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Search Results: 1 - 10 of 6518 matches for " Alex Graudenzi "
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Effects of delayed immune-response in tumor immune-system interplay
Giulio Caravagna,Alex Graudenzi,Marco Antoniotti,Giancarlo Mauri
Electronic Proceedings in Theoretical Computer Science , 2012, DOI: 10.4204/eptcs.92.8
Abstract: Tumors constitute a wide family of diseases kinetically characterized by the co-presence of multiple spatio-temporal scales. So, tumor cells ecologically interplay with other kind of cells, e.g. endothelial cells or immune system effectors, producing and exchanging various chemical signals. As such, tumor growth is an ideal object of hybrid modeling where discrete stochastic processes model agents at low concentrations, and mean-field equations model chemical signals. In previous works we proposed a hybrid version of the well-known Panetta-Kirschner mean-field model of tumor cells, effector cells and Interleukin-2. Our hybrid model suggested -at variance of the inferences from its original formulation- that immune surveillance, i.e. tumor elimination by the immune system, may occur through a sort of side-effect of large stochastic oscillations. However, that model did not account that, due to both chemical transportation and cellular differentiation/division, the tumor-induced recruitment of immune effectors is not instantaneous but, instead, it exhibits a lag period. To capture this, we here integrate a mean-field equation for Interleukins-2 with a bi-dimensional delayed stochastic process describing such delayed interplay. An algorithm to realize trajectories of the underlying stochastic process is obtained by coupling the Piecewise Deterministic Markov process (for the hybrid part) with a Generalized Semi-Markovian clock structure (to account for delays). We (i) relate tumor mass growth with delays via simulations and via parametric sensitivity analysis techniques, (ii) we quantitatively determine probabilistic eradication times, and (iii) we prove, in the oscillatory regime, the existence of a heuristic stochastic bifurcation resulting in delay-induced tumor eradication, which is neither predicted by the mean-field nor by the hybrid non-delayed models.
Investigating the Relation between Stochastic Differentiation, Homeostasis and Clonal Expansion in Intestinal Crypts via Multiscale Modeling
Alex Graudenzi, Giulio Caravagna, Giovanni De Matteis, Marco Antoniotti
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097272
Abstract: Colorectal tumors originate and develop within intestinal crypts. Even though some of the essential phenomena that characterize crypt structure and dynamics have been effectively described in the past, the relation between the differentiation process and the overall crypt homeostasis is still only partially understood. We here investigate this relation and other important biological phenomena by introducing a novel multiscale model that combines a morphological description of the crypt with a gene regulation model: the emergent dynamical behavior of the underlying gene regulatory network drives cell growth and differentiation processes, linking the two distinct spatio-temporal levels. The model relies on a few a priori assumptions, yet accounting for several key processes related to crypt functioning, such as: dynamic gene activation patterns, stochastic differentiation, signaling pathways ruling cell adhesion properties, cell displacement, cell growth, mitosis, apoptosis and the presence of biological noise. We show that this modeling approach captures the major dynamical phenomena that characterize the regular physiology of crypts, such as cell sorting, coordinate migration, dynamic turnover, stem cell niche correct positioning and clonal expansion. All in all, the model suggests that the process of stochastic differentiation might be sufficient to drive the crypt to homeostasis, under certain crypt configurations. Besides, our approach allows to make precise quantitative inferences that, when possible, were matched to the current biological knowledge and it permits to investigate the role of gene-level perturbations, with reference to cancer development. We also remark the theoretical framework is general and may be applied to different tissues, organs or organisms.
Proceedings Wivace 2013 - Italian Workshop on Artificial Life and Evolutionary Computation
Alex Graudenzi,Giulio Caravagna,Giancarlo Mauri,Marco Antoniotti
Computer Science , 2013, DOI: 10.4204/EPTCS.130
Abstract: The Wivace 2013 Electronic Proceedings in Theoretical Computer Science (EPTCS) contain some selected long and short articles accepted for the presentation at Wivace 2013 - Italian Workshop on Artificial Life and Evolutionary Computation, which was held at the University of Milan-Bicocca, Milan, on the 1st and 2nd of July, 2013.
