Kinetic Monte Carlo and Cellular Particle Dynamics Simulations of Multicellular Systems

Computer modeling of multicellular systems has been a valuable tool for interpreting and guiding in vitro experiments relevant to embryonic morphogenesis, tumor growth, angiogenesis and, lately, structure formation following the printing of cell aggregates as bioink particles. Computer simulations based on Metropolis Monte Carlo (MMC) algorithms were successful in explaining and predicting the resulting stationary structures (corresponding to the lowest adhesion energy state). Here we present two alternatives to the MMC approach for modeling cellular motion and self-assembly: (1) a kinetic Monte Carlo (KMC), and (2) a cellular particle dynamics (CPD) method. Unlike MMC, both KMC and CPD methods are capable of simulating the dynamics of the cellular system in real time. In the KMC approach a transition rate is associated with possible rearrangements of the cellular system, and the corresponding time evolution is expressed in terms of these rates. In the CPD approach cells are modeled as interacting cellular particles (CPs) and the time evolution of the multicellular system is determined by integrating the equations of motion of all CPs. The KMC and CPD methods are tested and compared by simulating two experimentally well known phenomena: (1) cell-sorting within an aggregate formed by two types of cells with different adhesivities, and (2) fusion of two spherical aggregates of living cells.Comment: 11 pages, 7 figures; submitted to Phys Rev

Aspiration of biological viscoelastic drops

Spherical cellular aggregates are in vitro systems to study the physical and biophysical properties of tissues. We present a novel approach to characterize the mechanical properties of cellular aggregates using micropipette aspiration technique. We observe an aspiration in two distinct regimes, a fast elastic deformation followed by a viscous flow. We develop a model based on this viscoelastic behavior to deduce the surface tension, viscosity, and elastic modulus. A major result is the increase of the surface tension with the applied force, interpreted as an effect of cellular mechanosensing.Comment: 4 pages, 4 figures

Exponential Distribution of Locomotion Activity in Cell Cultures

In vitro velocities of several cell types have been measured using computer controlled video microscopy, which allowed to record the cells' trajectories over several days. On the basis of our large data sets we show that the locomotion activity displays a universal exponential distribution. Thus, motion resulting from complex cellular processes can be well described by an unexpected, but very simple distribution function. A simple phenomenological model based on the interaction of various cellular processes and finite ATP production rate is proposed to explain these experimental results.Comment: 4 pages, 3 figure

Mechanical Stress Inference for Two Dimensional Cell Arrays

Many morphogenetic processes involve mechanical rearrangement of epithelial tissues that is driven by precisely regulated cytoskeletal forces and cell adhesion. The mechanical state of the cell and intercellular adhesion are not only the targets of regulation, but are themselves likely signals that coordinate developmental process. Yet, because it is difficult to directly measure mechanical stress {\it in vivo} on sub-cellular scale, little is understood about the role of mechanics of development. Here we present an alternative approach which takes advantage of the recent progress in live imaging of morphogenetic processes and uses computational analysis of high resolution images of epithelial tissues to infer relative magnitude of forces acting within and between cells. We model intracellular stress in terms of bulk pressure and interfacial tension, allowing these parameters to vary from cell to cell and from interface to interface. Assuming that epithelial cell layers are close to mechanical equilibrium, we use the observed geometry of the two dimensional cell array to infer interfacial tensions and intracellular pressures. Here we present the mathematical formulation of the proposed Mechanical Inverse method and apply it to the analysis of epithelial cell layers observed at the onset of ventral furrow formation in the {\it Drosophila} embryo and in the process of hair-cell determination in the avian cochlea. The analysis reveals mechanical anisotropy in the former process and mechanical heterogeneity, correlated with cell differentiation, in the latter process. The method opens a way for quantitative and detailed experimental tests of models of cell and tissue mechanics

Homeostatic competition drives tumor growth and metastasis nucleation

We propose a mechanism for tumor growth emphasizing the role of homeostatic regulation and tissue stability. We show that competition between surface and bulk effects leads to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property can qualitatively explain the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. In addition, it potentially explains the observed preferential growth of metastases on tissue surfaces and membranes such as the pleural and peritoneal layers, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889 and yields realistic values for metastatic inefficiency. We propose a number of key experiments to test these concepts. The homeostatic pressure as introduced in this work could constitute a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.Comment: 13 pages, 11 figures, to be published in the HFSP Journa

Verifying a questionnaire diagnosis of asthma in children using health claims data

