Effectiveness factor for spatial gradient sensing in living cells

We consider the steady-state pattern of messenger molecules produced in the membrane of a cell perceiving and responding to an extracellular gradient of chemoattractant, which directs cell movement towards the chemoattractant source. Specifically, we analyze the undesirable effect of lateral diffusion in blurring the intracellular messenger profile. The concept of an effectiveness factor, akin to the analysis of reactions in porous catalysts, is applied to the spatial gradient sensing problem, with the distinction that slow, not fast, diffusion is required for effective gradient sensing. Analytical effectiveness factor expressions are derived for ideal geometries and then generalized to arbitrary cell shapes. In the case of mouse fibroblasts responding to gradients of platelet-derived growth factor, we conclude that the cell morphology and orientation with respect to the gradient can dictate whether messenger diffusion obliterates gradient sensing or has very little effect. The analysis outlined here allows the effect of intracellular messenger diffusion on spatial gradient sensing to be quantified for individual cells.     

Halloysite clay nanotube in regenerative medicine for tissue and wound healing

The vital necessity of effective treatment at damaged tissue or wound site has resulted in emerging tissue engineering and regenerative medicine. Tissue engineering has been introduced as an alternative approach for common available therapeutic strategies in the terms of restoring deformed tissue structure and its functionality via the developing of new bio-scaffold. Designed three-dimensional (3D) scaffolds, alone or in combination with bioactive agents, should be able to stimulate and accelerate the development of engineered tissues and provide proper mechanical support during in-vivo implantation and later regeneration process. To cover it up, a series of new bio-structures with higher mechanical strength were designed through the combination of halloysite nanotubes (HNTs) into 3D bio-polymeric networks. HNTs clay mineral with its unique rod-like structure and distinctive chemical surface features, exhibits excellent biocompatibility and biosafety for doping into regenerative scaffolds to enhance their mechanical stiffness and biological performance. In this paper, the ongoing procedures of bone/cartilage tissue engineering and wound healing strategies focusing on the designing of 3D-HNTs bio-composites and their multi-cellular interactions in-vitro and in-vivo preclinical studies are reviewed. Furthermore, the challenges and prospects of 3D-HNTs and HNTs-based functional bio-devices for regenerative medicine are also discussed.     

A protein diffusion model of the sealing effect

Water transport across the arterial endothelium is believed primarily to occur through breaks in the tight junction strands at the cell periphery between neighboring cells. Additional proteins arriving at the tight junction can close these breaks, thereby attenuating this water flux. Motivated by evidence that the diffusion of presynthesized protein from the interior of the cell to and incorporation into the cell border is the mechanism of endothelial tight junctional sealing, we develop a diffusion-limited mathematical model of intercellular gap sealing. A single endothelial cell is represented as a thin, axisymmetric disk, initially containing a uniform distribution of junctional protein that does not interact with the apical or basal cell surfaces. Upon application of a transmural pressure gradient, water flows through the junctional cleft, and tight junction remodeling begins. We assume that proteins at the junction are instantaneously incorporated into its strand, dropping the free protein concentration at the cell periphery to zero. This sets the diffusion of intracellular proteins toward the junction in motion. The solution of this one-dimensional initial value problem provides excellent fits to current and previously published experimental data over a wide variety of conditions. It yields three physically meaningful parameters for each fit, including a protein diffusivity in the cytoplasm that varies little within experimental treatments. Statistical variation of these parameters allows rational comparison of experimental runs and identification of outlier runs.     

Modelling the mechanical properties of yeast cells

An analytical model has been developed to describe the compression of a single yeast cell between parallel flat surfaces. Such cells were considered to be thin walled, liquid filled, spheres. Because yeast cells can be compressed at high deformation rates, time dependent effects such as water loss during compression and visco-elasticity of the cell wall could be and were neglected in the model. As in previously published work, a linear elastic constitutive equation was assumed for the material of the cell walls. However, yeast compression to failure requires large deformations, with high wall strains and associated rotations. New model equations appropriate to such high strains with rotations were therefore developed, based on work-conjugate Kirchhoff stresses and Hencky strains. This is an improvement on the earlier use of infinitesimal strains, and on the alternative of Green strains and 2nd Piola-Kirchhoff stresses. It is shown that the choice of stress and strain definition has a significant influence on model predictions for given wall material properties, and will affect estimates of the wall elastic modulus or other wall material property parameters obtained by fitting experimental data.     

