MOTIVATION: Constraint-based modeling of metabolic networks helps researchers gain insight into the metabolic processes of many organisms, both prokaryotic and eukaryotic. Minimal cut sets (MCSs) are minimal sets of reactions whose inhibition blocks a target reaction in a metabolic network. Most approaches for finding the MCSs in constrained-based models require, either as an intermediate step or as a byproduct of the calculation, the computation of the set of elementary flux modes (EFMs), a convex basis for the valid flux vectors in the network. Recently, Ballerstein et al. proposed a method for computing the MCSs of a network without first computing its EFMs, by creating a dual network whose EFMs are a superset of the MCSs of the original network. However, their dual network is always larger than the original network and depends on the target reaction. Here we propose the construction of a different dual network, which is typically smaller than the original network and is independent of the target reaction, for the same purpose. We prove the correctness of our approach, minimal coordinated support (MCS2), and describe how it can be modified to compute the few smallest MCSs for a given target reaction. RESULTS: We compare MCS2 to the method of Ballerstein et al. and two other existing methods. We show that MCS2 succeeds in calculating the full set of MCSs in many models where other approaches cannot finish within a reasonable amount of time. Thus, in addition to its theoretical novelty, our approach provides a practical advantage over existing methods. AVAILABILITY AND IMPLEMENTATION: MCS2 is freely available at https://github.com/RezaMash/MCS under the GNU 3.0 license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Elemental balance, the property of having the same number of each type of atom on both sides of the equation, is a fundamental feature of chemical reactions. In metabolic network models, this property is typically verified on a reaction-by-reaction basis. In this paper we show how violations of elemental balance can be efficiently detected in an entire network, without the need for specifying the chemical formula of each of the metabolites, which enhances a modeler's ability to automatically verify that their model satisfies elemental balance. Our method makes use of duality theory, linear programming, and mixed integer linear programming, and runs efficiently on genome-scale metabolic networks (GSMNs). We detect elemental balance violations in 40 out of 84 metabolic network models in the BiGG database. We also identify a short list of reactions that are candidates for being elementally imbalanced. Out of these candidates, nearly half turn out to be truly imbalanced reactions, and the rest can be seen as witnesses of elemental balance violations elsewhere in the network. The majority of these violations involve a proton imbalance, a known challenge of metabolic network reconstruction. Our approach is efficient, easy to use and powerful. It can be helpful to metabolic network modelers during model verification. Our methods are fully integrated into the MONGOOSE software suite and are available at https://github.com/WGS-TB/MongooseGUI3.

The problem of computing the dual of a monotone Boolean function f is a fundamental problem in theoretical computer science with numerous applications. The related problem of duality testing (given two monotone Boolean functions f and g, declare that they are dual or provide a certificate that shows they are not) has a complexity that is not yet known. However, two quasi-polynomial time algorithms for it, often referred to as FK-A and FK-B, were proposed by Fredman and Khachiyan in 1996, with the latter having a better complexity guarantee. These can be naturally used as a subroutine in computing the dual of f. In this paper, we investigate this use of the FK-B algorithm for the computation of the dual of a monotone Boolean function, and present practical improvements to its performance. First, we show how FK-B can be modified to produce multiple certificates (Boolean vectors on which the functions defined by the original f and the current dual g do not provide outputs consistent with duality). Second, we show how the number of redundancy tests - one of the more costly and time-consuming steps of FK-B - can be substantially reduced in this context. Lastly, we describe a simple memoization technique that avoids the solution of multiple identical subproblems. We test our approach on a number of inputs coming from computational biology as well as combinatorics. These modifications provide a substantial speed-up, as much as an order of magnitude, for FK-B dualization relative to a naive implementation. Although other methods may end up being faster in practice, our work paves the way for a principled optimization process for the generation of monotone Boolean functions and their duals from an oracle.

Grone and Merris conjectured that the Laplacian spectrum of a graph is majorized by its conjugate vertex degree sequence. In this paper, we prove that this conjecture holds for a class of graphs, including trees. We also show that this conjecture and its generalization to graphs with Dirichlet boundary conditions are equivalent.