Geometric Path Integrals. A Language for Multiscale Biology and Systems Robustness

In this paper we suggest that, under suitable conditions, supervised learning can provide the basis to formulate at the microscopic level quantitative questions on the phenotype structure of multicellular organisms. The problem of explaining the robustness of the phenotype structure is rephrased as a real geometrical problem on a fixed domain. We further suggest a generalization of path integrals that reduces the problem of deciding whether a given molecular network can generate specific phenotypes to a numerical property of a robustness function with complex output, for which we give heuristic justification. Finally, we use our formalism to interpret a pointedly quantitative developmental biology problem on the allowed number of pairs of legs in centipedes

Multi-agent decision-making dynamics inspired by honeybees

When choosing between candidate nest sites, a honeybee swarm reliably chooses the most valuable site and even when faced with the choice between near-equal value sites, it makes highly efficient decisions. Value-sensitive decision-making is enabled by a distributed social effort among the honeybees, and it leads to decision-making dynamics of the swarm that are remarkably robust to perturbation and adaptive to change. To explore and generalize these features to other networks, we design distributed multi-agent network dynamics that exhibit a pitchfork bifurcation, ubiquitous in biological models of decision-making. Using tools of nonlinear dynamics we show how the designed agent-based dynamics recover the high performing value-sensitive decision-making of the honeybees and rigorously connect investigation of mechanisms of animal group decision-making to systematic, bio-inspired control of multi-agent network systems. We further present a distributed adaptive bifurcation control law and prove how it enhances the network decision-making performance beyond that observed in swarms

Biological control networks suggest the use of biomimetic sets for combinatorial therapies

Cells are regulated by networks of controllers having many targets, and targets affected by many controllers, but these "many-to-many" combinatorial control systems are poorly understood. Here we analyze distinct cellular networks (transcription factors, microRNAs, and protein kinases) and a drug-target network. Certain network properties seem universal across systems and species, suggesting the existence of common control strategies in biology. The number of controllers is ~8% of targets and the density of links is 2.5% \pm 1.2%. Links per node are predominantly exponentially distributed, implying conservation of the average, which we explain using a mathematical model of robustness in control networks. These findings suggest that optimal pharmacological strategies may benefit from a similar, many-to-many combinatorial structure, and molecular tools are available to test this approach.Comment: 33 page

Characterizing Distances of Networks on the Tensor Manifold

At the core of understanding dynamical systems is the ability to maintain and control the systems behavior that includes notions of robustness, heterogeneity, or regime-shift detection. Recently, to explore such functional properties, a convenient representation has been to model such dynamical systems as a weighted graph consisting of a finite, but very large number of interacting agents. This said, there exists very limited relevant statistical theory that is able cope with real-life data, i.e., how does perform analysis and/or statistics over a family of networks as opposed to a specific network or network-to-network variation. Here, we are interested in the analysis of network families whereby each network represents a point on an underlying statistical manifold. To do so, we explore the Riemannian structure of the tensor manifold developed by Pennec previously applied to Diffusion Tensor Imaging (DTI) towards the problem of network analysis. In particular, while this note focuses on Pennec definition of geodesics amongst a family of networks, we show how it lays the foundation for future work for developing measures of network robustness for regime-shift detection. We conclude with experiments highlighting the proposed distance on synthetic networks and an application towards biological (stem-cell) systems.Comment: This paper is accepted at 8th International Conference on Complex Networks 201

Representability of algebraic topology for biomolecules in machine learning based scoring and virtual screening

This work introduces a number of algebraic topology approaches, such as multicomponent persistent homology, multi-level persistent homology and electrostatic persistence for the representation, characterization, and description of small molecules and biomolecular complexes. Multicomponent persistent homology retains critical chemical and biological information during the topological simplification of biomolecular geometric complexity. Multi-level persistent homology enables a tailored topological description of inter- and/or intra-molecular interactions of interest. Electrostatic persistence incorporates partial charge information into topological invariants. These topological methods are paired with Wasserstein distance to characterize similarities between molecules and are further integrated with a variety of machine learning algorithms, including k-nearest neighbors, ensemble of trees, and deep convolutional neural networks, to manifest their descriptive and predictive powers for chemical and biological problems. Extensive numerical experiments involving more than 4,000 protein-ligand complexes from the PDBBind database and near 100,000 ligands and decoys in the DUD database are performed to test respectively the scoring power and the virtual screening power of the proposed topological approaches. It is demonstrated that the present approaches outperform the modern machine learning based methods in protein-ligand binding affinity predictions and ligand-decoy discrimination