Selection of Projects

NOTE:

Due to a change in job location by JVF, currently director of the Superior Polytechnical School at University of Vic, this site is currently on hold for the length of such assignment. The site will be kept up to date with respect to academic and research activity, but will not represent the current work by JVF

Below there is a list of some relevant projects the lab is or has been involved in. In addition to them, which sometimes represent collateral interests, the lab’s ground funding comes from the Spanish Plan Nacional, which supports the work on the development and application of tools for macromolecular structure function relationships.

• Selected current projects
• Selected past projects

Currently funded projects

Marató TV3: “Modulation of immune receptors function as a novel therapeutic strategy for acute CNS damage”

The existence of different types of immune receptors with the capability to regulate microglia/macrophage function opens a new window for the development of new neuroprotective strategies in acute CNS damage. This project aims to analyse the therapeutic potential of some of those proteins (CD200R, TREM-2 and the CD300 family of receptors) in different experimental in vitro and in vivo models. This proposal will be developed by 5 teams covering a wide range of expertise including bioinformatics, molecular immunology, neurobiology, neuropathology, and behavioural neuroscience. The role of the CBBL is to provide support on protein structure and protein interaction predictions.

VPH NoE

The Virtual Physiological Human Network of Excellence (VPH NoE) has been designed with ‘service to the community’ of VPH researchers as its primary purpose. The aims of the network range from the development of a VPH ToolKit and associated infrastructural resources, integration of models and data across the various relevant levels of physiological structure and functional organisation, through to VPH community building, training activities and support.

• [2009,incollection] bibtex
  B. Alsina, A. L. García–Lomana, J. Villà–Freixa, and F. Giráldez, "Developmental biology and mathematics: the rules of an embryo," , Giráldez, F. and Herrero, M. A., Eds., Am. Math. Soc. and Real Soc. Mat. Esp, 2009, vol. 492, pp. 1-12.
  @INCOLLECTION{Alsina2009,
  author = {Berta Alsina and Adri\'an L. Garc\'ia--Lomana and Jordi Vill\`a--Freixa and Fernando Gir\'aldez},
  title = {Developmental biology and mathematics: the rules of an embryo},
  booktitle = {{Mathematics, Developmental Biology and Tumour Growth}},
  publisher = {Am. Math. Soc. and Real Soc. Mat. Esp},
  year = {2009},
  editor = {Fernando Gir\'aldez and Miguel A. Herrero},
  volume = {492},
  pages = {1--12},
  url = {http://books.google.es/books?id=l5FthtzbKMoC&pg=PA1&lpg=PA1&dq=Developmental+biology+and+mathematics:+the+rules+of+an+embryo&source=bl&ots=ut9RM7ou6N&sig=-n3uA72FSU27B4JapNHHJHFqsco&hl=es&ei=MjFxTI3PAp-U4gbMuuneCA&sa=X&oi=book_result&ct=result&resnum=1&ved=0CBwQ6AEwAA#v=onepage&q=Developmental%20biology%20and%20mathematics%3A%20the%20rules%20of%20an%20embryo&f=false}
}

