Two-Dimensional Kinetics Of Beta(2)-Integrin And Icam-1 Bindings Between Neutrophils And Melanoma Cells In A Shear Flow

Cell adhesion, mediated by specific receptor-ligand interactions, plays an important role in biological processes such as tumor metastasis and inflammatory cascade. For example, interactions between beta(2)-integrin ( lymphocyte function-associated antigen-1 and/or Mac-1) on polymorphonuclear neutrophils (PMNs) and ICAM-1 on melanoma cells initiate the bindings of melanoma cells to PMNs within the tumor microenvironment in blood flow, which in turn activate PMN-melanoma cell aggregation in a near-wall region of the vascular endothelium, therefore enhancing subsequent extravasation of melanoma cells in the microcirculations. Kinetics of integrin-ligand bindings in a shear flow is the determinant of such a process, which has not been well understood. In the present study, interactions of PMNs with WM9 melanoma cells were investigated to quantify the kinetics of beta(2)-integrin and ICAM-1 bindings using a cone-plate viscometer that generates a linear shear flow combined with a two-color flow cytometry technique. Aggregation fractions exhibited a transition phase where it first increased before 60 s and then decreased with shear durations. Melanoma-PMN aggregation was also found to be inversely correlated with the shear rate. A previously developed probabilistic model was modified to predict the time dependence of aggregation fractions at different shear rates and medium viscosities. Kinetic parameters of beta(2)-integrin and ICAM-1 bindings were obtained by individual or global fittings, which were comparable to respectively published values. These findings provide new quantitative understanding of the biophysical basis of leukocyte-tumor cell interactions mediated by specific receptor-ligand interactions under shear flow conditions.

Protein A tangential flow affinity membrane cartridge for extracorporeal immunoadsorption therapy

Tangential flow affinity membrane cartridge (TFAMC) fs a new model of immunoadsorption therapy for hemoperfusion. Recombinant Protein A was immobilized on the membrane cartridge through Schiff base formation for extracorporeal IgG and immune complex removal from blood. Flow characteristics, immunoadsorption capacity and biocompatibility of protein A TFAMC were studied. The results showed that the pressure drop increased with the increasing flow rate of water, plasma and blood, demonstrating reliable strength of membrane at high now rare. The adsorption capacities of protein A TFAMC for IgG from human plasma and blood were measured. The cartridge with 139 mg protein A immobilized on the matrix (6 mg protein A/g dry matrix) adsorbed 553 mg IgG (23.8 mg IgG/g dry matrix) from human plasma and 499.4 mg IgG (21.5 mg IgG/g dry matrix) from human blood, respectively. The circulation time had a major influence on IgG adsorption capacity, but the flow rate had little influence. Experiments in vitro and in vivo confirmed that protein A TFAMC mainly adsorbed Ige and Little of other plasma proteins, and that blood cell damage was negligible. The extracorporeal circulation system is safe and reliable. Copyright (C) 1999 John Wiley & Sons, Ltd.

Forced Dissociation of Selectin-ligand Complexes Using Steered Molecular Dynamics Simulation

Selectin-ligand interactions are crucial to such biological processes as inflammatory cascade or tumor metastasis. How transient formation and dissociation of selectin-ligand bonds in blood flow are coupled to molecular conformation at atomic level, however, has not been well understood. In this study, steered molecular dynamics (SMD) simulations were used to elucidate the intramolecular and intermolecular conformational evolutions involved in forced dissociation of three selectin-ligand systems: the construct consisting of P-selectin lectin (Lec) and epidermal growth factor (EGF)-like domains (P-LE) interacting with synthesized sulfoglycopeptide or SGP-3, P-LE with sialyl Lewis X (sLeX), and E-LE with sLeX. SMD simulations were based on newly built-up force field parameters including carbohydrate units and sulfated tyrosine(s) using an analogy approach. The simulations demonstrated that the complex dissociation was coupled to the molecular extension. While the intramolecular unraveling in P-LESGP-3 system mainly resulted from the destroy of the two anti-parallel sheets of EGF domain and the breakage of hydrogen-bond cluster at the Lec-EGF interface, the intermolecular dissociation was mainly determined by separation of fucose (FUC) from Ca2+ ion in all three systems. Conformational changes during forced dissociations depended on pulling velocities and forces, as well as on how the force was applied. This work provides an insight into better understanding of conformational changes and adhesive functionality of selectin-ligand interactions under external forces.

