The Reasoning Engine: A Satisfiability Modulo Theories-Based Framework for Reasoning About Discrete Biological Models.

We present a framework called the Reasoning Engine, which implements Satisfiability Modulo Theories (SMT)-based methods within a unified computational environment to address diverse biological analysis problems. The Reasoning Engine was used to reproduce results from key scientific studies, as well as supporting new research in stem cell biology. The framework utilizes an intermediate language for encoding partially specified discrete dynamical systems, which bridges the gap between high-level domain-specific languages and low-level SMT solvers.

Entropy sorting of single-cell RNA sequencing data reveals the inner cell mass in the human pre-implantation embryo.

A major challenge in single-cell gene expression analysis is to discern meaningful cellular heterogeneity from technical or biological noise. To address this challenge, we present entropy sorting (ES), a mathematical framework that distinguishes genes indicative of cell identity. ES achieves this in an unsupervised manner by quantifying if observed correlations between features are more likely to have occurred due to random chance versus a dependent relationship, without the need for any user-defined significance threshold.

Computational Stem Cell Biology: Open Questions and Guiding Principles.

Computational biology is enabling an explosive growth in our understanding of stem cells and our ability to use them for disease modeling, regenerative medicine, and drug discovery. We discuss four topics that exemplify applications of computation to stem cell biology: cell typing, lineage tracing, trajectory inference, and regulatory networks. We use these examples to articulate principles that have guided computational biology broadly and call for renewed attention to these principles as computation becomes increasingly important in stem cell biology.

Formal Analysis of Network Motifs Links Structure to Function in Biological Programs.

A recurring set of small sub-networks have been identified as the building blocks of biological networks across diverse organisms. These network motifs are associated with certain dynamic behaviors and define key modules that are important for understanding complex biological programs. Besides studying the properties of motifs in isolation, current algorithms typically evaluate the occurrence frequency of a specific motif in a given biological network compared to that in random networks of similar structure.

Automated Formal Reasoning to Uncover Molecular Programs of Self-Renewal.

The Reasoning Engine for Interaction Networks (RE:IN) is a tool that was developed initially for the study of pluripotency in mouse embryonic stem cells. A set of critical factors that regulate the pluripotent state had been identified experimentally, but it was not known how these genes interacted to stabilize self-renewal or commit the cell to differentiation. The methodology encapsulated in RE:IN enabled the exploration of a space of possible network interaction models, allowing for uncertainty in whether individual interactions exist between the pluripotency factors.

A common molecular logic determines embryonic stem cell self-renewal and reprogramming.

During differentiation and reprogramming, new cell identities are generated by reconfiguration of gene regulatory networks. Here, we combined automated formal reasoning with experimentation to expose the logic of network activation during induction of naïve pluripotency. We find that a Boolean network architecture defined for maintenance of naïve state embryonic stem cells (ESC) also explains transcription factor behaviour and potency during resetting from primed pluripotency.

A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis.

Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here, we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation.

A Method to Identify and Analyze Biological Programs through Automated Reasoning.

Predictive biology is elusive because rigorous, data-constrained, mechanistic models of complex biological systems are difficult to derive and validate. Current approaches tend to construct and examine static interaction network models, which are descriptively rich but often lack explanatory and predictive power, or dynamic models that can be simulated to reproduce known behavior. However, in such approaches implicit assumptions are introduced as typically only one mechanism is considered, and exhaustively investigating all scenarios is impractical using simulation.

How computational models contribute to our understanding of the germ line.

Computational models are an invaluable tool in modern biology. They provide a framework within which to summarize existing knowledge, enable competing hypotheses to be compared qualitatively and quantitatively, and to facilitate the interpretation of complex data. Moreover, models allow questions to be investigated that are difficult to approach experimentally.

Computational models reveal a passive mechanism for cell migration in the crypt.

Cell migration in the intestinal crypt is essential for the regular renewal of the epithelium, and the continued upward movement of cells is a key characteristic of healthy crypt dynamics. However, the driving force behind this migration is unknown. Possibilities include mitotic pressure, active movement driven by motility cues, or negative pressure arising from cell loss at the crypt collar.

Chaste: an open source C++ library for computational physiology and biology.

Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high-performance computational investigations of defibrillation on realistic human cardiac geometries.

Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling.

Oligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood. It is not known whether adult-born OLs ensheath previously unmyelinated axons or remodel existing myelin. We quantified OP division and OL production in different regions of the adult mouse CNS including the 4-month-old optic nerve, in which practically all axons are already myelinated.

A two-dimensional model of the colonic crypt accounting for the role of the basement membrane and pericryptal fibroblast sheath.

The role of the basement membrane is vital in maintaining the integrity and structure of an epithelial layer, acting as both a mechanical support and forming the physical interface between epithelial cells and the surrounding connective tissue. The function of this membrane is explored here in the context of the epithelial monolayer that lines the colonic crypt, test-tube shaped invaginations that punctuate the lining of the intestine and coordinate a regular turnover of cells to replenish the epithelial layer every few days. To investigate the consequence of genetic mutations that perturb the system dynamics and can lead to colorectal cancer, it must be possible to track the emerging tissue level changes that arise in the crypt.

Modelling the role of the basement membrane beneath a growing epithelial monolayer.

The role of the basement membrane is vital in maintaining the integrity and structure of an epithelial layer, acting as both a mechanical support and forming the physical interface between epithelial cells and the surrounding connective tissue. The function of this membrane is explored here in the context of a growing epithelial monolayer, defined such that the epithelial cells divide and migrate along a deformable substrate. A discrete, off-lattice cell-centre modelling approach is undertaken, which permits definition of a basement membrane component, separating the epithelial cells from the tissue stroma whilst responding to forces from both that arise due to cell division, migration and apoptosis.

Modeling alveolar volume changes during periodic breathing in heterogeneously ventilated lungs.

A simplified model of periodic breathing, proposed by Whiteley et al. (Math. Med.