• [2009,article] bibtex
  F. X. Guix, G. Ill-Raga, R. Bravo, T. Nakaya, G. de Fabritiis, M. Coma, G. P. Miscione, J. Villà-Freixa, T. Suzuki, X. Fernandez-Busquets, M. A. Valverde, B. de Strooper, and F. J. Munoz, "Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation," Brain, vol. 132, iss. 5, pp. 1335-1345, 2009.
  @ARTICLE{Guix2009,
  author = {Guix, Francesc X. and Ill-Raga, Gerard and Bravo, Ramona and Nakaya, Tadashi and de Fabritiis, Gianni and Coma, Mireia and Miscione, Gian Pietro and Vill\`a-Freixa, Jordi and Suzuki, Toshiharu and Fernandez-Busquets, Xavier and Valverde, Miguel A. and de Strooper, Bart and Munoz, Francisco J.},
  title = {{Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation}},
  journal = {Brain},
  year = {2009},
  volume = {132},
  pages = {1335-1345},
  number = {5},
  abstract = {Alzheimer's disease neuropathology is characterized by neuronal death, amyloid {beta}-peptide deposits and neurofibrillary tangles composed of paired helical filaments of tau protein. Although crucial for our understanding of the pathogenesis of Alzheimer's disease, the molecular mechanisms linking amyloid {beta}-peptide and paired helical filaments remain unknown. Here, we show that amyloid {beta}-peptide-induced nitro-oxidative damage promotes the nitrotyrosination of the glycolytic enzyme triosephosphate isomerase in human neuroblastoma cells. Consequently, nitro-triosephosphate isomerase was found to be present in brain slides from double transgenic mice overexpressing human amyloid precursor protein and presenilin 1, and in Alzheimer's disease patients. Higher levels of nitro-triosephosphate isomerase (P < 0.05) were detected, by Western blot, in immunoprecipitates from hippocampus (9 individuals) and frontal cortex (13 individuals) of Alzheimer's disease patients, compared with healthy subjects (4 and 9 individuals, respectively). Triosephosphate isomerase nitrotyrosination decreases the glycolytic flow. Moreover, during its isomerase activity, it triggers the production of the highly neurotoxic methylglyoxal (n = 4; P < 0.05). The bioinformatics simulation of the nitration of tyrosines 164 and 208, close to the catalytic centre, fits with a reduced isomerase activity. Human embryonic kidney (HEK) cells overexpressing double mutant triosephosphate isomerase (Tyr164 and 208 by Phe164 and 208) showed high methylglyoxal production. This finding correlates with the widespread glycation immunostaining in Alzheimer's disease cortex and hippocampus from double transgenic mice overexpressing amyloid precursor protein and presenilin 1. Furthermore, nitro-triosephosphate isomerase formed large {beta}-sheet aggregates in vitro and in vivo, as demonstrated by turbidometric analysis and electron microscopy. Transmission electron microscopy (TEM) and atomic force microscopy studies have demonstrated that nitro-triosephosphate isomerase binds tau monomers and induces tau aggregation to form paired helical filaments, the characteristic intracellular hallmark of Alzheimer's disease brains. Our results link oxidative stress, the main etiopathogenic mechanism in sporadic Alzheimer's disease, via the production of peroxynitrite and nitrotyrosination of triosephosphate isomerase, to amyloid {beta}-peptide-induced toxicity and tau pathology.},
  doi = {10.1093/brain/awp023},
  eprint = {http://brain.oxfordjournals.org/cgi/reprint/132/5/1335.pdf},
  url = {http://brain.oxfordjournals.org/cgi/content/abstract/132/5/1335}
}

• [2010,article] bibtex
  J. Cooper, F. Cervenansky, G. de Fabritiis, J. Fenner, D. Friboulet, T. Giorgino, S. Manos, Y. Martelli, J. Villà–Freixa, S. Zasada, S. Lloyd, K. McCormack, and P. V. Coveney, "The Virtual Physiological Human Toolkit," Phil. Trans. R. Soc. A, vol. 368, pp. 3925-3936, 2010.
  @ARTICLE{Cooper2010,
  author = {Johnathan Cooper and Frederic Cervenansky and Gianni de Fabritiis and John Fenner and Denis Friboulet and Toni Giorgino and Steven Manos and Yves Martelli and Jordi Vill\`a--Freixa and Stefan Zasada and Sharon Lloyd and Keith McCormack and Peter V. Coveney},
  title = {{The Virtual Physiological Human Toolkit}},
  journal = {Phil. Trans. R. Soc. A},
  year = {2010},
  volume = {368},
  pages = {3925--3936},
  url = {http://www.ncbi.nlm.nih.gov/pubmed/20643685}
}

• [2011,article] bibtex
  C. Ávila, N. Drechsel, R. Alcántara, and J. Villà-Freixa, "Multiscale Simulations of Protein Aggregation," Curr. Prot. Pept. Sci., vol. 12, pp. 221-234, 2011.
  @ARTICLE{Avila2011,
  author = {C\'esar \'Avila and Nils Drechsel and Ra\'ul Alc\'antara and Jordi Vill\`a-Freixa},
  title = {{Multiscale Simulations of Protein Aggregation}},
  journal = {Curr. Prot. Pept. Sci.},
  year = {2011},
  volume = {12},
  pages = {221--234},
  url = {http://www.ncbi.nlm.nih.gov/pubmed/21348836}
}

