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PubMed2006

Hydrodynamics-based gene delivery of naked DNA encoding fetal liver kinase-1 gene effectively suppresses the growth of pre-existing tumors.

Antiangiogenic gene therapy is a promising strategy for cancer treatment, which generally requires highly efficient delivery systems. To date, success of this strategy has depended almost exclusively on the delivery of high titers of viral vectors, which can result in effective transgene expression. However, their cytotoxicity and immunogenicity are a major concern for clinical applications. Recent advances in delivery efficiency of naked DNA could potentially meet the requirement for both high transgene expression and minimal side effects. To investigate whether naked DNA can be used for antiangiogenic cancer therapy, an expression plasmid was generated that encodes a soluble form of fetal liver kinase-1 (Flk-1) gene, a receptor for vascular endothelial growth factor (VEGF). Hydrodynamic injection of this plasmid resulted in close to 0.1 mg/ml of soluble Flk-1 protein in mouse serum and blocked VEGF-driven angiogenesis in matrigel in vivo. The same delivery significantly suppressed the growth of two different pre-existing subcutaneous tumors, Renca renal cell carcinoma and 3LL lung carcinoma. CD31 immunohistochemistry revealed that the tumor-associated angiogenesis was also highly attenuated in soluble Flk-1-treated mice. Thus, expression of genes by hydrodynamics-based gene delivery of naked DNA appears to be a promising approach for antiangiogenic cancer gene therapy.

Animals↗
PubMed2000

Long-term expression of human alpha1-antitrypsin gene in mouse liver achieved by intravenous administration of plasmid DNA using a hydrodynamics-based procedure.

The liver is an important target organ for gene transfer due to its large capacity for synthesizing serum proteins and its involvement in numerous genetic and acquired diseases. Previously, we and others have shown that an efficient gene transfer to liver cells in vivo can be achieved by an intravenous injection of plasmid DNA using a hydrodynamics-based procedure. In this study, we systematically characterized the expression of transgene encoding a secretory protein in mouse. Using human alpha1-antitrypsin (hAAT) gene as a reporter, we demonstrate that the serum level of hAAT can reach as high as 0.5 mg/ml by a simple tail vein injection of 10-50 microg plasmid DNA into a mouse. The serum hAAT reaches the peak level 1 day after DNA injection and then declines during the following 2 to 4 weeks to 2-5 microg/ml, a level which persists for at least 6 months. Southern analysis of extracted DNA and RT-PCR analysis of RNA from the liver reveal that hAAT gene is active and present as episomal form after 6 months. These results suggest that the hydrodynamics-based transfection procedure provides a valuable tool for screening genes for therapeutic purposes in whole animals.

Animals↗
PubMed2003

Hydrodynamic interactions between rolling leukocytes in vivo.

OBJECTIVE: The aim of this study was to characterize the hydrodynamic interactions between rolling and free-stream leukocytes in an in vivo model of selectin-mediated rolling, and to identify those physical mechanisms that influence the dynamics of transient adhesion with the walls of postcapillary venules. METHODS: Postcapillary venules of diameter 22-37 microm in the cheek pouch of anesthetized hamsters were visualized using intravital microscopy, with selectin-mediated rolling occurring in response to surgical preparation. RESULTS: Rolling velocity was found to be a strong function of the center-to-center separation with the nearest cell, and also was found to correlate strongly with the number of nearby cells. These effects are shown to be beyond that attributable to variations along the length of the vessel. Adherent leukocytes were observed to provide a nucleation site, precipitating further adhesion events of free-stream cells. CONCLUSIONS: The dynamics of the transient adhesion of leukocytes to the vessel wall in postcapillary venules is strongly dependent on the local concentration of adherent leukocytes, due to the complex hydrodynamics induced by their presence. The results are shown to agree well with theoretical considerations of the flow field induced by multiple nearby cells, suggesting a need for the future exploration of multicellular effects in the microcirculation.

Animals↗
PubMed1984

Hydrodynamic properties of human cervical-mucus glycoproteins in 6M-guanidinium chloride.