Recent developments in research on catalytic reaction networks
Chiara Damiani,Alessandro Filisetti,Alex Graudenzi,Marco Villani,Roberto Serra
Computer Science , 2013, DOI: 10.4204/EPTCS.130.3
Abstract: Over the last years, analyses performed on a stochastic model of catalytic reaction networks have provided some indications about the reasons why wet-lab experiments hardly ever comply with the phase transition typically predicted by theoretical models with regard to the emergence of collectively self-replicating sets of molecule (also defined as autocatalytic sets, ACSs), a phenomenon that is often observed in nature and that is supposed to have played a major role in the emergence of the primitive forms of life. The model at issue has allowed to reveal that the emerging ACSs are characterized by a general dynamical fragility, which might explain the difficulty to observe them in lab experiments. In this work, the main results of the various analyses are reviewed, with particular regard to the factors able to affect the generic properties of catalytic reactions network, for what concerns, not only the probability of ACSs to be observed, but also the overall activity of the system, in terms of production of new species, reactions and matter.
A model of protocell based on the introduction of a semi-permeable membrane in a stochastic model of catalytic reaction networks
Roberto Serra,Alessandro Filisetti,Alex Graudenzi,Chiara Damiani,Marco Villani
Computer Science , 2013, DOI: 10.4204/EPTCS.130.10
Abstract: In this work we introduce some preliminary analyses on the role of a semi-permeable membrane in the dynamics of a stochastic model of catalytic reaction sets (CRSs) of molecules. The results of the simulations performed on ensembles of randomly generated reaction schemes highlight remarkable differences between this very simple protocell description model and the classical case of the continuous stirred-tank reactor (CSTR). In particular, in the CSTR case, distinct simulations with the same reaction scheme reach the same dynamical equilibrium, whereas, in the protocell case, simulations with identical reaction schemes can reach very different dynamical states, despite starting from the same initial conditions.
Analysis of the spatial and dynamical properties of a multiscale model of intestinal crypts
Giulio Caravagna,Alex Graudenzi,Marco Antoniotti,Giovanni de Matteis
Computer Science , 2013, DOI: 10.4204/EPTCS.130.12
Abstract: The preliminary analyses on a multiscale model of intestinal crypt dynamics are here presented. The model combines a morphological model, based on the Cellular Potts Model (CPM), and a gene regulatory network model, based on Noisy Random Boolean Networks (NRBNs). Simulations suggest that the stochastic differentiation process is itself sufficient to ensure the general homeostasis in the asymptotic states, as proven by several measures.
On RAF Sets and Autocatalytic Cycles in Random Reaction Networks
Alessandro Filisetti,Marco Villani,Chiara Damiani,Alex Graudenzi,Andrea Roli,Wim Hordijk,Roberto Serra
Physics , 2015, DOI: 10.1007/978-3-319-12745-3_10
Abstract: The emergence of autocatalytic sets of molecules seems to have played an important role in the origin of life context. Although the possibility to reproduce this emergence in laboratory has received considerable attention, this is still far from being achieved. In order to unravel some key properties enabling the emergence of structures potentially able to sustain their own existence and growth, in this work we investigate the probability to observe them in ensembles of random catalytic reaction networks characterized by different structural properties. From the point of view of network topology, an autocatalytic set have been defined either in term of strongly connected components (SCCs) or as reflexively autocatalytic and food-generated sets (RAFs). We observe that the average level of catalysis differently affects the probability to observe a SCC or a RAF, highlighting the existence of a region where the former can be observed, whereas the latter cannot. This parameter also affects the composition of the RAF, which can be further characterized into linear structures, autocatalysis or SCCs. Interestingly, we show that the different network topology (uniform as opposed to power-law catalysis systems) does not have a significantly divergent impact on SCCs and RAFs appearance, whereas the proportion between cleavages and condensations seems instead to play a role. A major factor that limits the probability of RAF appearance and that may explain some of the difficulties encountered in laboratory seems to be the presence of molecules which can accumulate without being substrate or catalyst of any reaction.
