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1.  Projection to latent pathways (PLP): a constrained projection to latent variables (PLS) method for elementary flux modes discrimination 
BMC Systems Biology  2011;5:181.
Background
Elementary flux modes (EFM) are unique and non-decomposable sets of metabolic reactions able to operate coherently in steady-state. A metabolic network has in general a very high number of EFM reflecting the typical functional redundancy of biological systems. However, most of these EFM are either thermodynamically unfeasible or inactive at pre-set environmental conditions.
Results
Here we present a new algorithm that discriminates the "active" set of EFM on the basis of dynamic envirome data. The algorithm merges together two well-known methods: projection to latent structures (PLS) and EFM analysis, and is therefore termed projection to latent pathways (PLP). PLP has two concomitant goals: (1) maximisation of correlation between EFM weighting factors and measured envirome data and (2) minimisation of redundancy by eliminating EFM with low correlation with the envirome.
Conclusions
Overall, our results demonstrate that PLP slightly outperforms PLS in terms of predictive power. But more importantly, PLP is able to discriminate the subset of EFM with highest correlation with the envirome, thus providing in-depth knowledge of how the environment controls core cellular functions. This offers a significant advantage over PLS since its abstract structure cannot be associated with the underlying biological structure.
doi:10.1186/1752-0509-5-181
PMCID: PMC3750108  PMID: 22044634
2.  Cell functional enviromics: Unravelling the function of environmental factors 
BMC Systems Biology  2011;5:92.
Background
While functional genomics, focused on gene functions and gene-gene interactions, has become a very active field of research in molecular biology, equivalent methodologies embracing the environment and gene-environment interactions are relatively less developed. Understanding the function of environmental factors is, however, of paramount importance given the complex, interactive nature of environmental and genetic factors across multiple time scales.
Results
Here, we propose a systems biology framework, where the function of environmental factors is set at its core. We set forth a "reverse" functional analysis approach, whereby cellular functions are reconstructed from the analysis of dynamic envirome data. Our results show these data sets can be mapped to less than 20 core cellular functions in a typical mammalian cell culture, while explaining over 90% of flux data variance. A functional enviromics map can be created, which provides a template for manipulating the environmental factors to induce a desired phenotypic trait.
Conclusion
Our results support the feasibility of cellular function reconstruction guided by the analysis and manipulation of dynamic envirome data.
doi:10.1186/1752-0509-5-92
PMCID: PMC3118353  PMID: 21645360
3.  Modelling biochemical networks with intrinsic time delays: a hybrid semi-parametric approach 
BMC Systems Biology  2010;4:131.
Background
This paper presents a method for modelling dynamical biochemical networks with intrinsic time delays. Since the fundamental mechanisms leading to such delays are many times unknown, non conventional modelling approaches become necessary. Herein, a hybrid semi-parametric identification methodology is proposed in which discrete time series are incorporated into fundamental material balance models. This integration results in hybrid delay differential equations which can be applied to identify unknown cellular dynamics.
Results
The proposed hybrid modelling methodology was evaluated using two case studies. The first of these deals with dynamic modelling of transcriptional factor A in mammalian cells. The protein transport from the cytosol to the nucleus introduced a delay that was accounted for by discrete time series formulation. The second case study focused on a simple network with distributed time delays that demonstrated that the discrete time delay formalism has broad applicability to both discrete and distributed delay problems.
Conclusions
Significantly better prediction qualities of the novel hybrid model were obtained when compared to dynamical structures without time delays, being the more distinctive the more significant the underlying system delay is. The identification of the system delays by studies of different discrete modelling delays was enabled by the proposed structure. Further, it was shown that the hybrid discrete delay methodology is not limited to discrete delay systems. The proposed method is a powerful tool to identify time delays in ill-defined biochemical networks.
doi:10.1186/1752-0509-4-131
PMCID: PMC2955604  PMID: 20863397
4.  Metabolic modelling of polyhydroxyalkanoate copolymers production by mixed microbial cultures 
BMC Systems Biology  2008;2:59.
Background
This paper presents a metabolic model describing the production of polyhydroxyalkanoate (PHA) copolymers in mixed microbial cultures, using mixtures of acetic and propionic acid as carbon source material. Material and energetic balances were established on the basis of previously elucidated metabolic pathways. Equations were derived for the theoretical yields for cell growth and PHA production on mixtures of acetic and propionic acid as functions of the oxidative phosphorylation efficiency, P/O ratio. The oxidative phosphorylation efficiency was estimated from rate measurements, which in turn allowed the estimation of the theoretical yield coefficients.
Results
The model was validated with experimental data collected in a sequencing batch reactor (SBR) operated under varying feeding conditions: feeding of acetic and propionic acid separately (control experiments), and the feeding of acetic and propionic acid simultaneously. Two different feast and famine culture enrichment strategies were studied: (i) either with acetate or (ii) with propionate as carbon source material. Metabolic flux analysis (MFA) was performed for the different feeding conditions and culture enrichment strategies. Flux balance analysis (FBA) was used to calculate optimal feeding scenarios for high quality PHA polymers production, where it was found that a suitable polymer would be obtained when acetate is fed in excess and the feeding rate of propionate is limited to ~0.17 C-mol/(C-mol.h). The results were compared with published pure culture metabolic studies.
Conclusion
Acetate was more conducive toward the enrichment of a microbial culture with higher PHA storage fluxes and yields as compared to propionate. The P/O ratio was not only influenced by the selected microbial culture, but also by the carbon substrate fed to each culture, where higher P/O ratio values were consistently observed for acetate than propionate. MFA studies suggest that when mixtures of acetate and propionate are fed to the cultures, the catabolic activity is primarily guaranteed through acetate uptake, and the characteristic P/O ratio of acetate prevails over that of propionate. This study suggests that the PHA production process by mixed microbial cultures has the potential to be comparable or even more favourable than pure cultures.
doi:10.1186/1752-0509-2-59
PMCID: PMC2483998  PMID: 18611259

Results 1-4 (4)