Pedro Mendes
Profile Url: pedro-mendes
Researcher at University of Connecticut School of Medicine
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Background: In metabolic network reconstruction the stoichiometric balancing of reactions is essential to create realistic constraint-based models. At the genome scale, balancing is a repetitive task that consumes valuable curator resource that could be deployed elsewhere. Automatic reaction balancing is possible and could be useful across computational systems biology, but widespread use of the appropriate code has been limited by the diversity of non-interoperable programming languages used in the field. RESTful web services offer a language-agnostic way of binding services together. Results: Reaction balancing can be posed as a mixed integer linear programming problem to identify stoichiometric coefficients and infer commonly missing components. This functionality has been exposed as a web service that consumes a list of reactions as JSON or SBML. The reaction balancing web service has been deployed at http://www.nactem.ac.uk/balancer. Code is available via Github. By way of demonstration the service has been applied to a Chinese hamster ovary cell metabolic reconstruction to bring a further 219 reactions into balance. Conclusions: The majority of systems biology software cannot access existing automatic reaction balancing tools due to a lack of language-specific bindings. Web services bridge different languages by using widely-spoken web communication protocols, meaning that one binding works for almost all languages. Automatic reaction balancing can now be consumed by any systems biology software via a RESTful web service.
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As common commensals residing on mucosal tissues, Lactobacillus species are known to encourage health, while recent findings highlight the pathogenic roles of Streptococcus species in these environments. In this study we used a combination of in vivo imaging experiments and computational modeling to explore biofilm interactions between Streptococcus oralis, an accessory pathogen in oral Candidiasis, and Lactobacillus paracasei, an organism with known probiotic properties. A computational agent-based model was created where the two species only interact by competing for space and nutrients. Quantification of bacterial growth in live biofilms indicated that S. oralis biomass and cell numbers were much lower than predicted by the model. Two subsequent models were then created to examine more complex interactions between these species, one where L. paracasei secretes a surfactant, and another where L. paracasei secretes an inhibitor of S. oralis growth. Further biofilm experiments support the hypothesis that L. paracasei may secrete an inhibitor of S. oralis growth, although they do not exclude that a surfactant could also be involved. This contribution shows how agent-based modeling and experiments can be used in synergy to address multiple species biofilm interactions, with important roles in mucosal health and disease.
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Cancer complexity is consequence of genomic instability leading to aneuploidy. We hypothesize that dosage compensation of critical genes arise from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We developed a computational platform to identify a network of miRNAs and transcription factors interacting with candidate dosage-compensated genes using NCI-60 multi-omic data. We next constructed a mathematical model where the property of dosage compensation emerged for MYC and STAT3 and was dependent on the kinetic parameters of their feedback and feed-forward interactions with four miRNAs. We developed a genetic tug-of-war approach by overexpressing an exogenous MYC sequence to experimentally validate MYC dosage compensation circuits as demonstrated by the over-expression of the three microRNAs involved and the respective down-regulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. The study of TCGA breast cancer patient data indicated that MYC dosage compensation could lead to lower patient survival, highlighting the potential of targeting gene dosage compensation to prevent aneuploid cancer progression.
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BMC Systems Biology, 2017-05-18
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BMC Systems Biology
Background: Iron is an essential element of most living organisms but is a dangerous substance when poorly liganded in solution. The hormone hepcidin regulates the export of iron from tissues to the plasma contributing to iron homeostasis and also restricting its availability to infectious agents. Disruption of iron regulation in mammals leads to disorders such as anemia and hemochromatosis, and contributes to the etiology of several other diseases such as cancer and neurodegenerative diseases. Here we test the hypothesis that hepcidin alone is able to regulate iron distribution in different dietary regimes in the mouse using a computational model of iron distribution calibrated with radioiron tracer data. Results: A model was developed and calibrated to the data from adequate iron diet, which was able to simulate the iron distribution under a low iron diet. However simulation of high iron diet shows considerable deviations from the experimental data. Namely the model predicts more iron in red blood cells and less iron in the liver than what was observed in experiments. Conclusions: These results suggest that hepcidin alone is not sufficient to regulate iron homeostasis in high iron conditions and that other factors are important. The model was able to simulate anemia when hepcidin was increased but was unable to simulate hemochromatosis when hepcidin was suppressed, suggesting that in high iron conditions additional regulatory interactions are important.
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Cancer complexity is consequence of enormous genomic instability leading to aneuploidy, a hallmark of most cancers. We hypothesize that dosage compensation of critical genes could arise from systems-level properties of complex networks of microRNAs (miRNA) and transcription factors (TF) as a way for cancer cells to withstand the negative effects of aneuploidy. We studied gene dosage compensation at the transcriptional level on data of the NCI-60 cancer cell line panel with the aid of computational models to identify candidate genes with low tolerance to variation in gene expression despite high variation in copy numbers. We identified a network of TF and miRNAs validated interactions with those genes to construct a mathematical model where the property of dosage compensation emerged for MYC and STAT3. Compensation was mediated by feedback and feed-forward motifs with 4 miRNAs and was dependent on the kinetic parameters of these TF-miRNA interactions, indicating that network analysis was not enough to identify this emergent property. The inhibition of miRNAs compensating MYC suggest a therapeutic potential of targeting gene dosage compensation against aneuploid cancer.
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Molecular Microbiology, 2018-09-16
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Molecular Microbiology
Biological systems require precise copper homeostasis enabling metallation of cuproproteins while preventing metal toxicity. In bacteria, sensing, transport and storage molecules act in coordination to fulfill these roles. However, there is not yet a kinetic schema explaining the system integration. Here, we report a model emerging from experimental and computational approaches that describes the dynamics of copper distribution in Pseudomonas aeruginosa. Based on copper uptake experiments, a minimal kinetic model describes well the copper distribution in the wild type bacteria but is unable to explain the behavior of the mutant strain lacking CopA1, a key Cu+ efflux ATPase. The model was expanded through an iterative hypothesis-driven approach, arriving to a mechanism that considers the induction of compartmental pools and the parallel function of CopA and Cus efflux systems. Model simulations support the presence of a periplasmic copper storage with a crucial role under dyshomeostasis conditions in P. aeruginosa. Importantly, the model predicts not only the interplay of periplasmic and cytoplasmic pools but also the existence of a threshold in the concentration of external copper beyond which cells lose their ability to control copper levels.
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