Quantitative Biology - Tissues and Organs Publications (50)


Quantitative Biology - Tissues and Organs Publications

The Quadrant-Slope Index (QSI) method was created in order to detect subtle patterns of organization in tumor images that have metaplastic elements, such as streams of spindle cells [1]. However, metaplastic tumors also have nuclei that may be aligned like a stream but are not obvious to the pathologist because the shape of the cytoplasm is unclear. The previous method that I developed, the Nearest-Neighbor Angular Profile (N-NAP) method [2], is good for detecting subtle patterns of order based on the assumption that breast tumor cells are attempting to arrange themselves side-by-side (like bricks), as in the luminal compartment of a normal mammary gland [3]. Read More

Pathologists routinely classify breast tumors according to recurring patterns of nuclear grades, cytoplasmic coloration, and large-scale morphological formations (i.e. streams of spindle cells, adenoid islands, etc. Read More

Collective cell migration is a highly regulated process involved in wound healing, cancer metastasis and morphogenesis. Mechanical interactions among cells provide an important regulatory mechanism to coordinate such collective motion. Using a Self-Propelled Voronoi (SPV) model that links cell mechanics to cell shape and cell motility, we formulate a generalized mechanical inference method to obtain the spatio-temporal distribution of cellular stresses from measured traction forces in motile tissues and show that such traction-based stresses match those calculated from instantaneous cell shapes. Read More

Intra-tumour phenotypic heterogeneity limits accuracy of clinical diagnostics and hampers the efficiency of anti-cancer therapies. Dealing with this cellular heterogeneity requires adequate understanding of its sources, which is extremely difficult, as phenotypes of tumour cells integrate hardwired (epi)mutational differences with the dynamic responses to microenvironmental cues. The later come in form of both direct physical interactions, as well as inputs from gradients of secreted signalling molecules. Read More

The effect of heart geometry and anisotropy on cardiac re-entry dynamics and self-termination is studied here in anatomically realistic computer simulations of human foetal heart. 20 weeks of gestational age human foetal heart isotropic and anisotropic anatomy models from diffusion tensor MRI data sets are used in the computer simulations. The fibre orientation angles of the heart were obtained from the DT-MRI primary eigenvalues. Read More

Affiliations: 1Department of Mathematics, Universidad Sergio Arboleda, 2School of Physics, Georgia Institute of Technology

The mechanisms underlying cardiac fibrillation have been investigated for over a century, but we are still finding surprising results that change our view of this phenomenon. The present study focuses on the transition from normal rhythm to atrial fibrillation associated with a gradual increase in the pacing rate. While some of our findings are consistent with existing experimental, numerical, and theoretical studies of this problem, one result appears to contradict the accepted picture. Read More

Recent experimental work on the nephrotoxicity of contaminants in drinking water using laboratory mice, motivated by the need to understand the origin of chronic kidney disease of unknown aetiology is examined within our understanding of the hydration of ions and proteins. Qualitative considerations based on Hofmeister-type action of these ions, as well as quantitative electrochemical models for the Gibbs free-energy change for ion-pair formation are used to explain why Cd$^{2+}$ in the presence of F$^-$ and water hardness due to Mg$^{2+}$ ions (but not Ca$^{2+}$) can be expected to be more nephrotoxic, while AsO$_3^{3-}$ in the presence of F$^-$ and hardness may be expected to be less nephrotoxic. The analysis is applied to a variety of ionic species typically found in water to predict their likely combined electro-chemical action. Read More

Whole body biodistribution of 100 nanometer sized polymer micellar nanoparticles (NPs) was determined following intranasal administration using PET/CT imaging on a clinical scanner. Nanoparticles labeled with Zirconium 89 were administered intranasally or intravenously to Sprague Dawley rats followed by serial ex vivo PET/CT imaging in a clinical scanner. At 30 minutes and 1 hour following intranasal delivery, the animals were sacrificed and placed in the PET/CT scanner. Read More

Wear on total knee replacements (TKRs) is an important criterion for their performance characteristics. Numerical simulations of such wear has seen increasing attention over the last years. They have the potential to be much faster and less expensive than the in vitro tests in use today. Read More