Forced extension of P-selectin construct using steered molecular dynamics

P-selectin, a 70-nm-long cellular adhesive molecule, possesses elastic and extensible properties when neutrophils roll over the activated endotheliam of blood vessel in inflammatory reaction. Transient formation and dissociation of P-selectin/ligand bond on applied force of blood flow induces the extension of P-selectin and relevant ligands. Steered molecular dynamics simulations were performed to stretch a single P-selectin construct consisting of a lectin (Lec) domain and an epithelial growth factor (EGF)-like domain, where P-selectin construct was forced to extend in water with pulling velocities of 0.005-0.05 nm/ps and with constant forces of 1000-2500 pN respectively. Resulting force-extension profiles exhibited a dual-peak pattern on various velocities, while both plateaus and shoulders appeared in the extension-time profiles on various forces. The force or extension profiles along stretching pathways were correlated to the conformational changes, suggesting that the structural collapses of P-selectin Lec/EGF domains were mainly attributed to the burst of hydrogen bonds within the major beta sheet of EGF domain and the disruptions of two hydrophobic cores of Lee domain. This work furthers the understanding of forced dissociation of P-selectin/ligand bond.

重力对锥形血管中血流压力的影响——基于考虑体位改变的三维流固耦合数学模型

重力是体位改变过程中最基本的生物力学刺激因素．血流压力是表征心血管功能状态的一个基本指标．目前，体位改 变影响心血管系统的确切内部机制尚不清楚．为此，采用在流体和固体方程中分别引入体力项的方法，建立一个基于血流动 力学概念的三维流固耦合数学模型，用以研究体位改变，确切量化重力对血流压力的影响．通过数值计算，得到以下结果． 水平卧位条件下：a．单一血管中血流压力由无重力影响的轴对称二维分布变为重力影响下的三维不对称分布；b．随着进出 口压差由小变大，重力对压力分布和极值的影响由大变小，当压差值分别达到10 665.6 Pa(80 mmHg)和2 666.4 Pa(20 mmHg) 时，重力的影响就不再随进出口压差增大而变化；对三维单一流体，重力影响的总体趋势类似．对正、倒直立位，压力均为 二维轴对称分布，其重力影响强度约为水平卧位的2 倍以上．结果表明：基于血流动力学概念，引入体力项，建立三维流固 耦合模型为研究体位改变提供了一种新思路，重力对单一血管中血流压力分布和大小的影响因体位不同而不同，并与进出口 压差密切相关，提示，若血管进出口压差较小，忽略重力影响，不考虑体位改变，以二维轴对称模型来研究血管中血流状 态，须谨慎解释所得结果．

地下水流动数值模拟的并行计算方法研究

Numerical modeling of groundwater is very important for understanding groundwater flow and solving hydrogeological problem. Today, groundwater studies require massive model cells and high calculation accuracy, which are beyond single-CPU computer’s capabilities. With the development of high performance parallel computing technologies, application of parallel computing method on numerical modeling of groundwater flow becomes necessary and important. Using parallel computing can improve the ability to resolve various hydro-geological and environmental problems. In this study, parallel computing method on two main types of modern parallel computer architecture, shared memory parallel systems and distributed shared memory parallel systems, are discussed. OpenMP and MPI (PETSc) are both used to parallelize the most widely used groundwater simulator, MODFLOW. Two parallel solvers, P-PCG and P-MODFLOW, were developed for MODFLOW. The parallelized MODFLOW was used to simulate regional groundwater flow in Beishan, Gansu Province, which is a potential high-level radioactive waste geological disposal area in China. 1. The OpenMP programming paradigm was used to parallelize the PCG (preconditioned conjugate-gradient method) solver, which is one of the main solver for MODFLOW. The parallel PCG solver, P-PCG, is verified using an 8-processor computer. Both the impact of compilers and different model domain sizes were considered in the numerical experiments. The largest test model has 1000 columns, 1000 rows and 1000 layers. Based on the timing results, execution times using the P-PCG solver are typically about 1.40 to 5.31 times faster than those using the serial one. In addition, the simulation results are the exact same as the original PCG solver, because the majority of serial codes were not changed. It is worth noting that this parallelizing approach reduces cost in terms of software maintenance because only a single source PCG solver code needs to be maintained in the MODFLOW source tree. 2. P-MODFLOW, a domain decomposition–based model implemented in a parallel computing environment is developed, which allows efficient simulation of a regional-scale groundwater flow. The basic approach partitions a large model domain into any number of sub-domains. Parallel processors are used to solve the model equations within each sub-domain. The use of domain decomposition method to achieve the MODFLOW program distributed shared memory parallel computing system will process the application of MODFLOW be extended to the fleet of the most popular systems, so that a large-scale simulation could take full advantage of hundreds or even thousands parallel processors. P-MODFLOW has a good parallel performance, with the maximum speedup of 18.32 (14 processors). Super linear speedups have been achieved in the parallel tests, indicating the efficiency and scalability of the code. Parallel program design, load balancing and full use of the PETSc were considered to achieve a highly efficient parallel program. 3. The characterization of regional ground water flow system is very important for high-level radioactive waste geological disposal. The Beishan area, located in northwestern Gansu Province, China, is selected as a potential site for disposal repository. The area includes about 80000 km2 and has complicated hydrogeological conditions, which greatly increase the computational effort of regional ground water flow models. In order to reduce computing time, parallel computing scheme was applied to regional ground water flow modeling. Models with over 10 million cells were used to simulate how the faults and different recharge conditions impact regional ground water flow pattern. The results of this study provide regional ground water flow information for the site characterization of the potential high-level radioactive waste disposal.

