In Silico Biology

Single cell transcriptomics has recently seen a surge in popularity, leading to the need for data analysis pipelines that are reproducible, modular, and interoperable across different systems and institutions.To meet this demand, we introduce scAN1.0, a processing pipeline for analyzing 10X single cell RNA sequencing data. scAN1.0 is built using the Nextflow DSL2 and can be run on most computational systems. The modular design of Nextflow pipelines enables easy integration and evaluation of different blocks for specific analysis steps...

Darwin's and Wallace's 1859 explanation that novel speciation resulted from natural variants that had been subjected to selection was refined over the next 150 years as genetic inheritance and the importance of mutation-induced change were discovered, the quantitative theory of evolutionary population genetics was produced, the speed of genetic change in small populations became apparent and the ramifications of the DNA revolution became clear. This paper first discusses the modern view of speciation in its historical context...

CABs (Concave Actin Bundles) are oriented against the scaffold transversally in a manner different from traditional longitudinal F-actin bundles. CABs are present in a specific area, and do not exist in random areas. Biologically, CABs are developed to attach cells to fibers firmly so that CABs are found near cells. Based on this knowledge, we closely examined 3D confocal microcopy images containing fiber scaffolds, actin, and cells. Then, we assumed that the areas containing high values of compactness of fiber, compactness of actin, and density of cells would have many numbers of CABs...

Yeasts exist in communities that expand over space and time to form complex structures and patterns. We developed a lattice-based framework to perform spatial-temporal Monte Carlo simulations of budding yeast colonies exposed to different nutrient and magnetic field conditions. The budding patterns of haploid and diploid yeast cells were incorporated into the framework, as well as the filamentous growth that occurs in yeast colonies under nutrient limiting conditions. Simulation of the framework predicted that magnetic fields decrease colony growth rate, solidity, and roundness...

Differentiation can be modeled at the single cell level as a stochastic process resulting from the dynamical functioning of an underlying Gene Regulatory Network (GRN), driving stem or progenitor cells to one or many differentiated cell types. Metastability seems inherent to differentiation process as a consequence of the limited number of cell types. Moreover, mRNA is known to be generally produced by bursts, which can give rise to highly variable non-Gaussian behavior, making the estimation of a GRN from transcriptional profiles challenging...

Many biological ecosystems exhibit chaotic behavior, demonstrated either analytically using parameter choices in an associated dynamical systems model or empirically through analysis of experimental data. In this paper, we use existing software tools (COPASI, R) to explore dynamical systems and uncover regions with positive Lyapunov exponents where thus chaos exists. We evaluate the ability of the software's optimization algorithms to find these positive values with several dynamical systems used to model biological populations...

To develop vaccines it is mandatory yet challenging to account for inter-individual variability during immune responses. Even in laboratory mice, T cell responses of single individuals exhibit a high heterogeneity that may come from genetic backgrounds, intra-specific processes (e.g. antigen-processing and presentation) and immunization protocols.To account for inter-individual variability in CD8 T cell responses in mice, we propose a dynamical model coupled to a statistical, nonlinear mixed effects model...

The role of the immune system in tumor development increasingly includes the idea of cancer immunoediting. It comprises three phases: elimination, equilibrium, and escape. In the first phase, elimination, transformed cells are recognized and destroyed by immune system. The rare tumor cells that are not destroyed in this phase may then enter the equilibrium phase, where their growth is prevented by immunity mechanisms. The escape phase represents the final phase of this process, where cancer cells begin to grow unconstrained by the immune system...

A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances. Cytokines are adsorbed onto associated receptors at the cell surface. The adsorption is described by the Langmuir model and gives rise to the production of more cytokines and associated receptors inside the cell...

Micro-Tissue Engineered Neural Networks (Micro-TENNs) are living three-dimensional constructs designed to replicate the neuroanatomy of white matter pathways in the brain and are being developed as implantable micro-tissue for axon tract reconstruction, or as anatomically-relevant in vitro experimental platforms. Micro-TENNs are composed of discrete neuronal aggregates connected by bundles of long-projecting axonal tracts within miniature tubular hydrogels. In order to help design and optimize micro-TENN performance, we have created a new computational model including geometric and functional properties...

Large-scale visualization and analysis of HPIs involved in microbial CVDs can provide crucial insights into the mechanisms of pathogenicity. The comparison of CVD associated HPIs with the entire set of HPIs can identify the pathways specific to CVDs. Therefore, topological properties of HPI networks in CVDs and all pathogens was studied using Cytoscape3.5.1. Ontology and pathway analysis were done using KOBAS 3.0. HPIs of Papilloma, Herpes, Influenza A virus as well as Yersinia pestis and Bacillus anthracis among bacteria were predominant in the whole (wHPI) and the CVD specific (cHPI) network...