During tissue invasion individual tumor cells exhibit two interconvertible migration modes, namely mesenchymal and amoeboid migration. The cellular microenvironment triggers the switch between both modes, thereby allowing adaptation to dynamic conditions. It is, however, unclear if this amoeboid-mesenchymal migration plasticity contributes to a more effective tumor invasion. Read More

Pimple is one of the most common skin diseases for humans. The mechanical modeling of pimple growth is very limited. A finite element model is developed to quantify the deformation field with the expansion of follicle, and then the mechanical stimulus is related to the sensation of pain during the development of pimple. Read More

Resection of primary tumors is often followed by accelerated growth of metastases. Here we propose that this effect may be due to the fact that resection of primary tumor results in a decrease in the total systemic amount of angiogenesis stimulators, such as VEGF and bFGF. This in turn causes decrease in the systemic level of angiogenesis inhibitors, such as PF-4 and TSP-1, which at least temporarily relieves inhibition of secondary tumors, allowing them to grow. Read More

While spiral wave breakup has been implicated in the emergence of atrial fibrillation, its role in maintaining this complex type of cardiac arrhythmia is less clear. We used the Karma model of cardiac excitation to investigate the dynamical mechanisms that sustain atrial fibrillation once it has been established. The results of our numerical study show that spatiotemporally chaotic dynamics in this regime can be described as a dynamical equilibrium between topologically distinct types of transitions that increase or decrease the number of wavelets, in general agreement with the multiple wavelets hypothesis. Read More

At present, multi-electrode array (MEA) approach and optical recording allow us to acquire plant electrical activity with higher spatio-temporal resolution. To understand the dynamic information flow of the electrical signaling system and estimate the effective connectivity, we proposed a solution to combine the two casualty analysis approaches, i.e. Read More

By means of a recently-proposed metric or structural derivative, called scale-q-derivative approach, we formulate differential equation that models the cell death by a radiation exposure in tumor treatments. The considered independent variable here is the absorbed radiation dose D instead of usual time. The survival factor, Fs, for radiation damaged cell obtained here is in agreement with the literature on the maximum entropy principle, as it was recently shown and also exhibits an excellent agreement with the experimental data. Read More

We study a non-local variant of a diffuse interface model proposed by Hawkins--Darrud et al. (2012) for tumour growth in the presence of a chemical species acting as nutrient. The system consists of a Cahn--Hilliard equation coupled to a reaction-diffusion equation. Read More

The aims of the current study were to establish a system of culture for induction of paralysed chondrocytes and to investigate if these cells are really dying. Chondrocytes were isolated from the growth cartilage of fetal equines, centrifuged and cultured as pellets in either 10% fetal calf serum or 10% horse serum for 28 days and processed for light and electron microscopy. Different cell types were counted and expressed as a percentage to the total cell number. Read More

The Zika virus has been found in individual cases but has not been confirmed as the cause of in the large number of cases of microcephaly in Brazil in 2015-6. Indeed, disparities between the incidence of Zika and microcephaly across geographic locations has led to questions about the virus's role. Here we consider whether the insecticide pyriproxyfen used in Brazilian drinking water might be the primary cause or a cofactor. Read More

Virtual heart models have been proposed to enhance the safety of implantable cardiac devices through closed loop validation. To communicate with a virtual heart, devices have been driven by cardiac signals at specific sites. As a result, only the action potentials of these sites are sensed. Read More

The spirally arranged stems of the spikemoss Selaginella lepidophylla, an ancient resurrection plant, compactly curl into a nest-ball shape upon dehydration. Due to its spiral phyllotaxy, older outer stems on the plant interlace and envelope the younger inner stems forming the plant centre. Stem curling is a morphological mechanism that limits photoinhibitory and thermal damages the plant might experience in arid environments. Read More