Past funded projects

The project ActivA purpose was to enhance and expand rehabilitation programs and facilities for a network of patients with Cystic Fibrosis, to create a network of interaction between research organizations, medical institutions and communities of patients, and to establish a more proactive communication stream based on the interchange of information to optimize the results of the factors involved. This was aimed at generating a true therapeutic community. The project focussed on the development of a WebGL based portal that provided an easy to use interface for clinicians, researchers and patients all related to a common disease, cystic fibrosis. In addition to the technological aspects of the project, lead by O2HLink, Inc., our lab was involved in the scientific developments. On the one side, we worked on developing a 3D model for the CFTR chloride channel, which is the key protein which deficiencies (lack of expression or malfuncioning) produced by a high number of different mutations, cause the disease. The model has been recently submitted for publication. In addition, the project served the CBBL to enter the world of web services workflow development with Taverna, and we provided some pipelines devoted to structural prediction or even molecular dynamics of target proteins that should be accessible through the portal. Although the overall result of the project lied behind the expectations, it paved the way for the use and development of new technologies within the CBBL, from advanced statistics through R to workflow deployments, as well as opened the possibility to continue with studies on the CFTR and membrane proteins.

• [2012,article] bibtex
  J. Dalton, O. Kalid, M. Schushan, N. Ben-Tal, and J. Villà–Freixa, "New model of CFTR proposes active channel-like conformation," J. Chem. Inf. Model., vol. 52(7), pp. 1842-1853, 2012.
  @article{Dalton2012,
  author = {Dalton, James and Kalid, Ori and Schushan, Maya and Ben-Tal, Nir and Vill\`a--Freixa, Jordi},
  title = {{New model of CFTR proposes active channel-like conformation}},
  year = {2012},
  journal={{J. Chem. Inf. Model.}},
  volume = {52(7)},
  pages = {1842--1853},
  url = {http://www.ncbi.nlm.nih.gov/pubmed/22747419}
}

QosCosGrid

Complex systems are defined as systems with many interdependent parts which give rise to non-linear and emergent properties determining the high-level functioning and behavior of such systems. Due to the interdependence of their constituent elements and other characteristics of complex systems, it is difficult to predict system behavior based on the ‘sum of their parts’ alone. Examples of complex systems include bee hives, bees themselves, human economies and societies, nervous systems, molecular interactions, cells and living things, ecosystems, as well as modern energy or telecommunication infrastructures. Arguably one of the most striking properties of complex systems is that conventional experimental and engineering approaches are inadequate to capture and predict the behavior of such systems.

To complement the conventional experimental and engineering approaches, computer-based simulations of complex natural phenomena and complex man-made artifacts are increasingly employed across a wide range of sectors. Typically, such simulations require computing environments which meet very high specifications in terms of processing units, primary and secondary storage, and communication. Supercomputers constitute the de factotechnology to deliver the required specifications. Acquiring, operating and maintaining supercomputers involve considerable costs, which many organizations cannot afford. The working assumption of the QosCosGrid project is that a grid could be enhanced by suitable middleware to provide features and performance characteristics that resemble those of a supercomputer. We refer to such a grid as quasi-opportunistic supercomputer. The QosCosGrid projects aim is to develop such a system.

• [2007,inproceedings] bibtex
  M. Charlot, G. de Fabritiis, A. L. García–Lomana, À. Gómez–Garrido, D. Groen, L. Gulyás, A. Hoekstra, M. A. Johnston, G. Kampis, G. Zwart, S. Robinson, M. Strathern, M. Swain, G. Szemes, and J. Villà–Freixa, "The QosCosGrid project: Quasi-opportunistic supercomputing for complex systems simulations. description of a general framework from different types of applications.," in Proceedings of Ibergrid 2007 conference, Santiago de Compostela, 2007.
  @INPROCEEDINGS{Charlot2007,
  author = {Magali Charlot and Gianni de Fabritiis and Adri\'an L. Garc\'ia--Lomana and \`Alex G\'omez--Garrido and Derek Groen and Laszlo Guly\'as and Alfons Hoekstra and Michael A. Johnston and George Kampis and G. Zwart and Steve Robinson and Mark Strathern and Martin Swain and G\'abor Szemes and Jordi Vill\`a--Freixa},
  title = { The QosCosGrid project: Quasi-opportunistic supercomputing for complex systems simulations. description of a general framework from different types of applications.},
  booktitle = {{Proceedings of Ibergrid 2007 conference}},
  year = {2007},
  address = {Santiago de Compostela}
}