<p>Abstract</p> <p>Background</p> <p>Childhood asthma prevalence is widely measured by parental proxy report of physician-diagnosed asthma in questionnaires. Our objective was to validate this measure in a North American population.</p> <p>Methods</p> <p>The 2884 study participants were a subsample of 5619 school children aged 5 to 9 years from 231 schools participating in the Toronto Child Health Evaluation Questionnaire study in 2006. We compared agreement between "questionnaire diagnosis" and a previously validated "health claims data diagnosis". Sensitivity, specificity and kappa were calculated for the questionnaire diagnosis using the health claims diagnosis as the reference standard.</p> <p>Results</p> <p>Prevalence of asthma was 15.7% by questionnaire and 21.4% by health claims data. Questionnaire diagnosis was insensitive (59.0%) but specific (95.9%) for asthma. When children with asthma-related symptoms were excluded, the sensitivity increased (83.6%), and specificity remained high (93.6%).</p> <p>Conclusions</p> <p>Our results show that parental report of asthma by questionnaire has low sensitivity but high specificity as an asthma prevalence measure. In addition, children with "asthma-related symptoms" may represent a large fraction of under-diagnosed asthma and they should be excluded from the inception cohort for risk factor studies.</p

Do Questions Reflecting Indoor Air Pollutant Exposure from a Questionnaire Predict Direct Measure of Exposure in Owner-Occupied Houses?

Home characteristic questions are used in epidemiological studies and clinical settings to assess potentially harmful exposures in the home. The objective of this study was to determine whether questionnaire-reported home characteristics can predict directly measured pollutants. Sixty home inspections were conducted on a subsample of the 2006 population-based Toronto Child Health Evaluation Questionnaire. Indoor/outdoor air and settled dust samples were analyzed. Mean Fel d 1 was higher (p < 0.0001) in homes with a cat (450.58 μg/g) versus without (22.28 μg/g). Mean indoor NO2 was higher (p = 0.003) in homes with gas stoves (14.98 ppb) versus without (8.31 ppb). Self-reported musty odours predicted higher glucan levels (10554.37 μg/g versus 6308.58 μg/g, p = 0.0077). Der f 1 was predicted by the home’s age, but not by reports of carpets, and was higher in homes with mean relative humidity > 50% (61.30 μg/g, versus 6.24 μg/g, p = 0.002). Self-reported presence of a cat, a gas stove, musty odours, mice, and the home’s age and indoor relative humidity over 50% predicted measured indoor levels of cat allergens, NO2, fungal glucan, mouse allergens and dust mite allergens, respectively. These results are helpful for understanding the significance of indoor exposures ascertained by self-reporting in large epidemiological studies and also in the clinical setting

A statistical approach to estimating the strength of cell-cell interactions under the differential adhesion hypothesis

International audienceBACKGROUND: The Differential Adhesion Hypothesis (DAH) is a theory of the organization of cells within a tissue which has been validated by several biological experiments and tested against several alternative computational models. RESULTS: In this study, a statistical approach was developed for the estimation of the strength of adhesion, incorporating earlier discrete lattice models into a continuous marked point process framework. This framework allows to describe an ergodic Markov Chain Monte Carlo algorithm that can simulate the model and reproduce empirical biological patterns. The estimation procedure, based on a pseudo-likelihood approximation, is validated with simulations, and a brief application to medulloblastoma stained by beta-catenin markers is given. CONCLUSION: Our model includes the strength of cell-cell adhesion as a statistical parameter. The estimation procedure for this parameter is consistent with experimental data and would be useful for high-throughput cancer studies

Studying the emergence of invasiveness in tumours using game theory

Tumour cells have to acquire a number of capabilities if a neoplasm is to become a cancer. One of these key capabilities is increased motility which is needed for invasion of other tissues and metastasis. This paper presents a qualitative mathematical model based on game theory and computer simulations using cellular automata. With this model we study the circumstances under which mutations that confer increased motility to cells can spread through a tumour made of rapidly proliferating cells. The analysis suggests therapies that could help prevent the progression towards malignancy and invasiveness of benign tumours

Single-spin readout for buried dopant semiconductor qubits

In the design of quantum computer architectures that take advantage of the long coherence times of dopant nuclear and electron spins in the solid-state, single-spin detection for readout remains a crucial unsolved problem. Schemes based on adiabatically induced spin-dependent electron tunnelling between individual donor atoms, detected using a single electron transistor (SET) as an ultra-sensitive electrometer, are thought to be problematic because of the low ionisaton energy of the final D- state. In this paper we analyse the adiabatic scheme in detail. We find that despite significant stabilization due to the presence of the D+, the field strengths required for the transition lead to a shortened dwell-time placing severe constraints on the SET measurement time. We therefore investigate a new method based on resonant electron transfer, which operates with much reduced field strengths. Various issues in the implementation of this method are also discussed.Comment: 12 pages, 5 figures, 1 tabl