techniques. Validation studies

Researchers declaration of conformity

Researchers declaration of conformity will be submitted on-line to the portal

Integrated experimental-modeling platform to tailor treatments in a patient-specific

An Integrated experimental-modeling platform will be developed to tailor treatments in a patient-specific and leukemia-specific chemotherapy schedule

Multi-scale models to capture heterogeneity in biological systems

New multi-scale population balance models to capture heterogeneity in biological systems

Methodology for global dynamic optimization of cellular processes

A new methodology for global dynamic optimization of cellular processes will be investigated. The methodology will be validated in several problems in collaboration with the partners..

Model-based dynamic optimization methods to explain (a posteriori use) or predict

Optimal control formulations will be developed (using a mixed-integer dynamic optimization framework) to explain (a posteriori use) or predict (a priori use) the operating principles in metabolic and signaling pathways

Public dissemination of project results

In order to ensure that the project results are efficiently disseminated to scientific and industrial communities, the partners will implement specific measures. A dedicated work package has been defined to ensure the implementation of these measures as well as effective knowledge transfer among the partners. The partners will disseminate information about the goals of the project, ongoing activities, progress, results and the potential benefits and opportunities for Academia and the private sector. As first measure, the partners will use their own academic and industrial networks for dissemination. In addition, it is expected that at least 30 scientific papers (at least two per ESR), will be published in peer-reviewed journals. For each of the ESRs, one of the required publications will be submitted to a journal familiar to the biological systems engineering community (e.g. Biotechnology and Bioengineering, IEEE Transactions on Biomedical Engineering, Computers and Chemical Engineering, PLOS Computational Biology) and one publication will be submitted to a journal transcending the community (for more mathematical projects, relevant publications include: Journal of Global Optimization, INFORMS Journal of Computing, Optimization Methods and Software; for more biological projects, relevant publications include Proceedings of the National Academy of Sciences; Leukemia). Further dissemination activities will include: - Reporting software to facilitate exchange of data between the partners (Emdesk); - Presentations at scientific conferences; - Press-releases for the local and international media; - Organization of workshops with the participation of renowned scientists and external industrial leaders. The project partners will communicate and disseminate the results to several target sectors: scientific community (researchers and students), relevant industrial sectors, general public, potential investors/stakeholders. To ensure the access to the project results, all scientific publications will be made under the open-access concept – i.e. free of charge online access for the user. Both open access publishing and self-archiving options will be considered (also called ‚gold‛ or ‚green‛ open access model, respectively).

Development of an in silico leukemia model

A novel in silico leukemia model will be developed and solved using efficient computational; techniques.

Methodology for a more systematic model building, and subsequent model

A systematic methodology will be investigated for a more systematic model building, and subsequent model reduction for control and optimization purposes. Novel model-reduction techniques will be investigated and their accuracy will be assessed in example problems.

Kinetic model describing E.coli central metabolism

A new kinet model describing E.coli central metabolism. The model will account for the underlying complexities and constraints

Methodology to model jointly signaling, regulatory and metabolic networks

Kinetic modeling of metabolic behavior including transcriptional regulation. The proposed modelling framework will integrate signal transduction, regulation and metabolism into dynamic mathematical models

Methodology to identify both structure and parameters of large signalling models

A systematic methodology will be investigated to to identify both structure and parameters of large signalling models. Validation studies will be also performed.

Mathematical model-based strategy for the detection of drug targets

A novel mathematical model-based strategy will be investigated for the detection of drug targets

Final report

The final report will be prepared and submitted according the contractual requirements and reporting rules.

Kinetic model of human metabolism derived

To derive a new model of human metabolism. The model will account for uncertainty and incorporate stoichiometric, thermodynamic and physiological constraints

Mathematical model to describe regulation of metabolism by dynamic cell

New mathematical model to describe regulation of metabolism by dynamic cell signalling.