• [2008,article] bibtex
  L. G. A. de Lomana, À. Gómez-Garrido, D. Sportouch, and J. Villà-Freixa, "Optimal Experimental Design in the Modelling of Pattern Formation," LNCS, vol. 5101, pp. 610-619, 2008.
  @ARTICLE{Lomana2008,
  author = {A. L\'{o}pez Garc\'{i}a de Lomana and \`{A}. G\'{o}mez-Garrido and D. Sportouch and J. Vill\`{a}-Freixa},
  title = {Optimal Experimental Design in the Modelling of Pattern Formation},
  journal = {LNCS},
  year = {2008},
  volume = {5101},
  pages = {610-619},
  url = {http://www.springerlink.com/content/kk7774170666m254/fulltext.pdf}
}

• [2009,incollection] bibtex
  B. Alsina, A. L. García–Lomana, J. Villà–Freixa, and F. Giráldez, "Developmental biology and mathematics: the rules of an embryo," , Giráldez, F. and Herrero, M. A., Eds., Am. Math. Soc. and Real Soc. Mat. Esp, 2009, vol. 492, pp. 1-12.
  @INCOLLECTION{Alsina2009,
  author = {Berta Alsina and Adri\'an L. Garc\'ia--Lomana and Jordi Vill\`a--Freixa and Fernando Gir\'aldez},
  title = {Developmental biology and mathematics: the rules of an embryo},
  booktitle = {{Mathematics, Developmental Biology and Tumour Growth}},
  publisher = {Am. Math. Soc. and Real Soc. Mat. Esp},
  year = {2009},
  editor = {Fernando Gir\'aldez and Miguel A. Herrero},
  volume = {492},
  pages = {1--12},
  url = {http://books.google.es/books?id=l5FthtzbKMoC&pg=PA1&lpg=PA1&dq=Developmental+biology+and+mathematics:+the+rules+of+an+embryo&source=bl&ots=ut9RM7ou6N&sig=-n3uA72FSU27B4JapNHHJHFqsco&hl=es&ei=MjFxTI3PAp-U4gbMuuneCA&sa=X&oi=book_result&ct=result&resnum=1&ved=0CBwQ6AEwAA#v=onepage&q=Developmental%20biology%20and%20mathematics%3A%20the%20rules%20of%20an%20embryo&f=false}
}

• [2010,phdthesis] bibtex
  A. L. G. de Lomana, "Computational Approaches to the Modelling of Topological and Dynamical Aspects of Biochemical Networks," PhD Thesis , 2010.
  @PHDTHESIS{Lopez2010,
  author = {Adri\'an L\'opez Garc\'ia de Lomana},
  title = {{Computational Approaches to the Modelling of Topological and Dynamical Aspects of Biochemical Networks}},
  school = {Universitat Pompeu Fabra},
  year = {2010},
  abstract = {Regulatory mechanisms of cells can be modelled to control and understand cellular biology. Di�ent levels of abstraction are used to describe biological processes. In this work we have used graphs and di�ential equations to model cellular interactions qualitatively and quantitatively. From di�ent organisms, E. coli and S. cerevisiae, we have analysed data available for they complete interaction and activity networks. At the level of interaction, the protein-protein interaction network, the transcriptional regulatory networks and the metabolic network have been studied; for the activity, both gene and protein proles of the whole organism have been examined. From the rich variety of graph measures, one of primer importance is the degree distribution. I have applied statistical analysis tools to such biological networks in order to characterise the degree distribution. In all cases the studied degree distributions have a heavy-tailed shape, but most of them present signicant di�ences from a power-law model according to a statistical test. Moreover, none of the networks could be unequivocally assigned to any of the tested distribution. On the other hand, in a more ne-grained view, I have used di�ential equations to model dynamics of biochemical systems. First, a software tool called ByoDyn has been created from scratch incorporating a fairly complete range of analysis methods. Both deterministic and stochastic simulations can be performed, models can be analysed by means of parameter estimation, sensitivity, identiability analysis, and optimal experimental design. Moreover, a web interface has been created that provides with the possibility interact with the program in a graphical manner, independent of the user conguration, allowing the execution of the program at di�ent computational environments. Finally, we have applied a protocol of optimal experimental design on a multicellular model of embryogenesis.},
  url = {http://dl.dropbox.com/u/8542277/web/thesis/main.260710.colour.pdf}
}

