BACKGROUND: Microbial community simulations using genome scale metabolic networks (GSMs) are relevant for many application areas, such as the analysis of the human microbiome. Such simulations rely on assumptions about the culturing environment, affecting if the culture may reach a metabolically stationary state with constant microbial concentrations. They also require assumptions on decision making by the microbes: metabolic strategies can be in the interest of individual community members or of the whole community. However, the impact of such common assumptions on community simulation results has not been investigated systematically. RESULTS: Here, we investigate four combinations of assumptions, elucidate how they are applied in literature, provide novel mathematical formulations for their simulation, and show how the resulting predictions differ qualitatively. Our results stress that different assumption combinations give qualitatively different predictions on microbial coexistence by differential substrate utilization. This fundamental mechanism is critically under explored in the steady state GSM literature with its strong focus on coexistence states due to crossfeeding (division of labor). Furthermore, investigating a realistic synthetic community, where the two involved strains exhibit no growth in isolation, but grow as a community, we predict multiple modes of cooperation, even without an explicit cooperation mechanism. CONCLUSIONS: Steady state GSM modelling of microbial communities relies both on assumed decision making principles and environmental assumptions. In principle, dynamic flux balance analysis addresses both. In practice, our methods that address the steady state directly may be preferable, especially if the community is expected to display multiple steady states.

SUMMARY: Random flux sampling is a powerful tool for the constraint-based analysis of metabolic networks. The most efficient sampling method relies on a rounding transform of the constraint polytope, but no available rounding implementation can round all relevant models. By removing redundant polytope constraints on the go, PolyRound simplifies the numerical problem and rounds all the 108 models in the BiGG database without parameter tuning, compared to ∼50% for the state-of-the-art implementation. AVAILABILITY AND IMPLEMENTATION: The implementation is available on gitlab: https://gitlab.com/csb.ethz/PolyRound. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Metabolic network analysis is an accessible and versatile modeling approach for biology that has taken much inspiration from electric circuit analysis. After introducing its main concepts, we focus on numerical tools, such as optimization and sampling, to predict cellular features and behaviors at a large scale. Optimization approaches exploit that metabolic networks are shaped by evolution and are, thus, assumed to embed a fitness condition reflecting the environment that they evolved in. In the past ten years, there is a trend to generalize metabolic network analysis to consortia of interacting species. This raises technical questions on, for example, optimality in consortia but also more general ones on metabolic coevolution, information exchange, and adaptation. This suggests and allows us to explore interesting analogies to technological systems, specifically to smart grids.

SUMMARY: The C++ library Highly Optimized Polytope Sampling (HOPS) provides implementations of efficient and scalable algorithms for sampling convex-constrained models that are equipped with arbitrary target functions. For uniform sampling, substantial performance gains were achieved compared to the state-of-the-art. The ease of integration and utility of non-uniform sampling is showcased in a Bayesian inference setting, demonstrating how HOPS interoperates with third-party software. AVAILABILITY AND IMPLEMENTATION: Source code is available at https://github.com/modsim/hops/, tested on Linux and MS Windows, includes unit tests, detailed documentation, example applications and a Dockerfile. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: The validity of model based inference, as used in systems biology, depends on the underlying model formulation. Often, a vast number of competing models is available, that are built on different assumptions, all consistent with the existing knowledge about the studied biological phenomenon. As a remedy for this, Bayesian Model Averaging (BMA) facilitates parameter and structural inferences based on multiple models simultaneously. However, in fields where a vast number of alternative, high-dimensional and non-linear models are involved, the BMA-based inference task is computationally very challenging. RESULTS: Here we use BMA in the complex setting of Metabolic Flux Analysis (MFA) to infer whether potentially reversible reactions proceed uni- or bidirectionally, using 13C labeling data and metabolic networks. BMA is applied on a large set of candidate models with differing directionality settings, using a tailored multi-model Markov Chain Monte Carlo (MCMC) approach. The applicability of our algorithm is shown by inferring the in vivo probability of reaction bidirectionalities in a realistic network setup, thereby extending the scope of 13C MFA from parameter to structural inference. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Microfluidic platforms for live-cell analysis are in dire need of automated image analysis pipelines. In this context, producing reliable tracks of single cells in colonies has proven to be notoriously difficult without manual assistance, especially when image sequences experience low frame rates. RESULTS: With Uncertainty-Aware Tracking (UAT), we propose a novel probabilistic tracking paradigm for simultaneous tracking and estimation of tracking-induced errors in biological quantities derived from live-cell experiments. To boost tracking accuracy, UAT relies on a Bayesian approach which exploits temporal information on growth patterns to guide the formation of lineage hypotheses. A biological study is presented, in which UAT demonstrates its ability to track cells, with comparable to better accuracy than state-of-the-art trackers, while simultaneously estimating tracking-induced errors. AVAILABILITY AND IMPLEMENTATION: Image sequences and Java executables for reproducing the results are available at https://doi.org/10.5281/zenodo.1299526. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.