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A modular minimal cell model: Purine and pyrimidine transport and metabolism

Castellanos, M.; Wilson, D. B.; Shuler, M. L.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
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446.21613%
A more complete understanding of the relationship of cell physiology to genomic structure is desirable. Because of the intrinsic complexity of biological organisms, only the simplest cells will allow complete definition of all components and their interactions. The theoretical and experimental construction of a minimal cell has been suggested as a tool to develop such an understanding. Our ultimate goal is to convert a “coarse-grain” lumped parameter computer model of Escherichia coli into a genetically and chemically detailed model of a “minimal cell.” The base E. coli model has been converted into a generalized model of a heterotrophic bacterium. This coarse-grain minimal cell model is functionally complete, with growth rate, composition, division, and changes in cell morphology as natural outputs from dynamic simulations where only the initial composition of the cell and of the medium are specified. A coarse-grain model uses pseudochemical species (or modules) that are aggregates of distinct chemical species that share similar chemistry and metabolic dynamics. This model provides a framework in which these modules can be “delumped” into chemical and genetic descriptions while maintaining connectivity to all other functional elements. Here we demonstrate that a detailed description of nucleotide precursors transport and metabolism is successfully integrated into the whole-cell model. This nucleotide submodel requires fewer (12) genes than other theoretical predictions in minimal cells. The demonstration of modularity suggests the possibility of developing modules in parallel and recombining them into a fully functional chemically and genetically detailed model of a prokaryote cell.

Action potential conduction between a ventricular cell model and an isolated ventricular cell.

Wilders, R; Kumar, R; Joyner, R W; Jongsma, H J; Verheijck, E E; Golod, D; van Ginneken, A C; Goolsby, W N
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1996 EN
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449.2664%
We used the Luo and Rudy (LR) mathematical model of the guinea pig ventricular cell coupled to experimentally recorded guinea pig ventricular cells to investigate the effects of geometrical asymmetry on action potential propagation. The overall correspondence of the LR cell model with the recorded real cell action potentials was quite good, and the strength-duration curves for the real cells and for the LR model cell were in general correspondence. The experimental protocol allowed us to modify the effective size of either the simulation model or the real cell. 1) When we normalized real cell size to LR model cell size, required conductance for propagation between model cell and real cell was greater than that found for conduction between two LR model cells (5.4 nS), with a greater disparity when we stimulated the LR model cell (8.3 +/- 0.6 nS) than when we stimulated the real cell (7.0 +/- 0.2 nS). 2) Electrical loading of the action potential waveform was greater for real cell than for LR model cell even when real cell size was normalized to be equal to that of LR model cell. 3) When the size of the follower cell was doubled, required conductance for propagation was dramatically increased; but this increase was greatest for conduction from real cell to LR model cell...

Gene expression signatures of a fibroblastoid preosteoblast and cuboidal osteoblast cell model compared to the MLO-Y4 osteocyte cell model☆

Yang, Wuchen; Harris, Marie A.; Heinrich, Jelica Gluhak; Guo, Dayong; Bonewald, Lynda F.; Harris, Stephen E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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442.6793%
In the osteoblast 2T3 cell model, 326 genes significantly increase in expression as subconfluent fibroblastic 2T3 cells become confluent and cuboidal. This gene set includes BMP2/4, Dlx2/5, Runx2, Osterix and Lrp5, as well as TGFβ regulated genes. Both activated or total nuclear Smad158 and Smad2 levels increase as they become confluent, and β-catenin protein expression increases as 2T3 cells become confluent, reflecting a set of genes involved in early preosteoblast to osteoblast commitment, as observed in vitro and in vivo. Gene Set Enrichment Analysis (GSEA) demonstrated that this 326 dataset is very similar to several early osteoblast geneset signatures. The MLO-Y4 cell model is a well-known in vitro osteocyte model. The MLO-Y4 expression pattern was directly compared with the 2T3 osteoblast cell model. 181 genes that are highly expressed in MLO-Y4 osteocytes compared to osteoblasts were identified. Very few genes expressed in MLO-Y4 cells are found in osteocytes directly isolate from bone, suggesting that osteocyte specific gene programs most likely require the osteocytes to be embedded in the proper mineralized matrix. The MLO-Y4 dataset includes few established in vivo osteocyte markers, but does include several transcription factors such as Vitamin D receptor...