BioBridge

The omics revolution of recent years has led to an explosion of data.  This information, however, is currently fragmented, which limits progress on the understanding of the underlying mechanisms of complex chronic disorders.  A major constraint for small and medium enterprises (SMEs) in the biomedical field is the lack of appropriate tools for data integration and simultaneous analysis of different levels of information. BioBridge proposes to tackle this problem with the creation of the BioBridge portal, where 1) structured databases including genomic, proteomic, and metabolomic information for the metabolic pathways affected by these disorders will be 2) integrated to model the underlying metabolic networks. This, in turn, will be utilised by 3) a simulation environment for simultaneous analysis of multilevel data able to improve existing knowledge on complex disorders.

• [2008,inproceedings] bibtex
  À. Gómez–Garrido, S. Márquez, M. Hernández, V. Selivanov, M. Cascante, J. Villà–Freixa, and S. Kalko, "Integration of transcriptomics data into systems biology modeling in the BioBridge portal," in Schriftenreihe Informatik 26. BIRD08 2nd International Conference on Bioinformatics Research and Development., 2008, pp. 75-81.
  @INPROCEEDINGS{GomezProc2008,
  author = {\`Alex G\'omez--Garrido and Susanna M\'arquez and Miguel Hern\'andez and Vitaly Selivanov and Marta Cascante and Jordi Vill\`a--Freixa and Susana Kalko},
  title = {Integration of transcriptomics data into systems biology modeling in the BioBridge portal},
  booktitle = {Schriftenreihe Informatik 26. BIRD08 2nd International Conference on Bioinformatics Research and Development.},
  year = {2008},
  editor = {Josef K�ng, Kristan Schneider, Roland Wagner},
  pages = {75--81},
  publisher = {Schriftenreihe Informatik 26},
  abstract = {Information coming from omics disciplines is currently fragmented, and frequently the lack of appropriate tools for their integration into global models severely limits progress in the understanding of the underlying mechanisms of complex chronic disorders. EC-funded BioBridge project focusses on the creation of systemic dynamical models to link molecular mechanisms to complex diseases. Thus, the BioBridge portal integrates: 1) structured databases (including metabolic pathways affected by complex disorders); 2) tools for the integration of this data into mathematical models; 3) analysis of multilevel data through simulation to improve previous knowledge; 4) interface for the management of computing resources. Here we present the integration of chronic obstructive pulmonary disease (COPD) transcriptomics data (specifically oligonucleotide microarrays from local or public data) into the simulation of a previously reported model for central metabolism. First, fold change (FC) values of contrasts of interest on these datasets were incorporated into the BioXM-based BioBridge database. Quantitative integration of the FC and correlation values is being considered for the modulation and refinement of the set of parameters used in the differential equations of the model.},
  isbn = {978-3-85499-422-0},
  journal = {Communications in Computer and Information Science}
}

• [2011,article] bibtex
  D. Maier, W. Kalus, M. Wolff, S. G. Kalko, J. Roca, I. M. Mas, N. Turan, M. Cascante, F. Falciani, M. Hernández, J. Villà-Freixa, and S. Losko, "Knowledge Management for Systems Biology; a general and visually driven framework applied to translational medicine," BMC Syst. Biol., vol. 5, p. 38, 2011.
  @ARTICLE{Maier2010,
  author = {Dieter Maier and Wenzel Kalus and Martin Wolff and Susana G. Kalko and Josep Roca and Igor Mar�n de Mas and Nil Turan and Marta Cascante and Francesco Falciani and Miguel Hern\'andez and Jordi Vill\`a-Freixa and Sascha Losko},
  title = {{Knowledge Management for Systems Biology; a general and visually driven framework applied to translational medicine}},
  journal = {BMC Syst. Biol.},
  volume = {5},
  pages = {38},
  year = {2011},
  url = {http://www.biomedcentral.com/1752-0509/5/38}
}

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