Quantitative Biology

We developed simulation methodology to assess eventual therapeutic efficiency of exogenous multiparametric changes in a four-component cellular system described by the system of ordinary differential equations. The method is numerically implemented to simulate the temporal behavior of a cellular system of multiple myeloma cells. The problem is conceived as an inverse optimization task where the alternative temporal changes of selected parameters of the ordinary differential equations represent candidate solutions and the objective function quantifies the goals of the therapy. The system under study consists of two main cellular components, tumor cells and their cellular environment, respectively. The subset of model parameters closely related to the environment is substituted by exogenous time dependencies - therapeutic pulses combining continuous functions and discrete parameters subordinated thereafter to the optimization. Synergistic interaction of temporal parametric changes has been observed and quantified whereby two or more dynamic parameters show effects that absent if either parameter is stimulated alone. We expect that the theoretical insight into unstable tumor growth provided by the sensitivity and optimization studies could, eventually, help in designing combination therapies.

For years, extensive efforts have been made to discover effective, non-invasive anti-cancer therapies. Cold atmospheric plasma (CAP), is a near room temperature ionized gas composed of reactive species, charged particles, neutral particles, and electrons. CAP also has several physical factors including thermal radiation, ultraviolet (UV) radiation, and electromagnetic (EM) waves. Most of the previously reported biological effects of CAP have relied on direct contact between bulk plasma and cells, resulting in the chemical effects generally seen after CAP treatment. In this paper, we demonstrate that the electromagnetic emission produced by CAP can lead to the death of B16F10 melanoma cancer cells via a transbarrier contactless method. When compared with the effect of reactive species, the effect of the physical factors causes much greater growth inhibition. The physical-triggered growth inhibition is due to a new type of cell death, characterized by rapid leakage of bulk water from the cells, resulting in bubbles on the cell membrane, and cytoplasm shrinkage. The results of this study introduce a new possible mechanism of CAP induced cancer cell death and build a foundation for CAP to be used as a non-invasive cancer treatment in the future.

A mathematical model from a previous work was re-fitted and analyzed for experimental data regarding the cellular immune response to the lymphocytic choriomeningitis virus. Specifically, the CD 8 + T cell response to six MHC class I-restricted epitopes (GP* and NP*) and CD 4 + T cell responses to two MHC class II-restricted epitopes\cite{de2003different}. In this work, we use calibration through log likelihood maximization to investigate if different parameters can produce a more accurate fit of the model presented previously in the paper titled \textit{Different Dynamics of CD 4 + and CD 8 + T Cell Responses During and After Acute Lymphocytic Choriomeningitis Virus Infection}\cite{de2003different}

Background. Models of cancer-induced neuropathy are designed by injecting cancer cells near the peripheral nerves. The interference of tissue-resident immune cells does not allow a direct contact with nerve fibres which affects the tumor microenvironment and the invasion process. Methods. Anaplastic tumor-1 (AT-1) cells were inoculated within the sciatic nerves (SNs) of male Copenhagen rats. Lumbar dorsal root ganglia (DRGs) and the SNs were collected on days 3, 7, 14, and 21. SN tissues were examined for morphological changes and DRG tissues for immunofluorescence, electrophoretic tendency, and mRNA quantification. Hypersensitivities to cold, mechanical, and thermal stimuli were determined. HC-030031, a selective TRPA1 antagonist, was used to treat cold allodynia. Results. Nociception thresholds were identified on day 6. Immunofluorescent micrographs showed overexpression of TRPA1 on days 7 and 14 and of CGRP on day 14 until day 21. Both TRPA1 and CGRP were coexpressed on the same cells. Immunoblots exhibited an increase in TRPA1 expression on day 14. TRPA1 mRNA underwent an increase on day 7 (normalized to 18S). Injection of HC-030031 transiently reversed the cold allodynia. Conclusion. A novel and a promising model of cancer-induced neuropathy was established, and the role of TRPA1 and CGRP in pain transduction was examined.

The objective of this study was to investigate the relationship between erectile pressure (EP) and shear wave speed of the corpus cavernosa obtained via a specific ultrasound vibro-elastography (UVE) technique. This study builds upon our prior investigation, in which UVE was used to evaluate the viscoelastic properties of the corpus cavernosa in the flaccid and erect states. A two-dimensional poroviscoelastic finite element model (FEM) was developed to simulate wave propagation in the penile tissue according to our experimental setup. Various levels of EP were applied to the corpus cavernosa, and the relationship between shear wave speed in the corpus cavernosa and EP was investigated. Results demonstrated non-linear, positive correlations between shear wave speeds in the corpus cavernosa and increasing EP at different vibration frequencies (100-200 Hz). These findings represent the first report of the impact of EP on shear wave speed and validates the use of UVE in the evaluation of men with erectile dysfunction. Further evaluations are warranted to determine the clinical utility of this instrument in the diagnosis and treatment of men with erectile dysfunction.