Cervical mucins and fragments thereof were studied by sedimentation-velocity, rotatory viscometry and laser light-scattering performed as photon-correlation spectroscopy as well as low-angle total-intensity measurements. The Mr of the whole mucins is 10 X 10(6)-15 X 10(6), whereas fragments obtained after reduction of disulphide bonds ('subunits') have Mr 2.1 X 10(6)-2.9 X 10(6), depending on the method used. Subsequent trypsin digestion of subunits afforded glycopeptides with Mr approx. 0.4 X 10(6). The high frictional ratio for the whole mucins is interpreted as a large degree of expansion. The Stokes radius calculated from the diffusion coefficient is approx. 110nm for the whole mucins, which is in agreement with that estimated from the radius of gyration (130nm) by using the concept of the equivalent hydrodynamic sphere. The ratio of the concentration-dependence parameter for the reciprocal sedimentation coefficient (Ks) to the intrinsic viscosity ( [eta] ) for the whole mucins is 1.42, suggesting that the individual macromolecule occupies a spheroidal domain in solution. The relationship between [eta] and Mr for whole mucins, subunits and T-domains suggests that they are linear flexible macromolecules behaving as somewhat 'stiff' random coils. This conclusion is supported by the relationships between the sedimentation coefficients, the diffusion coefficients and the Mr. The hydrodynamic behaviour of the mucins is thus close to that expected for coiling macromolecules entrapping a lot of solvent, which is consistent with the postulated polymeric structure.

Cervix Mucus↗
PubMed1985

Physicochemical studies on turnip-yellow-mosaic virus. Homogeneity, relative molecular masses, hydrodynamic radii and concentration-dependence of parameters in non-dissociating solvents.

Turnip-yellow-mosaic virus, with its stable, highly spherical and monodisperse character, was chosen as a suitable model substance with which to test hydrodynamic theories of transport. Sedimentation coefficients, diffusion coefficients (obtained through photon correlation spectroscopy) and viscosities were measured accurately as a function of concentration in well-defined and nearly neutral buffer systems. Ancillary information was also obtained from very-low-speed sedimentation-equilibrium experiments. The coefficients expressing the variation in sedimentation and diffusion coefficients with weight concentration were obtained, and by combination with other data it was possible to avoid assumptions concerning solvation and transform such regression coefficients into the form appropriate to volume fractions. Some measure of support for Batchelor's [(1972) J. Fluid Mech. 52, 245-268] calculations was thus obtained, but over most of the pH range the coefficients were significantly smaller than those calculated from his theory. It seems likely that electrostatic interactions are responsible for the discrepancies. Hydrodynamic radii (from diffusion coefficients) were in very fair agreement with those calculated from the thermodynamic excluded-volume term, but were higher than indicated by electron microscopy and X-ray diffraction, a discrepancy ascribable to solvation.

Chemical Phenomena↗
PubMed1990

Hydrodynamic properties of connective-tissue polysaccharides.

The major hydrodynamic properties of the connective-tissue polysaccharides are those that describe polysaccharide-water interaction as embodied in their osmotic-pressure and hydraulic-conductivity properties. This study shows that, for polysaccharides such as chondroitin sulphate, hyaluronate and the heparin-like polysaccharides, their hydrodynamic properties depend primarily on the presence of the uronic residue and the nature of the glycosidic linkage. Other parameters such as the degree of N-acetylation and sulphation were found not to influence these properties to any great extent. These studies particularly delineate structural-functional aspects of the connective-tissue polysaccharides in terms of their primary structure.

Animals↗
PubMed1996

[Percutaneous transluminal hydrodynamic thrombectomy--the initial results].

PURPOSE: First clinical applications in the femoro-popliteal vessels of a new system for percutaneous, transluminal hydrodynamic thrombectomy are presented. MATERIAL AND METHOD: Three patients suffering from femoro-popliteal thromboembolic obstruction were treated. A new hydrodynamic 8-F catheter with two lumina was used. The jet leaving at the tip of the catheter shredded the thrombotic material. Using the Venturi effect the thrombus was collected. The shredded material was transported outside through the second channel of the catheter. RESULTS: All obstructions could be removed. Underlying degenerative vessel disease and older thromboemboli needed additional therapy like PTA or aspiration thrombectomy (PAT). CONCLUSIONS: The new catheter is helpful in removing arterial femoro-popliteal thromboembolic obstructions. Additional interventions may be necessary. More clinical experience is needed.