单（多）井抽灌对浅部地温场的影响研究

The technique of energy extraction using groundwater source heat pumps, as a sustainable way of low-grade thermal energy utilization, has widely been used since mid-1990's. Based on the basic theories of groundwater flow and heat transfer and by employing two analytic models, the relationship of the thermal breakthrough time for a production well with the effect factors involved is analyzed and the impact of heat transfer by means of conduction and convection, under different groundwater velocity conditions, on geo-temperature field is discussed.A mathematical model, coupling the equations for groundwater flow with those for heat transfer, was developed. The impact of energy mining using a single well system of supplying and returning water on geo-temperature field under different hydrogeological conditions, well structures, withdraw-and-reinjection rates, and natural groundwater flow velocities was quantitatively simulated using the finite difference simulator HST3D. Theoretical analyses of the simulated results were also made. The simulated results of the single well system indicate that neither the permeability nor the porosity of a homogeneous aquifer has significant effect on the temperature of the production segment provided that the production and injection capability of each well in the aquifers involved can meet the designed value. If there exists a lower permeable interlayer, compared with the main aquifer, between the production and injection segments, the temperature changes of the production segment will decrease. The thicker the interlayer and the lower the interlayer permeability, the longer the thermal breakthrough time of the production segment and the smaller the temperature changes of the production segment. According to the above modeling, it can also be found that with the increase of the aquifer thickness, the distance between the production and injection screens, and/or the regional groundwater flow velocity, and/or the decrease of the production-and-reinjection rate, the temperature changes of the production segment decline. For an aquifer of a constant thickness, continuously increase the screen lengths of production and injection segments may lead to the decrease of the distance between the production and injection screens, and the temperature changes of the production segment will increase, consequently.According to the simulation results of the single well system, the parameters, that can cause significant influence on heat transfer as well as geo-temperature field, were chosen for doublet system simulation. It is indicated that the temperature changes of the pumping well will decrease as the aquifer thickness, the distance between the well pair and/or the screen lengths of the doublet increase. In the case of a low permeable interlayer embedding in the main aquifer, if the screens of the pumping and the injection wells are installed respectively below and above the interlayer, the temperature changes of the pumping well will be smaller than that without the interlay. The lower the permeability of the interlayer, the smaller the temperature changes. The simulation results also indicate that the lower the pumping-and-reinjection rate, the greater the temperature changes of the pumping well. It can also be found that if the producer and the injector are chosen reasonably, the temperature changes of the pumping well will decline as the regional groundwater flow velocity increases. Compared with the case that the groundwater flow direction is perpendicular to the well pair, if the regional flow is directed from the pumping well to the injection well, the temperature changes of the pumping well is relatively smaller.Based on the above simulation study, a case history was conducted using the data from an operating system in Beijing. By means of the conceptual model and the mathematical model, a 3-D simulation model was developed and the hydrogeological parameters and the thermal properties were calibrated. The calibrated model was used to predict the evolution of the geo-temperature field for the next five years. The simulation results indicate that the calibrated model can represent the hydrogeological conditions and the nature of the aquifers. It can also be found that the temperature fronts in high permeable aquifers move very fast and the radiuses of temperature influence are large. Comparatively, the temperature changes in clay layers are smaller and there is an obvious lag of the temperature changes. According to the current energy mining load, the temperature of the pumping wells will increase by 0.7°C at the end of the next five years. The above case study may provide reliable base for the scientific management of the operating system studied.