Mathematical equations can be used as effectual tools in drug delivery systems modeling and are also highly helpful to have a theoretical understanding of controlled drug release and diffusion mechanisms. In this study we aim to present a mathematical combination between the Bernoulli equation and the Fick's equation as a diffusion controller in drug delivery systems. For this propose we have revised the Bernoulli equation as an additional, controller and complementary method of the Fick's diffusion equation to detect the optimal delivery direction to control the diffusion divergence of the drug carrier in vascular systems during the transportation process in biological tissues. Therefore, by utilizing the Bernoulli equation we could determine the real direction by the route function f.

Interactions between neighboring cells are essential for generating or refining patterns in a number of biological systems. We propose a discrete filtering approach to predict how networks of cells modulate spatially varying input signals to produce more complicated or precise output signals. The interconnections between cells determine the set of spatial modes that are amplified or suppressed based on the coupling and internal dynamics of each cell, analogously to the way a traditional digital filter modifies the frequency components of a discrete signal. We apply the framework to two systems in developmental biology: the Notch-Delta interaction that shapes \textit{Drosophila} wing veins and the Sox9/Bmp/Wnt network responsible for digit formation in vertebrate limbs. The latter case study demonstrates that Turing-like patterns may occur even in the absence of instabilities. Results also indicate that developmental biological systems may be inherently robust to both correlated and uncorrelated noise sources. Our work shows that a spatial frequency-based interpretation simplifies the process of predicting patterning in living organisms when both environmental influences and intercellular interactions are present.

Aging remains a fundamental open problem in modern biology. Although there exist a number of theories on aging on the cellular scale, nearly nothing is known about how microscopic failures cascade to macroscopic failures of tissues, organs and ultimately the organism. The goal of this work is to bridge microscopic cell failure to macroscopic manifestations of aging. We use tissue engineered constructs to control the cellular-level damage and cell-cell distance in individual tissues to establish the role of complex interdependence and interactions between cells in aging tissues. We found that while microscopic mechanisms drive aging, the interdependency between cells plays a major role in tissue death, providing evidence on how cellular aging is connected to its higher systemic consequences.

A critical barrier in the nephrology field is the lack of appropriate in vitro renal tubule models that allow manipulation of various mechanical factors, facilitating studies of disease pathophysiology and drug discovery. Here we report development of a novel in vitro assay system comprised of a renal tubule within an elasto-plastic extracellular matrix microenvironment. This in vitro tubule mimetic device consists of a container with two, pipette-accessible ports, filament-deposition (3D-) printed into 35 mm cell culture dishes. The container is filled with a hydrogel, such as a collagen I or fibrin gel, while a narrow masking tube is threaded through the ports. Following gelation, the masking material is pulled out leaving a tunnel within the gel. Seeding of the tunnels with M1 or MDCK renal epithelial cells through the side ports results in a monolayer with apical-basal polarity, such that laminin and fibronectin are present on the basal surface, while primary cilia project from the apical side of cells into the tubular lumen. The device is optically accessible, and can be live-imaged by phase contrast or epifluorescence microscopy. The lumen of the epithelial-lined tube can be connected through the side ports to a circulatory flow. We demonstrate that kidney epithelial cells are able to adjust the diameter of the model tubule by myosin-II dependent contractility. Furthermore, cells of the tubule are also able to remodel the surrounding hydrogel leading to budding from the main tubule. We propose that this versatile in vitro model system can be developed into a future pre-clinical tool to study pathophysiology of kidney diseases and identify therapeutic compounds.

We consider the mechanisms by which folds, or sulci (troughs) and gyri (crests), develop in the brain. This feature, common to many gyrencephalic species including humans, has attracted recent attention from soft matter physicists. It occurs due to inhomogeneous, and predominantly tangential, growth of the cortex, which causes circumferential compression, leading to a bifurcation of the solution path to a folded configuration. The problem can be framed as one of buckling in the regime of linearized elasticity. However, the brain is a very soft solid, which is subject to large strains due to inhomogeneous growth. As a consequence, the morphomechanics of the developing brain demonstrates an extensive post-bifurcation regime. Nonlinear elasticity studies of growth-driven brain folding have established the conditions necessary for the onset of folding, and for its progression to configurations broadly resembling gyrencephalic brains. The reference, unfolded, configurations in these treatments have a high degree of symmetry--typically, ellipsoidal. Depending on the boundary conditions, the folded configurations have symmetric or anti-symmetric patterns. However, these configurations do not approximate the actual morphology of, e.g., human brains, which display unsymmetric folding. More importantly, from a neurodevelopmental standpoint, many of the unsymmetric sulci and gyri are notably robust in their locations. Here, we initiate studies on the physical mechanisms and geometry that control the development of primary sulci and gyri. In this preliminary communication we carry out computations with idealized geometries, boundary conditions and parameters, seeking a pattern resembling one of the first folds to form: the Central Sulcus.