A stochastic model of catalytic reaction networks in protocells
Roberto Serra,Alessandro Filisetti,Marco Villani,Alex Graudenzi,Chiara Damiani,Tommaso Panini
Physics , 2014, DOI: 10.1007/s11047-014-9445-6
Abstract: Protocells are supposed to have played a key role in the self-organizing processes leading to the emergence of life. Existing models either (i) describe protocell architecture and dynamics, given the existence of sets of collectively self-replicating molecules for granted, or (ii) describe the emergence of the aforementioned sets from an ensemble of random molecules in a simple experimental setting (e.g. a closed system or a steady-state flow reactor) that does not properly describe a protocell. In this paper we present a model that goes beyond these limitations by describing the dynamics of sets of replicating molecules within a lipid vesicle. We adopt the simplest possible protocell architecture, by considering a semi-permeable membrane that selects the molecular types that are allowed to enter or exit the protocell and by assuming that the reactions take place in the aqueous phase in the internal compartment. As a first approximation, we ignore the protocell growth and division dynamics. The behavior of catalytic reaction networks is then simulated by means of a stochastic model that accounts for the creation and the extinction of species and reactions. While this is not yet an exhaustive protocell model, it already provides clues regarding some processes that are relevant for understanding the conditions that can enable a population of protocells to undergo evolution and selection.
TRONCO: An R Package for the Inference of Cancer Progression Models from Heterogeneous Genomic Data
Luca De Sano,Giulio Caravagna,Daniele Ramazzotti,Alex Graudenzi,Giancarlo Mauri,Bud Mishra,Marco Antoniotti
Quantitative Biology , 2015,
Abstract: Motivation: We introduce TRONCO (TRanslational ONCOlogy), an open-source R package that implements the state-of-the-art algorithms for the inference of cancer progression models from (epi)genomic mutational profiles. TRONCO can be used to extract population-level models describing the trends of accumulation of alterations in a cohort of cross-sectional samples, e.g., retrieved from publicly available databases, and individual-level models that reveal the clonal evolutionary history in single cancer patients, when multiple samples, e.g., multiple biopsies or single-cell sequencing data, are available. The resulting models can provide key hints in uncovering the evolutionary trajectories of cancer, especially for precision medicine or personalized therapy. Availability: TRONCO is released under the GPL license, is hosted in the Software section at http://bimib.disco.unimib.it/ and archived also at bioconductor.org. Contact: tronco@disco.unimib.it
CABeRNET: a Cytoscape app for Augmented Boolean models of gene Regulatory NETworks
Andrea Paroni,Alex Graudenzi,Giulio Caravagna,Chiara Damiani,Giancarlo Mauri,Marco Antoniotti
Quantitative Biology , 2015,
Abstract: Background. Dynamical models of gene regulatory networks (GRNs) are highly effective in describing complex biological phenomena and processes, such as cell differentiation and cancer development. Yet, the topological and functional characterization of real GRNs is often still partial and an exhaustive picture of their functioning is missing. Motivation. We here introduce CABeRNET, a Cytoscape app for the generation, simulation and analysis of Boolean models of GRNs, specifically focused on their augmentation when a only partial topological and functional characterization of the network is available. By generating large ensembles of networks in which user-defined entities and relations are added to the original core, CABeRNET allows to formulate hypotheses on the missing portions of real networks, as well to investigate their generic properties, in the spirit of complexity science. Results. CABeRNET offers a series of innovative simulation and modeling functions and tools, including (but not being limited to) the dynamical characterization of the gene activation patterns ruling cell types and differentiation fates, and sophisticated robustness assessments, as in the case of gene knockouts. The integration within the widely used Cytoscape framework for the visualization and analysis of biological networks, makes CABeRNET a new essential instrument for both the bioinformatician and the computational biologist, as well as a computational support for the experimentalist. An example application concerning the analysis of an augmented T-helper cell GRN is provided.
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