"Optimal operation profile capturing heterogeneity of ""high-fidelity"" bioprocess"

"To derive an optimal operation profile capturing heterogeneity of ""high-fidelity"" bioprocess models. A salient feature of the proposed approach is to develop model and techniques which are computationally tractable"

SyMBioSys Website

A SyMBioSys website will be set-up and maintained as an effective mean of communication between the participants and also for training and dissemination purposes.

Transferable skills courses

Scientific publishing and dissemination.: Writing with a clear and direct style and plan, research, organize and compose a literature review; Practice skills on both sides of the camera and microphone, as well as gaining experience of effective scientific writing under real time pressure; Research Ethics, and Bioethics which will cover topics such as “The fabrication/falsification of Data”, “Professional and Personal Integrity”, “Plagiarism and Collusion”, and “Medical Research”; The relationship between communication, science and policymaking in both the developed and developing world. Entrepreneurship and IP management: Development of entrepreneurship skills including: idea generation; learning how to get investors excited; understanding marketing, design, and legal matters; Understanding of the technology behind the product. The students will have the opportunity to understand development processes and acquire project management skills. The students will also end up with an overview of White and Red Biotech market; Protection of intellectual property including: obtaining patents; licensing technology to established companies; copyrighting software; initiating start-ups

Doctoral degrees

Doctoral degrees will be awarded to ESRs after succesfull completion of their Doctoral work.

SyMBioSys vacancies published

Vacancies will be published simultaneously through various media: European and world-wide read journals (e.g. Nature Jobs, jobs.ac.uk) for academic-related job adverts, the EU portal for jobs advert, the Commission’s own pages for the Marie Skłodowska-Curie Actions, SyMBioSys project website, beneficiaries’ graduate recruiting procedures, and informal approaches to colleagues both in academia and industry. The aim is to have a shortlist of candidates, with CVs and references available before the contracts are signed to ensure that prompt interviews would take place and researchers could be recruited on time.

Science-based courses

Selected Science-based courses include network-wide workshops and seminars to be attended by all recruited research. These includ: (i) Introduction to biological systems and bioprocesses model definition (ii) Fundamental Experimental Techniques for Biological Systems (iii) Kinetic model building in biological systems engineering (iv)Optimality principles in biological systems (v) Model-based metabolic engineering (vi) Informatics for Biological Systems

Conference organization

Organization of an open conference on “Systematic Models for Biological Systems Engineering”

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Publications

A guide to gene regulatory network inference for obtaining predictive solutions: Underlying assumptions and fundamental biological and data constraints

Author(s): Sara Barbosa, Bastian Niebel, Sebastian Wolf, Klaus Mauch, Ralf Takors
Published in: Biosystems, 174, 2018, Page(s) 37-48, ISSN 0303-2647
Publisher: Elsevier BV
DOI: 10.1016/j.biosystems.2018.10.008

Parameter estimation in models of biological oscillators: an automated regularised estimation approach

Author(s): Jake Alan Pitt, Julio R. Banga
Published in: BMC Bioinformatics, 20/1, 2019, ISSN 1471-2105
Publisher: BioMed Central
DOI: 10.1186/s12859-019-2630-y

Critical Assessment of Parameter Estimation Methods in Models of Biological Oscillators

Author(s): Jake Alan Pitt, Lucian Gomoescu, Constantinos C. Pantelides, Benoît Chachuat, Julio R. Banga
Published in: IFAC-PapersOnLine, 51/19, 2018, Page(s) 72-75, ISSN 2405-8963
Publisher: Elsevier
DOI: 10.1016/j.ifacol.2018.09.040

Optimality and identification of dynamic models in systems biology: an inverse optimal control framework

Author(s): Nikolaos Tsiantis, Eva Balsa-Canto, Julio R Banga
Published in: Bioinformatics, 34/14, 2018, Page(s) 2433-2440, ISSN 1367-4803
Publisher: Oxford University Press
DOI: 10.1093/bioinformatics/bty139