Transport mechanisms and densification during sintering: I. Viscous flow versus vacancy diffusion

Different materials transport mechanisms lead to distinctly different morphological evolution during the sintering of ceramic particles. These behaviors are analyzed using meso-scale, finite-element models based on rigorous formulations of coupled equations for continuum transport and interfacial phenomena. While such two-particle models are simplistic with respect to a real powder compact, they nevertheless provide important mechanistic understanding of the sintering behavior of different systems. Calculations clearly show how viscous flow mechanisms for glassy particles produce simultaneous shrinkage and neck growth due to the global nature of materials transport. In contrast, results for crystalline systems without grain boundaries show that the more localized nature of diffusive transport leads to neck growth with very little densification until late stages of sintering. Surprisingly, surface vacancy diffusion leads to system elongation before densification occurs. Changes caused by the presence of a grain boundary are discussed in a companion paper [Djohari, H., Derby, J.J., 2009. Transport mechanisms and densification during sintering: II. Grain boundaries. Chem. Eng. Sci., in press doi:10.1016/j.ces.2009.05.022].     

Transport mechanisms and densification during sintering: II. Grain boundaries

Finite element, meso-scale models provide a means to probe the mechanistic driving forces for particle evolution during sintering and were applied in a companion paper [Djohari, H., Martínez-Herrera J., Derby, J.J., 2009. Transport mechanisms and densification during sintering: I. Viscous flow versus vacancy diffusion. Chem. Eng. Sci., in press, doi:10.1016/j.ces.2009.05.018.] to compare different behaviors of the sintering of glassy particles by viscous flow and the sintering of idealized crystalline systems without a grain boundary via vacancy diffusion. Here, the effects of a grain boundary are included in the meso-scale model and resultant behavior is compared to prior cases. A grain boundary acts as a sink for vacancies, drawing a flux toward itself and allowing for their accumulation and collapse. The resultant solid-body motion of the particles leads to significant shrinkage at the onset of sintering; neck growth with little shrinkage was observed in systems without a grain boundary. These effects are scaled by the magnitude of the grain boundary diffusivity and the size of the dihedral angle.     

Modelling and optimisation of a transketolase-mediated carbon-carbon bond formation reaction

In this paper, we have integrated process characterisation and reaction kinetic data for a transketolase catalysed carbon-carbon bond formation to build a comprehensive reaction model. Based on the synthesis of erythrulose from β-hydroxypyruvate and glycolaldehyde, the model includes component degradation as a function of time and concentration as well as glycolaldehyde toxicity towards the enzyme. Using the ratio of initial substrate concentration as a process variable, simulations and analysis based on this model allowed process options to be evaluated. The model links bioconversion to upstream fermentation for enzyme production and downstream product purification and this could provide guidelines for process development.     

Computationally‐Efficient Simulation of Transport Phenomena in Fuel Cell Stacks via Electrical and Thermal Decoupling of the Cells

To overcome the prohibitive computational cost associated with detailed mechanistic models for fuel cell stacks, we derive an efficient computational strategy based on thermal and electrical decoupling of cells. The conditions that allow for decoupling are discussed and verified with a non‐isothermal model considering two‐dimensional conservation of mass, momentum, species, energy, charge, and electrochemistry for a 10‐cell proton exchange membrane fuel cell (PEMFC) stack. The derived strategy allows for simulation of large stacks comprising hundreds of cells at a low computational cost and complexity; e.g., for a PEMFC stack comprising 500 cells, the decoupled algorithm takes less than 30 min to solve and requires only 1 GB of random access memory.     

An extracellular stochastic model of early HIV infection and the formulation of optimal treatment policy

The problem of scheduling optimal treatment strategies for patients at the early stage of human immunodeficiency virus (HIV) infection is investigated. Unlike patients with an established HIV infection, complete eradication of the infection is still possible at this stage and treatment can further increase the probability of eradication. However, high dosages of drugs should be avoided, if possible, because of toxic side effects. Stochastic simulation is capable of determining the infection establishment probability at the early infection stage. Consequently, to obtain acceptable treatment strategies, an optimization problem was formulated, employing a stochastic model to predict the response of an average patient to treatment. Optimal treatment strategies for prompt and also a few days latency in treatment initiation were computed. These strategies were compared with constant treatment strategies and were shown to be more beneficial in silico, i.e., they either decreased the infection establishment probability or the dosage of the drugs.     

Cell Creeping and Controlled Migration by Magnetic Carbon Nanotubes

Carbon nanotubes (CNTs) are tubular nanostructures that exhibit magnetic properties due to the metal catalyst impurities entrapped at their extremities during fabrication. When mammalian cells are cultured in a CNT-containing medium, the nanotubes interact with the cells, as a result of which, on exposure to a magnetic field, they are able to move cells towards the magnetic source. In the present paper, we report on a model that describes the dynamics of this mammalian cell movement in a magnetic field consequent on CNT attachment. The model is based on Bell’s theory of unbinding dynamics of receptor-ligand bonds modified and validated by experimental data of the movement dynamics of mammalian cells cultured with nanotubes and exposed to a magnetic field, generated by a permanent magnet, in the vicinity of the cell culture wells. We demonstrate that when the applied magnetic force is below a critical value (about F _c ≈ 10⁻¹¹ N), the cell ‘creeps’ very slowly on the culture dish at a very low velocity (10–20 nm/s) but becomes detached from the substrate when this critical magnetic force is exceeded and then move towards the magnetic source.     