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
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443.39668%
Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine...

Isolation and Characterization of a Primary Proximal Tubular Epithelial Cell Model from Human Kidney by CD10/CD13 Double Labeling

Van der Hauwaert, Cynthia; Savary, Grégoire; Gnemmi, Viviane; Glowacki, François; Pottier, Nicolas; Bouillez, Audrey; Maboudou, Patrice; Zini, Laurent; Leroy, Xavier; Cauffiez, Christelle; Perrais, Michaël; Aubert, Sébastien
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 14/06/2013 EN
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441.9968%
Renal proximal tubular epithelial cells play a central role in renal physiology and are among the cell types most sensitive to ischemia and xenobiotic nephrotoxicity. In order to investigate the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries, a stable and well-characterized primary culture model of proximal tubular cells is required. An existing model of proximal tubular cells is hampered by the cellular heterogeneity of kidney; a method based on cell sorting for specific markers must therefore be developed. In this study, we present a primary culture model based on the mechanical and enzymatic dissociation of healthy tissue obtained from nephrectomy specimens. Renal epithelial cells were sorted using co-labeling for CD10 and CD13, two renal proximal tubular epithelial markers, by flow cytometry. Their purity, phenotypic stability and functional properties were evaluated over several passages. Our results demonstrate that CD10/CD13 double-positive cells constitute a pure, functional and stable proximal tubular epithelial cell population that displays proximal tubule markers and epithelial characteristics over the long term, whereas cells positive for either CD10 or CD13 alone appear to be heterogeneous. In conclusion...

Cell-type-specific modelling of intracellular calcium signalling: a urothelial cell model

Appleby, Peter A.; Shabir, Saqib; Southgate, Jennifer; Walker, Dawn
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
Publicado em 06/09/2013 EN
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444.87965%
Calcium signalling plays a central role in regulating a wide variety of cell processes. A number of calcium signalling models exist in the literature that are capable of reproducing a variety of experimentally observed calcium transients. These models have been used to examine in more detail the mechanisms underlying calcium transients, but very rarely has a model been directly linked to a particular cell type and experimentally verified. It is important to show that this can be achieved within the general theoretical framework adopted by these models. Here, we develop a framework designed specifically for modelling cytosolic calcium transients in urothelial cells. Where possible, we draw upon existing calcium signalling models, integrating descriptions of components known to be important in this cell type from a number of studies in the literature. We then add descriptions of several additional pathways that play a specific role in urothelial cell signalling, including an explicit ionic influx term and an active pumping mechanism that drives the cytosolic calcium concentration to a target equilibrium. The resulting one-pool model of endoplasmic reticulum (ER)-dependent calcium signalling relates the cytosolic, extracellular and ER calcium concentrations and can generate a wide range of calcium transients...

An In-Depth Comparison of Latent HIV-1 Reactivation in Multiple Cell Model Systems and Resting CD4+ T Cells from Aviremic Patients

Spina, Celsa A.; Anderson, Jenny; Archin, Nancie M.; Bosque, Alberto; Chan, Jonathan; Famiglietti, Marylinda; Greene, Warner C.; Kashuba, Angela; Lewin, Sharon R.; Margolis, David M.; Mau, Matthew; Ruelas, Debbie; Saleh, Suha; Shirakawa, Kotaro; Siliciano
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
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444.7049%
The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for “anti-latency” therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models...