In the context of tissue engineering, we recently proposed a lattice model for a bioactive porous tissue scaffold in order to understand the role of an active pore network in tissue growth [Lattice and Continuum Modelling of a Bioactive Porous Tissue Scaffold, preprint, 2017]. This model considered the scaffold as an evolving lattice of pores, with coupling between local cell growth in the pores, and fluid flow through the medium. Here we consider a variant of this lattice model as well as a spatially continuous analogue. Read More

A contemporary procedure to grow artificial tissue is to seed cells onto a porous biomaterial scaffold and culture it within a perfusion bioreactor to facilitate the transport of nutrients to growing cells. Typical models of cell growth for tissue engineering applications make use of spatially homogeneous or spatially continuous equations to model cell growth, flow of culture medium, nutrient transport, and their interactions. The network structure of the physical porous scaffold is often incorporated through parameters in these models, either phenomenologically or through techniques like mathematical homogenization. Read More

Cancer is a disease of cellular regulation, often initiated by genetic mutation within cells, and leading to a heterogeneous cell population within tissues. In the competition for nutrients and growth space within the tumors the phenotype of each cell determines its success. Selection in this process is imposed by both the microenvironment (neighboring cells, extracellular matrix, and diffusing substances), and the whole of the organism through for example the blood supply. Read More

This paper investigates cells proliferation dynamics in small tumor cell aggregates using an individual based model (IBM). The simulation model is designed to study the morphology of the cell population and of the cell lineages as well as the impact of the orientation of the division plane on this morphology. Our IBM model is based on the hypothesis that cells are incompressible objects that grow in size and divide once a threshold size is reached, and that newly born cell adhere to the existing cell cluster. Read More

We propose a one-dimensional model for collecting lymphatics coupled with a novel Electro-Fluid-Mechanical Contraction (EFMC) model for dynamical contractions, based on a modified FitzHugh-Nagumo model for action potentials. The one-dimensional model for a compliant lymphatic vessel is a set of hyperbolic Partial Differential Equations (PDEs). The EFMC model combines the electrical activity of lymphangions (action potentials) with fluid-mechanical feedback (stretch of the lymphatic wall and wall shear stress) and the mechanical variation of the lymphatic wall properties (contractions). Read More

The temporal and spatial development of Parkinson's disease has been characterised as the progressive formation of {\alpha}-synuclein aggregations through susceptible neuronal pathways. This article describes a new model for this progression mechanism in which Parkinsonian damage moves over time through the nervous system by the combined effect of the reaction kinetics of pathogenesis and molecular diffusion. In the reaction-diffusion model, the change from a healthy state to the disease state advances through the nervous system as a wave front of Parkinsonian damage, marking its path by accumulations of damaged {\alpha}-synuclein and neurotoxic levels of oxidative species. Read More

Osteocytes and their cell processes reside in a large, interconnected network of voids pervading the mineralized bone matrix of most vertebrates. This osteocyte lacuno-canalicular network (OLCN) is believed to play important roles in mechanosensing, mineral homeostasis, and for the mechanical properties of bone. While the extracellular matrix structure of bone is extensively studied on ultrastructural and macroscopic scales, there is a lack of quantitative knowledge on how the cellular network is organized. Read More

This article presents formalistic tool for description of structural and biochemical relations between cells in the course of development of the body of plants. This is flexible formalistic space, based on the Category theory and the Petri Net approach, which embeds and mutually supplements biological data from methodically different sources. Relation between functional and morphological ways of plant description was mathematically realized with help of the adjoint functors. Read More

We consider evolving networks in which each node can have various associated properties (a state) in addition to those that arise from network structure. For example, each node can have a spatial location and a velocity, or some more abstract internal property that describes something like social trait. Edges between nodes are created and destroyed, and new nodes enter the system. Read More

Expressing the energy content of food as the heat energy released by its combustion is potentially misleading. Food is used to produce adenosine triphosphate (ATP). The free energy of conversion of ATP into adenosine diphosphate is used directly for processes such as muscular contraction, without the need for intermediate heat production. Read More

The role of continua has been clear since antiquity in the mathematical approaches to physics, while discrete manifolds were brought to the limelight mostly by Quantum and Information Theories, in the XX century. We first recall how theorizing and measuring radically change in physics when using discrete vs. continuous mathematical manifolds. Read More