Vascular endothelial growth factor (VEGF) has been known as a key mediator of angiogenesis in cancer. Bevacizumab is anti-VEGF monoclonal antibody that has been approved by the FDA as a first-line treatment in many types of cancer. In this paper, we extend a previously validated multiscale tumor model to comprehensively include the multiple roles of VEGF during the course of angiogenesis and its binding mechanism with bevacizumab. We use the model to simulate tumor system response under various bevacizumab concentrations, both in stand-alone treatment and in combination with chemotherapy...

Moonlighting refers to a protein with at least two unrelated, mechanistically different functions. As a concept, moonlighting describes a large and diverse group of proteins which have been discovered in a multitude of organisms. As of today, a systematized view on these proteins is missing. Here, we propose a classification of moonlighting proteins by two classifiers. We use the function of the protein as a first classifier: activating - activating (Type I), activating - inhibiting (Type II), inhibiting - activating (Type III) and inhibiting - inhibiting (Type IV)...

The in vivo erythropoiesis, which is the generation of mature red blood cells in the bone marrow of whole organisms, has been described by a variety of mathematical models in the past decades. However, the in vitro erythropoiesis, which produces red blood cells in cultures, has received much less attention from the modelling community. In this paper, we propose the first mathematical model of in vitro erythropoiesis. We start by formulating different models and select the best one at fitting experimental data of in vitro erythropoietic differentiation obtained from chicken erythroid progenitor cells...

Global level network analysis of molecular links is necessary for systems level view of complex diseases like cancer. Using genome-wide expression datasets, we constructed and compared gene co-expression based specific networks of pre-cancerous tumors (adenoma) and cancerous tumors (carcinoma) with paired normal networks to assess for any possible changes in network connectivity. Previously, loss of connectivity was reported as a characteristics of cancer samples. Here, we observed that pre-cancerous conditions also had significantly less connections than paired normal samples...

 Quantitative modeling is quickly becoming an integral part of biology, due to the ability of mathematical models and computer simulations to generate insights and predict the behavior of living systems. Single-cell models can be incapable or misleading for inferring population dynamics, as they do not consider the interactions between cells via metabolites or physical contact, nor do they consider competition for limited resources such as nutrients or space. Here we examine methods that are commonly used to model and simulate cell populations...

Angiogenesis, a formation of blood vessels from an existing vasculature, plays a key role in tumor growth and its progression into cancer. The lining of blood vessels consists of endothelial cells (ECs) which proliferate and migrate, allowing the capillaries to sprout towards the tumor to deliver the needed oxygen. Various treatments aiming to suppress or even inhibit angiogenesis have been explored. Mesenchymal stem cells (MSCs) have recently been undergoing development in cell-based therapy for cancer due to their ability to migrate towards the capillaries and induce the apoptosis of the ECs, causing capillary degeneration...

A variety of mathematical models is used to describe and simulate the multitude of natural processes examined in life sciences. In this paper we present a scalable and adjustable foundation for the simulation of natural systems. Based on neighborhood relations in graphs and the complex interactions in cellular automata, the model uses recurrence relations to simulate changes on a mesoscopic scale. This implicit definition allows for the manipulation of every aspect of the model even during simulation. The definition of value rules ω facilitates the accumulation of change during time steps...

Cells maintain cellular homeostasis employing different regulatory mechanisms to respond external stimuli. We study two groups of signal-dependent transcriptional regulatory mechanisms. In the first group, we assume that repressor and activator proteins compete for binding to the same regulatory site on DNA (competitive mechanisms). In the second group, they can bind to different regulatory regions in a noncompetitive fashion (noncompetitive mechanisms). For both competitive and noncompetitive mechanisms, we studied the gene expression dynamics by increasing the repressor or decreasing the activator abundance (inhibition mechanisms), or by decreasing the repressor or increasing the activator abundance (activation mechanisms)...

Articular cartilage is characterized by low cell density of only one cell type, chondrocytes, and has limited self-healing properties. When articular cartilage is affected by traumatic injuries, a therapeutic strategy such as autologous chondrocyte implantation is usually proposed for its treatment. This approach requires in vitro chondrocyte expansion to yield high cell number for cell transplantation. To improve the efficiency of this procedure, it is necessary to assess cell dynamics such as migration, proliferation and cell death during culture...