Getting it right before transplantation: example of a stem cell model with regenerative potential for the CNS

Viero, Cedric; Forostyak, Oksana; Sykova, Eva; Dayanithi, Govindan
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 13/08/2014 EN
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537.3899%
The burden of neurodegenerative disorders in an aging population has become a challenge for the modern world. While the biomarkers available and the methods of diagnosis have improved to detect the onset of these diseases at early stages, the question of adapted and efficient therapies is still a major issue. The prospect of replacing the loss of functional neural cells remains an attractive but still audacious approach. A huge progress has been made in the generation of neurons derived from human stem cell lines and transplantation assays are tested in animals for a wide range of pathologies of the central nervous system. Here we take one step back and examine neuronal differentiation and the characterization of neural progenitors derived from human embryonic stem cells. We gather results from our previous studies and present a cell model that was successfully used in functional analyses and engraftment experiments. These neuronal precursors exhibit spontaneous and evoked activity, indicating that their electrophysiological and calcium handling properties are similar to those of matured neurons. Hence this summarized information will serve as a basis to design better stem cell-based therapies to improve neural regeneration.

Bayesian Sensitivity Analysis of a Cardiac Cell Model Using a Gaussian Process Emulator

Chang, Eugene T Y; Strong, Mark; Clayton, Richard H
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 26/06/2015 EN
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442.93055%
Models of electrical activity in cardiac cells have become important research tools as they can provide a quantitative description of detailed and integrative physiology. However, cardiac cell models have many parameters, and how uncertainties in these parameters affect the model output is difficult to assess without undertaking large numbers of model runs. In this study we show that a surrogate statistical model of a cardiac cell model (the Luo-Rudy 1991 model) can be built using Gaussian process (GP) emulators. Using this approach we examined how eight outputs describing the action potential shape and action potential duration restitution depend on six inputs, which we selected to be the maximum conductances in the Luo-Rudy 1991 model. We found that the GP emulators could be fitted to a small number of model runs, and behaved as would be expected based on the underlying physiology that the model represents. We have shown that an emulator approach is a powerful tool for uncertainty and sensitivity analysis in cardiac cell models.

Monte Carlo investigation of the increased radiation deposition due to gold nanoparticles using kilovoltage and megavoltage photons in a 3D randomized cell model

Douglass, M.; Bezak, E.; Penfold, S.
Fonte: Amer AssocPhysicists Amer Inst Physics Publicador: Amer AssocPhysicists Amer Inst Physics
Tipo: Artigo de Revista Científica
Publicado em //2013 EN
Relevância na Pesquisa
544.3027%
PURPOSE: Investigation of increased radiation dose deposition due to gold nanoparticles (GNPs) using a 3D computational cell model during x-ray radiotherapy. METHODS: Two GNP simulation scenarios were set up in Geant4; a single 400 nm diameter gold cluster randomly positioned in the cytoplasm and a 300 nm gold layer around the nucleus of the cell. Using an 80 kVp photon beam, the effect of GNP on the dose deposition in five modeled regions of the cell including cytoplasm, membrane, and nucleus was simulated. Two Geant4 physics lists were tested: the default Livermore and custom built Livermore/DNA hybrid physics list. 106 particles were simulated at 840 cells in the simulation. Each cell was randomly placed with random orientation and a diameter varying between 9 and 13 μm. A mathematical algorithm was used to ensure that none of the 840 cells overlapped. The energy dependence of the GNP physical dose enhancement effect was calculated by simulating the dose deposition in the cells with two energy spectra of 80 kVp and 6 MV. The contribution from Auger electrons was investigated by comparing the two GNP simulation scenarios while activating and deactivating atomic de-excitation processes in Geant4. RESULTS: The physical dose enhancement ratio (DER) of GNP was calculated using the Monte Carlo model. The model has demonstrated that the DER depends on the amount of gold and the position of the gold cluster within the cell. Individual cell regions experienced statistically significant (p < 0.05) change in absorbed dose (DER between 1 and 10) depending on the type of gold geometry used. The DER resulting from gold clusters attached to the cell nucleus had the more significant effect of the two cases (DER ∼ 55). The DER value calculated at 6 MV was shown to be at least an order of magnitude smaller than the DER values calculated for the 80 kVp spectrum. Based on simulations...