We present a continuum model for the mechanical behavior of the skeletal muscle tissue when its functionality is reduced due to aging. The loss of ability of activating is typical of the geriatric syndrome called sarcopenia. The material is described by a hyperelastic, polyconvex, transverse isotropic strain energy function. Read More

During embryogenesis tissue layers continuously rearrange and fold into specific shapes. Developmental biology identified patterns of gene expression and cytoskeletal regulation underlying local tissue dynamics, but how actions of multiple domains of distinct cell types coordinate to remodel tissues at the organ scale remains unclear. We use in toto light-sheet microscopy, automated image analysis, and physical modeling to quantitatively investigate the link between kinetics of global tissue transformations and force generation patterns during Drosophila gastrulation. Read More

We introduce an in silico model for the initial spread of an aberrant phenotype with Warburg-like overflow metabolism within a healthy homeostatic tissue in contact with a nutrient reservoir (the blood), aimed at characterizing the role of the microenvironment for aberrant growth. Accounting for cellular metabolic activity, competition for nutrients, spatial diffusion and their feedbacks on aberrant replication and death rates, we obtain a phase portrait where distinct asymptotic whole-tissue states are found upon varying the tissue-blood turnover rate and the level of blood-borne primary nutrient. Over a broad range of parameters, the spreading dynamics is bistable as random fluctuations can impact the final state of the tissue. Read More

We derive a Cahn-Hilliard-Darcy model to describe multiphase tumour growth taking interactions with multiple chemical species into account as well as the simultaneous occurrence of proliferating, quiescent and necrotic regions. Via a coupling of the Cahn-Hilliard-Darcy equations to a system of reaction-diffusion equations a multitude of phenomena such as nutrient diffusion and consumption, angiogenesis, hypoxia, blood vessel growth, and inhibition by toxic agents, which are released for example by the necrotic cells, can be included. A new feature of the modelling approach is that a volume-averaged velocity is used, which dramatically simplifies the resulting equations. Read More

Although redistribution of red blood cells at bifurcated vessels is highly dependent on flow rate, it is still challenging to quantitatively express the dependency of flow rate in plasma skimming due to nonlinear cellular interactions. We suggest a plasma skimming model that can involve the effect of fractional blood flow at each bifurcation point. For validating the new model, it is compared with \textit{in vivo} data at single bifurcation points, as well as microvascular network systems. Read More

In this paper we investigate the extent to which variable porosity drug-eluting coatings can provide better control over drug release than coatings where the porosity is constant throughout. In particular, we aim to establish the potential benefits of replacing a single-layer with a two-layer coating of identical total thickness and initial drug mass. In our study, what distinguishes the layers (other than their individual thickness and initial drug loading) is the underlying microstructure, and in particular the effective porosity and the tortuosity of the material. Read More

Aims. Clinical data indicating a heart rate (HR) target during rate control therapy for permanent atrial fibrillation (AF) and assessing its eventual relationship with reduced exercise tolerance are lacking. The present study aims at investigating the impact of resting HR on the hemodynamic response to exercise in permanent AF patients by means of a computational cardiovascular model. Read More

We introduce and study properties of phyllotactic and rhombic tilings on the cylin- der. These are discrete sets of points that generalize cylindrical lattices. Rhombic tilings appear as periodic orbits of a discrete dynamical system S that models plant pattern formation by stacking disks of equal radius on the cylinder. Read More

How can tissues generate large numbers of cells, yet keep the divisional load (the number of divisions along cell lineages) low in order to curtail the accumulation of somatic mutations and reduce the risk of cancer? To answer the question we consider a general model of hierarchically organized self-renewing tissues and show that the lifetime divisional load of such a tissue is independent of the details of the cell differentiation processes, and depends only on two structural and two dynamical parameters. Our results demonstrate that a strict analytical relationship exists between two seemingly disparate characteristics of self-renewing tissues: divisional load and tissue organization. Most remarkably, we find that a sufficient number of progressively slower dividing cell types can be almost as efficient in minimizing the divisional load, as non-renewing tissues. Read More