Aged↗
PubMed1991

Cyclic motion of ischemic ventricular wall area and hydrodynamics of the blood during ejection.

Analysis of dimensional changes of ischemic left ventricular wall segments evidenced a dilation immediately after onset of ejection; thereafter, contraction appears delayed but almost regular. This biphasic systolic wall motion was correlated in a retrospective study to parameters indicating local intramural disorders, intraventricular load changes, and hydrodynamics of the blood during ejection. Hemodynamic data stored on a 16-track tape recorder were analyzed from 12 consecutive experiments in anesthetized dogs in which the left circumflex coronary artery (LCX) was gradually narrowed (coronary flow restriction greater than or equal to 50%). Left ventricular and aortic pressure, aortic blood velocity (v), acceleration/deceleration (dv/dt), and instantaneous stroke volume (m = integral of v*dt), and segment lengths of normal and ischemic myocardial regions (sonomicrometry) were numerically evaluated with 5 msec resolution. Systolic shortening of the intact myocardium correlates with the diminution of the intraventricular volume during ejection (r greater than 0.98). In contrast, ischemic segments dilate early during systole when the blood is accelerated; the extent of dilation depends on the degree of coronary flow reduction. The time course of lengthening coincides with the development of force F = m*dv/dt (r greater than 0.90) originating from regularly contracting parts of the ventricle. During blood deceleration, ischemic wall segments shorten as F turns to negative (r greater than 0.95). Thus, the wall motion of ischemic myocardial regions is modulated by the hydrodynamic force resulting from acceleration and deceleration of blood consecutively impeding and supporting the systolic function of the ischemic myocardium in the course of ejection.

Animals↗
PubMed1994

Quasi-two-dimensional hydrodynamics and problems of two-dimensional turbulence.

The principal problems of quasi-two-dimensional (Q2-D) hydrodynamics are discussed. Accounting for Q2-D flow vertical structure is shown to eliminate "genetic" defects of the formal 2-D idealization of 3-D Navier-Stokes equations and allows under certain conditions to formulate corrected 2-D motion equations which adequately describe real hydrodynamic processes. The applicability of the approach is directly verified in laboratory experiments. Special attention is paid to the problem of 2-D turbulence. Its simulation on the basis of ordinary 2-D equations is unjustified because of the absence of the external Kolmogorov dissipation scale and reverse spectral energy flux. An alternative approach allows one to introduce the natural external scale of 2-D turbulence which depends only on physical properties of the system under consideration and to formulate the conditions under which the large scale vortex dynamics is expected to be universal at large Reynolds number, i.e., to be independent on the size and form of integration domain and lateral boundary conditions.

Journal Article↗
PubMed2004

Quantum hydrodynamics: application to N-dimensional reactive scattering.

The quantum hydrodynamic equations associated with the de Broglie-Bohm formulation of quantum mechanics are solved using a new methodology which gives an accurate, unitary, and stable propagation of a time dependent quantum wave packet [B. K. Kendrick, J. Chem. Phys. 119, 5805 (2003)]. The methodology is applied to an N-dimensional model chemical reaction with an activation barrier. A parallel version of the methodology is presented which is designed to run on massively parallel supercomputers. The computational scaling properties of the parallel code are investigated both as a function of the number of processors and the dimension N. A decoupling scheme is introduced which decouples the multidimensional quantum hydrodynamic equations into a set of uncoupled one-dimensional problems. The decoupling scheme dramatically reduces the computation time and is highly parallelizable. Furthermore, the computation time is shown to scale linearly with respect to the dimension N=2,...,100.

Journal Article↗
PubMed2004

Hydrodynamics of bacterial colonies: phase diagrams.

We present numerical simulations of a recent hydrodynamic model describing the growth of bacterial colonies on agar plates. We show that this model is able to qualitatively reproduce experimentally observed phase diagrams, which relate a colony shape to the initial quantity of nutrients on the plate and the initial wetness of the agar. We also discuss the principal features resulting from the interplay between hydrodynamic motions and colony growth, as described by our model.