Identifizierung Apoptose-induzierender Alkaloide der Pflanze Chelidonium Majus und des Präparates Ukrain in einem Lymphom-Modell; Identification of apoptosis-inducing alkaloids of Chelidonium Majus and the drug preparation Ukrain in a lymphoma model

Habermehl, Daniel Frédéric
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
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441.9968%
Für das Krebsmedikament Ukrain, von Herstellerseite als semisynthetisches Derivat aus dem Schöllkraut-Alkaloid Chelidonin und dem Alkylanz Thiotepa beschrieben, wurde eine selektive zytotoxische Wirkung auf humane Tumor-Zelllinien in vitro beschrieben. Auch einige klinische Studien berichten über eine positive Wirkung des Präparates in der onkologischen Therapie. Allerdings werden Wirksamkeit und Zusammensetzung des Präparates kontrovers diskutiert. Ziel der vorliegenden Arbeit war die Analyse der Bedeutung der Apoptose-Induktion für die potentielle anti-neoplastische Aktivität von Ukrain sowie der zugrunde liegenden molekularen Mechanismen der Zelltodinduktion. Weiterhin sollten in Zusammenarbeit mit dem Institut für Klinische Pharmakologie des Universitätsklinikums Tübingen die chemischen Bestandteile des Präparates analysiert werden. Die Induktion der Apoptose wurde in einem Jurkat T-Lymphom-Modell mit Hilfe von Fluoreszenz-Mikroskopie (Chromatin-Kondensierung und nukleäre Fragmentierung), Durchflusszytometrie (Änderung der Zellmorphologie, Depolarisation des mitochondrialen Membranpotentials, Caspasen-Aktivierung) und Western-Blot-Analysen (Caspasen-Aktivierung, PARP-Spaltung) untersucht. Die chemische Analyse von Ukrain sowie eines nativen Schöllkrautextrakts erfolgte mittels Massenspektrometrie und LC-MS-Kopplung (Datenmaterial Dr. Bernd Kammerer...

Establishment and Characterization of a Human in vitro Cell Model for Parkinson’s Disease; Etablierung und Charakterisierung eines iPS-Zell-basierten Zellmodells für die Parkinson Erkrankung

Schmid, Benjamin
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
EN
Relevância na Pesquisa
446.49645%
A major obstacle on the way to understand the molecular pathogenesis of Parkinson’s disease (PD) and to develop disease-modifying treatments is the lack of suitable model systems that capture the relevant molecular events leading to human disease and are also accessible to compound screening. This cumulative thesis describes the establishment of two novel cellular model systems based on induced pluripotent stem cells (iPSCs): the generation of an in vitro cell model for PD consisting of post-mitotic midbrain dopaminergic neurons, and the derivation and expansion of human neural progenitors for neurodegenerative disease modelling. For the first model, fibroblasts from two female PD patients with a G2019S mutation in the LRRK2 gene and four age- and sex-matched controls were reprogrammed into iPSCs. This was achieved through infection with the four factors Oct-4, Sox-2, Klf-4 and c-myc published by Shinia Yamanaka and isogenic gene-controls were generated using zinc finger nucleases (ZFNs) that differed from the original iPSCs only in the DNA base responsible for the G2019S mutation. Finally, one gene-corrected wild-type-LRRK2 line was obtained for each G2019S-LRRK2 line. In addition, an isogenic G2019S-LRRK2 line was generated for the wild-type-LRRK2 control C4...

Multiphysics model of a cardiac myocyte: A voltage-clamp study

Krishna, Abhilash
Fonte: Universidade Rice Publicador: Universidade Rice
ENG
Relevância na Pesquisa
442.1431%
We develop a composite multiphysics model of excitation-contraction coupling for a rat ventricular myocyte under voltage clamp (VC) conditions to: (1) probe mechanisms underlying the response to Ca2+-perturbation; (2) investigate the factors influencing its electromechanical response; and (3) examine its rate-dependent behavior (particularly the force-frequency response (FFR)). Motivation for the study was to pinpoint key control variables influencing calcium-induced calcium-release (CICR) and examine its role in the context of a physiological control system regulating cytosolic Ca2+ concentration and hence the cardiac contractile response. Our cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments. The model incorporates frequency-dependent calmodulin (CaM) mediated spatially heterogenous interaction of calcineurin (CaN) and Ca2+/calmodulin-dependent protein kinase-II (CaMKII) with their principal targets and accounts for rate-dependent, cyclic adenosine monophosphate (cAMP)-mediated up-regulation. We also incorporate a biophysical model for cardiac contractile mechanics to study the factors influencing force response. The model reproduces measured VC data published by several laboratories...