Network-based technologies for early drug discovery

Author(s): Chris Fotis, Asier Antoranz, Dimitris Hatziavramidis, Theodore Sakellaropoulos, Leonidas G. Alexopoulos
Published in: Drug Discovery Today, 23/3, 2018, Page(s) 626-635, ISSN 1359-6446
Publisher: Elsevier BV
DOI: 10.1016/j.drudis.2017.12.001

Oxidized alginate hydrogels with the GHK peptide enhance cord blood mesenchymal stem cell osteogenesis: A paradigm for metabolomics-based evaluation of biomaterial design

Author(s): Michail E. Klontzas, Supachai Reakasame, Raquel Silva, Jose C.F. Morais, Spyros Vernardis, Robert J. MacFarlane, Manolis Heliotis, Eleftherios Tsiridis, Nicki Panoskaltsis, Aldo R. Boccaccini, Athanasios Mantalaris
Published in: Acta Biomaterialia, 88, 2019, Page(s) 224-240, ISSN 1742-7061
Publisher: Elsevier BV
DOI: 10.1016/j.actbio.2019.02.017

A Review of Dynamic Modeling Approaches and Their Application in Computational Strain Optimization for Metabolic Engineering

Author(s): Osvaldo D. Kim, Miguel Rocha, Paulo Maia
Published in: Frontiers in Microbiology, 9, 2018, ISSN 1664-302X
Publisher: Frontiers Media
DOI: 10.3389/fmicb.2018.01690

Full observability and estimation of unknown inputs, states and parameters of nonlinear biological models

Author(s): Alejandro F. Villaverde, Nikolaos Tsiantis, Julio R. Banga
Published in: Journal of The Royal Society Interface, 16/156, 2019, Page(s) 20190043, ISSN 1742-5689
Publisher: The Royal Society
DOI: 10.1098/rsif.2019.0043

NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction

Author(s): Edoardo Gaude, Christina Schmidt, Payam A. Gammage, Aurelien Dugourd, Thomas Blacker, Sew Peak Chew, Julio Saez-Rodriguez, John S. O’Neill, Gyorgy Szabadkai, Michal Minczuk, Christian Frezza
Published in: Molecular Cell, 69/4, 2018, Page(s) 581-593.e7, ISSN 1097-2765
Publisher: Cell Press
DOI: 10.1016/j.molcel.2018.01.034

Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data

Author(s): Alexander Schäfer, Enio Gjerga, Richard WD Welford, Imke Renz, Francois Lehembre, Peter MA Groenen, Julio Saez-Rodriguez, Ruedi Aebersold, Matthias Gstaiger
Published in: Molecular Systems Biology, 15/8, 2019, Page(s) e8828, ISSN 1744-4292
Publisher: Nature Publishing Group
DOI: 10.15252/msb.20198828

Capturing Mesenchymal Stem Cell Heterogeneity during Osteogenic Differentiation: An Experimental–Modeling Approach

Author(s): Romuald Győrgy, Michail E. Klontzas, Margaritis Kostoglou, Nicki Panoskaltsis, Athanasios Mantalaris, Michael C. Georgiadis
Published in: Industrial & Engineering Chemistry Research, 58/31, 2019, Page(s) 13900-13909, ISSN 0888-5885
Publisher: American Chemical Society
DOI: 10.1021/acs.iecr.9b01988

An Integrated Experimental-Modelling Approach of Mesenchymal Stem Cell Bioprocess towards Osteogenic Differentiation

Author(s): Romuald Győrgy, Michail E. Klontzas, Margaritis Kostoglou, Nicki Panoskaltsis, Michael C. Georgiadis, Athanasios Mantalaris
Published in: IFAC-PapersOnLine, 50/1, 2017, Page(s) 9877-9882, ISSN 2405-8963
Publisher: Elsevier
DOI: 10.1016/j.ifacol.2017.08.1603

Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma

Author(s): Jan Rožanc, Theodore Sakellaropoulos, Asier Antoranz, Cristiano Guttà, Biswajit Podder, Vesna Vetma, Nicole Rufo, Patrizia Agostinis, Vaia Pliaka, Thomas Sauter, Dagmar Kulms, Markus Rehm, Leonidas G. Alexopoulos
Published in: Cell Death & Differentiation, 26/8, 2019, Page(s) 1365-1378, ISSN 1350-9047
Publisher: Nature Publishing Group
DOI: 10.1038/s41418-018-0210-8

Metabolomics Analysis of the Osteogenic Differentiation of Umbilical Cord Blood Mesenchymal Stem Cells Reveals Differential Sensitivity to Osteogenic Agents

Author(s): Michail E. Klontzas, Spyros I. Vernardis, Manolis Heliotis, Eleftherios Tsiridis, Athanasios Mantalaris
Published in: Stem Cells and Development, 26/10, 2017, Page(s) 723-733, ISSN 1547-3287
Publisher: Mary Ann Liebert Inc.
DOI: 10.1089/scd.2016.0315

Mechanism-based biomarker discovery

Author(s): Asier Antoranz, Theodore Sakellaropoulos, Julio Saez-Rodriguez, Leonidas G. Alexopoulos
Published in: Drug Discovery Today, 22/8, 2017, Page(s) 1209-1215, ISSN 1359-6446
Publisher: Elsevier BV
DOI: 10.1016/j.drudis.2017.04.013

Gli1 + Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target

Author(s): Rebekka K. Schneider, Ann Mullally, Aurelien Dugourd, Fabian Peisker, Remco Hoogenboezem, Paulina M.H. Van Strien, Eric M. Bindels, Dirk Heckl, Guntram Büsche, David Fleck, Gerhard Müller-Newen, Janewit Wongboonsin, Monica Ventura Ferreira, Victor G. Puelles, Julio Saez-Rodriguez, Benjamin L. Ebert, Benjamin D. Humphreys, Rafael Kramann
Published in: Cell Stem Cell, 20/6, 2017, Page(s) 785-800.e8, ISSN 1934-5909
Publisher: Cell Press
DOI: 10.1016/j.stem.2017.03.008

A Population Balance Model for Stem Cell Differentiation Bioprocesses

Author(s): Romuald Győrgy, Michail E. Klontzas, Margaritis Kostoglou, Nicki Panoskaltsis, Athanasios Mantalaris, Michael C. Georgiadis
Published in: 27th European Symposium on Computer Aided Process Engineering, 40, 2017, Page(s) 2761-2766, ISBN 9780-444639653
Publisher: Elsevier
DOI: 10.1016/b978-0-444-63965-3.50462-1

High-dimensional single cell-analysis of lymphocytic activation in melanoma

Author(s): Bosisio, F.M., Antoranz, A., Bolognesi, M.M., Chinello, C., Wouters, J., Magni, F., Alexopoulos, L., Cattoretti, G. and van den Oord, J.
Published in: bioRxiv, 2018
Publisher: Cold Spring Harbor Laboratory

A functional landscape of chronic kidney disease entities from public transcriptomic data

Author(s): Tajti, F., Antoranz, A., Ibrahim, M.M., Kim, H., Ceccarelli, F., Kuppe, C., Alexopoulos, L.G., Kramann, R. and Saez-Rodriguez, J
Published in: bioRxiv, 2019
Publisher: Cold Spring Harbor Laboratory

From expression footprints to causal pathways: Contextualizing large signalling networks with CARNIVAL

Author(s): Anika Liu, Panuwat Trairatphisan, Enio Gjerga, Athanasios Didangelos, Jonathan Barrat, Julio-Saez Rodriguez
Published in: biorxiv, 2019
Publisher: Cold Spring Harbor Laboratory
DOI: 10.1101/541888