Algorithms↗
PubMed2004

Effect of hydrodynamic interactions on the evolution of chemically reactive ternary mixtures.

We investigate the structural evolution of an A/B/C ternary mixture in which the A and B components can undergo a reversible chemical reaction to form C. We developed a lattice Boltzmann model for this ternary mixture that allows us to capture both the reaction kinetics and the hydrodynamic interactions within the system. We use this model to study a specific reactive mixture in which C acts as a surfactant, i.e., the formation of C at the A/B interface decreases the interfacial tension between the A and B domains. We found that the dynamics of the system is different for fluids in the diffusive and viscous regimes. In the diffusive regime, the formation of a layer of C at the interface leads to a freezing of the structural evolution in the fluid; the values of the reaction rate constants determine the characteristic domain size in the system. In the viscous regime, where hydrodynamic interactions are important, interfacial reactions cause a slowing down of the domain growth, but do not arrest the evolution of the mixture. The results provide guidelines for controlling the morphology of this complex ternary fluid.

Journal Article↗
PubMed2004

Coping with the node problem in quantum hydrodynamics: the covering function method.

A conceptually simple approach, the covering function method (CFM), is developed to cope with the node problem in the hydrodynamic formulation of quantum mechanics. As nodes begin to form in a scattering wave packet (detected by a monitor function), a nodeless covering wave function is added to it yielding a total function that is also nodeless. Both local and global choices for the covering function are described. The total and covering functions are then propagated separately in the hydrodynamic picture. At a later time, the actual wave function is recovered from the two propagated functions. The results obtained for Eckart barrier scattering in one dimension are in excellent agreement with exact results, even for very long propagation times t=1.2 ps. The capability of the CFM is also demonstrated for multidimensional propagation of a vibrationally excited wave packet.

Biophysics↗
PubMed2004

Long-time dynamics of Rouse-Zimm polymers in dilute solutions with hydrodynamic memory.

The dynamics of flexible polymers in dilute solutions is studied taking into account the hydrodynamic memory, as a consequence of fluid inertia. As distinct from the Rouse-Zimm (RZ) theory, the Boussinesq friction force acts on the monomers (beads) instead of the Stokes force, and the motion of the solvent is governed by the nonstationary Navier-Stokes equations. The obtained generalized RZ equation is solved approximately using the preaveraging of the Oseen tensor. It is shown that the time correlation functions describing the polymer motion essentially differ from those in the RZ model. The mean-square displacement (MSD) of the polymer coil is at short times approximately t(2) (instead of approximately t). At long times the MSD contains additional (to the Einstein term) contributions, the leading of which is approximately t. The relaxation of the internal normal modes of the polymer differs from the traditional exponential decay. It is displayed in the long-time tails of their correlation functions, the longest lived being approximately t(-3/2) in the Rouse limit and t(-5/2) in the Zimm case, when the hydrodynamic interaction is strong. It is discussed that the found peculiarities, in particular, an effectively slower diffusion of the polymer coil, should be observable in dynamic scattering experiments.

Journal Article↗
PubMed2005

From molecular dynamics to hydrodynamics: a novel Galilean invariant thermostat.

This paper proposes a novel thermostat applicable to any particle-based dynamic simulation. Each pair of particles is thermostated either (with probability P) with a pairwise Lowe-Andersen thermostat [C. P. Lowe, Europhys. Lett. 47, 145 (1999)] or (with probability 1-P) with a thermostat that is introduced here, which is based on a pairwise interaction similar to the Nosé-Hoover thermostat. When the pairwise Nosé-Hoover thermostat dominates (low P), the liquid has a high diffusion coefficient and low viscosity, but when the Lowe-Andersen thermostat dominates, the diffusion coefficient is low and viscosity is high. This novel Nosé-Hoover-Lowe-Andersen thermostat is Galilean invariant and preserves both total linear and angular momentum of the system, due to the fact that the thermostatic forces between each pair of the particles are pairwise additive and central. We show by simulation that this thermostat also preserves hydrodynamics. For the (noninteracting) ideal gas at P = 0, the diffusion coefficient diverges and viscosity is zero, while for P > 0 it has a finite value. By adjusting probability P, the Schmidt number can be varied by orders of magnitude. The temperature deviation from the required value is at least an order of magnitude smaller than in dissipative particle dynamics (DPD), while the equilibrium properties of the system are very well reproduced. The thermostat is easy to implement and offers a computational efficiency better than (DPD), with better temperature control and greater flexibility in terms of adjusting the diffusion coefficient and viscosity of the simulated system. Applications of this thermostat include all standard molecular dynamic simulations of dense liquids and solids with any type of force field, as well as hydrodynamic simulation of multiphase systems with largely different bulk viscosities, including surface viscosity, and of dilute gases and plasmas.