A discussion on transport phenomena and three-way kinetics of monolithic converters

A one-dimensional monolithic catalyst model is used to develop a global heterogeneous reaction mechanism for three-way applications. Separate conservation equations for the gas and the solid phase are coupled by the introduction of transport coefficients. Due to the relevance of transport phenomena on the overall conversion efficiency, the adequacy of the considered correlations for heat and mass transfer coefficients is elucidated, prior to the investigation of chemical kinetics. Resolved Nusselt (Nu) and Sherwood (Sh) number distributions in a monolith channel at steady-state and transient conditions, including catalytic reactions, are compared to local a priori correlations for constant and non-constant boundary conditions at the wall taken from literature. The reaction rate formulations are modified to achieve acceptable agreement with experimental data of palladium-rhodium catalysts for typical operating conditions of automobile applications. The conversion behavior of the lumped parameter model is validated against a wide range of air/fuel ratios and temperatures. Varying feed gas concentrations (λ-sweep) and light-off experiments for stoichiometric and lean inlet conditions as well as a typical operating condition for secondary air injection are considered. The reaction mechanism is then used to predict the conversion performance of an aged catalyst. Instead of calibrating the complete kinetic parameter set, the adaption to the aged system is achieved by a physically meaningful reduction of the available reactive surface area only. Finally, the simulation results of an FTP75 drive cycle are compared to experimental data without further tuning.     

Modeling and Parametric Study of a Single Solid Oxide Fuel Cell by Finite Element Method

A 2D isothermal axisymmetric model of an anode‐supported solid oxide fuel cell has been developed. The model, which is based on finite element approach, comprises electronic and ionic charge balance, Butler–Volmer charge transfer kinetic, flow distribution and gas phase mass balance in both channels and porous electrodes. The model has been validated using available experimental data coming from a single anode‐supported cell comprising Ni–YSZ/YSZ/LSM–YSZ as anode, electrolyte and cathode, respectively. Hydrogen and steam were used as fuel inlet and air as an oxidant. The validation has been carried out at 1 atm, 1,500 ml min^–1 air flow rate and three different operating conditions of temperature and fuel flow rate: 1,073 K and 400 ml min^–1, 1,073 K and 500 ml min^–1, and 1,003 K and 400 ml min^–1. The polarization and power density versus current density curves show a good agreement with the experimental data. A parametric analysis has been carried out to highlight which parameters have main effect on the overall cell performance as measured by polarization curve, especially focusing on the influence of two geometrical characteristics, temperature and some effective material properties.     

A systematic framework for the design,simulation and optimization of personalized healthcare: Making and healing blood

We review the key building blocks of a design framework for modeling and optimizing biomedical systems under development in the Biological Systems Engineering Laboratory and the Centre for Process Systems Engineering at Imperial College. The framework features the following components: (i) in vitro environment, where model parameters can be obtained and new setups can be tested; (ii) in silico environment, including a simulation module for representing relevant physical or biological processes, and an optimization module, for calculating improved in vitro or in vivo outcomes; (iii) in vivo environment, from which organ and patient-specific parameters are collected and which can also implement personalized suggestions for improved outcomes. Two applications in the area of healthy and diseased blood are thoroughly discussed to exemplify the framework's characteristics. We discuss progress in the different areas and the way in which they are connected and finally propose a hybrid in vitro/in silico/in vivo platform.     

野生型着丝粒蛋白-E基因沉默对人结肠癌HCT116细胞增殖、凋亡、迁移和侵袭能力的影响

目的利用RNA干扰技术下调野生型着丝粒蛋白E(Wild type centromere protein E,CENP-EWT)基因的表达,观察CENP-EWT基因沉默对结肠癌HCT116细胞增殖、凋亡、迁移和侵袭能力的影响。方法将HCT116细胞分为空白对照组、空载体转染组和CENP-EWT shRNA转染组,转染48 h后,采用巢式PCR检测细胞中CENP-EWT基因mRNA的转录水平;MTT法检测细胞的增殖活力;Hoechst法检测细胞的凋亡比例;Transwell小室试验检测细胞的迁移和侵袭能力。结果与空白对照组和空载体转染组相比,CENP-EWT shRNA转染组可有效抑制CENP-EWT基因的转录水平(P<0.05);CENP-EWT shRNA转染组细胞的增殖活力明显下降(P<0.05);细胞凋亡比例明显增加(P<0.01),细胞的迁移和侵袭能力明显增强(P<0.01)。结论 CENP-EWT基因沉默能够抑制人结肠癌HCT116细胞增殖,诱导细胞凋亡,但同时能增强细胞的迁移和侵袭能力。