General electrokinetic model for concentrated suspensions in aqueous electrolyte solutions: electrophoretic mobility and electrical conductivity in static electric fields

Carrique Fern??ndez, F??lix; Ruiz-Reina, Emilio; Roa, Rafael; Arroyo Rold??n, Francisco J.; Delgado, ??ngel V.
Fonte: Elsevier Publicador: Elsevier
Tipo: Pré-impressão
ENG
Relevância na Pesquisa
542.20203%
In recent years different electrokinetic cell models for concentrated colloidal suspensions in aqueous electrolyte solutions have been developed. They share some of its premises with the standard electrokinetic model for dilute colloidal suspensions, in particular, neglecting both the specific role of the so-called added counterions (i.e., those released by the particles to the solution as they get charged), and the realistic chemistry of the aqueous solution on such electrokinetic phenomena as electrophoresis and electrical conductivity. These assumptions, while having been accepted for dilute conditions (volume fractions of solids well below 1 %, say), are now questioned when dealing with concentrated suspensions. In this work, we present a general electrokinetic cell model for such kind of systems, including the mentioned effects, and we also carry out a comparative study with the standard treatment (the standard solution only contains the ions that one purposely adds, without ionic contributions from particle charging or water chemistry). We also consider an intermediate model that neglects the realistic aqueous chemistry of the solution but accounts for the correct contribution of the added counterions. The results show the limits of applicability of the classical assumptions and allow one to better understand the relative role of the added counterions and ions stemming from the electrolyte in a realistic aqueous solution...

A micro-mechanics model of dentin mechanical properties

Qin, Qing Hua; Swain, Michael Vincent
Fonte: Pergamon-Elsevier Ltd Publicador: Pergamon-Elsevier Ltd
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
539.5372%
Application of a micro-mechanics cell model to dentin composites for determination of their effective mechanical properties is discussed in this paper. The dilute micro-mechanics model for fibre-reinforced composites is utilized and the corresponding cell

Mechanism for collective cell alignment in Myxococcus xanthus bacteria

Balagam, Rajesh; Igoshin, Oleg A.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
444.3027%
Myxococcus xanthus cells self-organize into aligned groups, clusters, at various stages of their lifecycle. Formation of these clusters is crucial for the complex dynamic multi-cellular behavior of these bacteria. However, the mechanism underlying the cell alignment and clustering is not fully understood. Motivated by studies of clustering in self-propelled rods, we hypothesized that M. xanthus cells can align and form clusters through pure mechanical interactions among cells and between cells and substrate. We test this hypothesis using an agent-based simulation framework in which each agent is based on the biophysical model of an individual M. xanthus cell. We show that model agents, under realistic cell flexibility values, can align and form cell clusters but only when periodic reversals of cell directions are suppressed. However, by extending our model to introduce the observed ability of cells to deposit and follow slime trails, we show that effective trail-following leads to clusters in reversing cells. Furthermore, we conclude that mechanical cell alignment combined with slime-trail-following is sufficient to explain the distinct clustering behaviors observed for wild-type and non-reversing M. xanthus mutants in recent experiments. Our results are robust to variation in model parameters...

Poisson-Boltzmann Theory of Charged Colloids: Limits of the Cell Model for Salty Suspensions

Denton, Alan R.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 24/04/2010
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446.22977%
Thermodynamic properties of charge-stabilised colloidal suspensions are commonly modeled by implementing the mean-field Poisson-Boltzmann (PB) theory within a cell model. This approach models a bulk system by a single macroion, together with counterions and salt ions, confined to a symmetrically shaped, electroneutral cell. While easing solution of the nonlinear PB equation, the cell model neglects microion-induced correlations between macroions, precluding modeling of macroion ordering phenomena. An alternative approach, avoiding artificial constraints of cell geometry, maps a macroion-microion mixture onto a one-component model of pseudo-macroions governed by effective interactions. In practice, effective-interaction models are usually based on linear screening approximations, which can accurately describe nonlinear screening only by incorporating an effective (renormalized) macroion charge. Combining charge renormalization and linearized PB theories, in both the cell model and an effective-interaction (cell-free) model, we compute osmotic pressures of highly charged colloids and monovalent microions over a range of concentrations. By comparing predictions with primitive model simulation data for salt-free suspensions, and with predictions of nonlinear PB theory for salty suspensions...