This paper addresses the problem of quantifying biomarkers in multi-stained tissues, based on color and spatial information. A deep learning based method that can automatically localize and quantify the cells expressing biomarker(s) in a whole slide image is proposed. The deep learning network is a fully convolutional network (FCN) whose input is the true RGB color image of a tissue and output is a map of the different biomarkers. Read More

Cerebral autoregulation refers to regulation mechanisms that aim to maintain cerebral blood flow approximately constant. It is often assessed by autoregulation index (ARI), which uses arterial blood pressure and cerebral blood flow velocity time series to produce a ten-scale index of autoregulation performance (0 denoting the absence of and 9 the strongest autoregulation). Unfortunately, data are rarely free from various artefacts. Read More

We consider a partial differential equation associated with a mathematical model describing the concentration of nutrients in blood which interferes directly on the erythrocyte sedimentation rate in the case of an average fluid velocity equal to zero. Introducing the fractional derivative in the Caputo sense, we propose a time-fractional mathematical model which contains, as a particular case, the model proposed by Sharma et al. Our main purpose is to obtain an analytic solution of this time-fractional partial differential equation in terms of the Mittag-Leffler function and Wright function. Read More

Cells in tissues can organize into a broad spectrum of structures according to their function. Drastic changes of organization, such as epithelial-mesenchymal transitions or the formation of spheroidal aggregates, are often associated either to tissue morphogenesis or to cancer progression. Here, we study the organization of cell colonies by means of simulations of self-propelled particles with generic cell-like interactions. Read More

The understanding of the macroscopic phenomenological models of the population growth at a microscopic level is important to predict the population behaviors emerged from the interactions between the individuals. In this work we consider the influence of the cell-cell interaction on the population growth rate $R$ in a tumor system, and show that, in most cases especially small proliferative probabilities, the regulative role of the interaction will be strengthened with the decline of the intrinsic proliferative probabilities. For the high replication rates of an individual and the cooperative interactions, the proliferative probability almost has no effect. Read More

The human body is a complex organism whose gross mechanical properties are enabled by an interconnected musculoskeletal network controlled by the nervous system. The nature of musculoskeletal interconnection facilitates stability, voluntary movement, and robustness to injury. However, a fundamental understanding of this network and its control by neural systems has remained elusive. Read More

Mounting evidence for the role of oxidative stress in the degeneration of articular cartilage after an injurious impact requires our modeling & simulation efforts to temporarily shift from just describing the effect of mechanical stress and inflammation on osteoarthritis (OA). The hypothesis that the injurious impact causes irreversible damage to chondrocyte mitochondria, which in turn increase their production of free radicals, affecting their energy production and their ability to rebuild the extracellular matrix, has to be modeled and the processes quantified in order to further the understanding of OA, its causes, and viable treatment options. The current article presents a calibrated model that captures the damage oxidative stress incurs on the cell viability, ATP production, and cartilage stability in a cartilage explant after a drop-tower impact. Read More

Mathematical models of cardiac electrical excitation are increasingly complex, with multiscale models seeking to represent and bridge physiological behaviours across temporal and spatial scales. The increasing complexity of these models makes it computationally expensive to both evaluate long term (>60 seconds) behaviour and determine sensitivity of model outputs to inputs. This is particularly relevant in models of atrial fibrillation (AF), where individual episodes last from seconds to days, and inter-episode waiting times can be minutes to months. Read More

Understanding active electrolocation in weakly electric fish remains a challenging issue. In this article we propose a mathematical formulation of this problem, in terms of partial differential equations. This allows us to detail two algorithms: one for localizing a target using the multi-frequency aspect of the signal, and antoher one for identifying the shape of this target. Read More

The pathogenesis and progression of many tumors, including hematologic malignancies is highly dependent on enhanced lipogenesis. De novo fatty-acid synthesis permits accelerated proliferation of tumor cells by providing structural components to build the membranes. It may also lead to alterations of physicochemical properties of the formed membranes, which can have an impact on signaling or even increase resistance to drugs in cancer cells. Read More