Journal Article↗
PubMed2005

Quantum hydrodynamics: capturing a reactive scattering resonance.

The hydrodynamic equations of motion associated with the de Broglie-Bohm formulation of quantum mechanics are solved using a meshless method based upon a moving least-squares approach. An arbitrary Lagrangian-Eulerian frame of reference and a regridding algorithm which adds and deletes computational points are used to maintain a uniform and nearly constant interparticle spacing. The methodology also uses averaged fields to maintain unitary time evolution. The numerical instabilities associated with the formation of nodes in the reflected portion of the wave packet are avoided by adding artificial viscosity to the equations of motion. A new and more robust artificial viscosity algorithm is presented which gives accurate scattering results and is capable of capturing quantum resonances. The methodology is applied to a one-dimensional model chemical reaction that is known to exhibit a quantum resonance. The correlation function approach is used to compute the reactive scattering matrix, reaction probability, and time delay as a function of energy. Excellent agreement is obtained between the scattering results based upon the quantum hydrodynamic approach and those based upon standard quantum mechanics. This is the first clear demonstration of the ability of moving grid approaches to accurately and robustly reproduce resonance structures in a scattering system.

Journal Article↗
PubMed2006

Hydrodynamics of an endothermic gas with application to bubble cavitation.

The hydrodynamics for a gas of hard spheres which sometimes experience inelastic collisions resulting in the loss of a fixed, velocity-independent, amount of energy Delta is investigated with the goal of understanding the coupling between hydrodynamics and endothermic chemistry. The homogeneous cooling state of a uniform system and the modified Navier-Stokes equations are discussed and explicit expressions given for the pressure, cooling rates, and all transport coefficients for D dimensions. The Navier-Stokes equations are solved numerically for the case of a two-dimensional gas subject to a circular piston so as to illustrate the effects of the energy loss on the structure of shocks found in cavitating bubbles. It is found that the maximal temperature achieved is a sensitive function of Delta with a minimum occurring near the physically important value of Delta approximately 12,000 K approximately 1 eV.

Journal Article↗
PubMed2006

N log N method for hydrodynamic interactions of confined polymer systems: Brownian dynamics.

A Brownian dynamics simulation technique is presented where a Fourier-based N log N approach is used to calculate hydrodynamic interactions in confined flowing polymer systems between two parallel walls. A self-consistent coarse-grained Langevin description of the polymer dynamics is adopted in which the polymer beads are treated as point forces. Hydrodynamic interactions are therefore included in the diffusion tensor through a Green's function formalism. The calculation of Green's function is based on a generalization of a method developed for sedimenting particles by Mucha et al. [J. Fluid Mech. 501, 71 (2004)]. A Fourier series representation of the Stokeslet that satisfies no-slip boundary conditions at the walls is adopted; this representation is arranged in such a way that the total O(N2) contribution of bead-bead interactions is calculated in an O(N log N) algorithm. Brownian terms are calculated using the Chebyshev polynomial approximation proposed by Fixman [Macromolecules 19, 1195 (1986); 19, 1204 (1986)] for the square root of the diffusion tensor. The proposed Brownian dynamics simulation methodology scales as O(N1.25 log N). Results for infinitely dilute systems of dumbbells are presented to verify past predictions and to examine the performance and numerical consistency of the proposed method.

Algorithms↗