Multicellular Tumor Spheroid in an off-lattice Voronoi/Delaunay cell model

Schaller, Gernot; Meyer-Hermann, Michael
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
442.7361%
We study multicellular tumor spheroids by introducing a new three-dimensional agent-based Voronoi/Delaunay hybrid model. In this model, the cell shape varies from spherical in thin solution to convex polyhedral in dense tissues. The next neighbors of the cells are provided by a weighted Delaunay triangulation with in average linear computational complexity. The cellular interactions include direct elastic forces and cell-cell as well as cell-matrix adhesion. The spatiotemporal distribution of two nutrients -- oxygen and glucose -- is described by reaction-diffusion equations. Viable cells consume the nutrients, which are converted into biomass by increasing the cell size during G_1 phase. We test hypotheses on the functional dependence of the uptake rates and use the computer simulation to find suitable mechanisms for induction of necrosis. This is done by comparing the outcome with experimental growth curves, where the best fit leads to an unexpected ratio of oxygen and glucose uptake rates. The model relies on physical quantities and can easily be generalized towards tissues involving different cell types. In addition, it provides many features that can be directly compared with the experiment.; Comment: 38 pages, 10 figures, referees suggestions included

The Myogenic Response in Isolated Rat Cerebrovascular Arteries: Smooth Muscle Cell Model

Yang, Jin; Clark Jr., John W.; Bryan, Robert M.; Robertson, Claudia S.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 26/03/2013
Relevância na Pesquisa
545.90508%
Previous models of the cerebrovascular smooth muscle cell have not addressed the interaction between the electrical, chemical and mechanical components of cell function during the development of active tension. These models are primarily electrical, biochemical or mechanical in their orientation, and do not permit a full exploration of how the smooth muscle responds to electrical or mechanical forcing. To address this issue, we have developed a new model that consists of two major components: electrochemical and chemomechanical subsystems of the cell. Included in the electrochemical model are models of the electrophysiological behavior of the cell membrane, fluid compartments, Ca2+ release and uptake by the sarcoplasmic reticulum, and cytosolic Ca2+ buffering, particularly by calmodulin. With this subsystem model, we can study the mechanics of the production of intracellular Ca2+ transient in response to membrane voltage clamp pulses. The chemomechanical model includes models of: (a) the chemical kinetics of myosin phosphorylation, and the formation of phosphorylated myosin cross-bridges with actin, as well as, attached latch-type cross-bridges; and (b) a model of force generation and mechanical coupling to the contractile filaments and their attachments to protein structures and the skeletal framework of the cell. The two subsystem models are tested independently and compared with data. Likewise...

Bayesian Statistical Models of Cell-Cycle Progression at Single-Cell and Population Levels

Mayhew, Michael Benjamin
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Tese de Doutorado
Publicado em //2014
Relevância na Pesquisa
447.32188%

Cell division is a biological process fundamental to all life. One aspect of the process that is still under investigation is whether or not cells in a lineage are correlated in their cell-cycle progression. Data on cell-cycle progression is typically acquired either in lineages of single cells or in synchronized cell populations, and each source of data offers complementary information on cell division. To formally assess dependence in cell-cycle progression, I develop a hierarchical statistical model of single-cell measurements and extend a previously proposed model of population cell division in the budding yeast, Saccharomyces cerevisiae. Both models capture correlation and cell-to-cell heterogeneity in cell-cycle progression, and parameter inference is carried out in a fully Bayesian manner. The single-cell model is fit to three published time-lapse microscopy datasets and the population-based model is fit to simulated data for which the true model is known. Based on posterior inferences and formal model comparisons, the single-cell analysis demonstrates that budding yeast mother and daughter cells do not appear to correlate in their cell-cycle progression in two of the three experimental settings. In contrast...