Fast Approximate Shortest Hyperpaths for Inferring Pathways in Cell Signaling Hypergraphs

Cell signaling pathways, which are a series of reactions that start at receptors and end at transcription factors, are basic to systems biology. Properly modeling the reactions in such pathways requires directed hypergraphs, where an edge is now directed between two sets of vertices. Inferring a pathway by the most parsimonious series of reactions then corresponds to finding a shortest hyperpath in a directed hypergraph, which is NP-complete. The state of the art for shortest hyperpaths in cell-signaling hypergraphs solves a mixed-integer linear program to find an optimal hyperpath that is restricted to be acyclic, and offers no efficiency guarantees. We present for the first time a heuristic for general shortest hyperpaths that properly handles cycles, and is guaranteed to be efficient. Its accuracy is demonstrated through exhaustive experiments on all instances from the standard NCI-PID and Reactome pathway databases, which show the heuristic finds a hyperpath that matches the state-of-the-art mixed-integer linear program on over 99% of all instances that are acyclic. On instances where only cyclic hyperpaths exist, the heuristic surpasses the state-of-the-art, which finds no solution; on every such cyclic instance, enumerating all possible hyperpaths shows that the solution found by the heuristic is in fact optimal

Signatures of arithmetic simplicity in metabolic network architecture

Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that several of the properties predicted by the artificial chemistry model hold for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity

Using ILP to Identify Pathway Activation Patterns in Systems Biology

We show a logical aggregation method that, combined with propositionalization methods, can construct novel structured biological features from gene expression data. We do this to gain understanding of pathway mechanisms, for instance, those associated with a particular disease. We illustrate this method on the task of distinguishing between two types of lung cancer; Squamous Cell Carcinoma (SCC) and Adenocarcinoma (AC). We identify pathway activation patterns in pathways previously implicated in the development of cancers. Our method identified a model with comparable predictive performance to the winning algorithm of a recent challenge, while providing biologically relevant explanations that may be useful to a biologist

Dimensions of Timescales in Neuromorphic Computing Systems

This article is a public deliverable of the EU project "Memory technologies with multi-scale time constants for neuromorphic architectures" (MeMScales, https://memscales.eu, Call ICT-06-2019 Unconventional Nanoelectronics, project number 871371). This arXiv version is a verbatim copy of the deliverable report, with administrative information stripped. It collects a wide and varied assortment of phenomena, models, research themes and algorithmic techniques that are connected with timescale phenomena in the fields of computational neuroscience, mathematics, machine learning and computer science, with a bias toward aspects that are relevant for neuromorphic engineering. It turns out that this theme is very rich indeed and spreads out in many directions which defy a unified treatment. We collected several dozens of sub-themes, each of which has been investigated in specialized settings (in the neurosciences, mathematics, computer science and machine learning) and has been documented in its own body of literature. The more we dived into this diversity, the more it became clear that our first effort to compose a survey must remain sketchy and partial. We conclude with a list of insights distilled from this survey which give general guidelines for the design of future neuromorphic systems