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PubMed2003

Scattering and separators in dissipative systems.

Scattering of particlelike patterns in dissipative systems is studied, especially we focus on the issue how the input-output relation is controlled at a head-on collision in the one-dimensional(1D) space where traveling pulses interact strongly. It remains an open problem due to the large deformation of patterns at a colliding point. We found that a special type of steady or time-periodic solutions called separators and their stable and unstable manifolds direct the traffic flow of orbits. Such separators are, in general, highly unstable even in the 1D case which causes a variety of input-output relations through the scattering process. We illustrate the ubiquity of separators by using the Gray-Scott model and a three-component reaction diffusion model arising in gas-discharge phenomena.

Journal Article↗
PubMed2005

Geometry of dynamically available empty space is the key to near-arrest dynamics.

We study several examples of kinetically constrained lattice models using dynamically accessible volume as an order parameter. Thereby we identify two distinct regimes exhibiting dynamical slowing, with a sharp threshold between them. These regimes are identified both by a new response function in dynamically available volume, as well as directly in the dynamics. Results for the self-diffusion constant in terms of the connected hole density are presented, and some evidence is given for scaling in the limit of dynamical arrest.

Journal Article↗
PubMed1986

Concentration dependence of halide fluxes and selectivity of the anion pathway in toad skin.

The isolated toad (Bufo bufo) skin was mounted under voltage-clamp conditions in a chamber shown to cause no significant edge damage. The serosal side of the skin was bathed with NaCl-Ringer's, and the passive voltage-sensitive anion conductance studied in its fully voltage activated state, V = -80 mV (apical bath negative). The active sodium currents were eliminated by replacing external Na+ with K+. With [Cl-]o varying between 1.45 mM and 110 mM (gluconate substitution) and [I-]o = 3 mM, the total clamping current (y) and the sum of halide currents (x), estimated from flux measurements, were related by y = 1.0x-3.7 microA cm-2 (r2 = 0.98, n = 50 preparations). The increase in [Cl-]o produced a sigmoidal increase in Cl- influx and clamping current, with the rate coefficient for the influx increasing with [Cl-]o for 1.45 less than [Cl-]o less than 60 mM, but decreasing slightly again as [Cl-]o was further raised to 110 mM. A similar relationship was obtained between the rate coefficient for the Br- influx and [Br-]o, and the I- influx and [Cl-]o, indicating that these three ions are transported by a pathway that is activated by Cl-o and Br-o. The rate coefficients for the influxes ranked as follows, I-:Cl-:Br- = 0.7:1:1.3. The I-/Cl- selectivity was shown to be independent of the degree of Cl-o activation of the anion pathway, and identical with the I-/Cl- selectivity of a furosemide-sensitive, conductive pathway. With [Cl-]o, [Br-]o, or [I-]o = 110 mM, the currents ranked as follows, Cl-:Br-:I- = 1:0.68:0.06, indicating that Cl-, to a lesser extent Br-, and I-, poorly activate the conductive anion pathway. External I- was a potent inhibitor of the Cl-o activation of the Cl- conductance. The unidirectional I- fluxes ([I-]o = [I-]i = 3 mM, [Cl-]o = [Cl-]i = 110 mM) revealed passive transport for V less than -50 mV, active transport for V = o mV, and exchange diffusion for V = 50 mV, confirming our previous finding that depending on the transepithelial potential, the toad skin exhibits three modes of anion transport. A model that shares some properties with that of the anion transport system of the red cell membrane accounts for our findings, and for an inwardly directed active Cl- flux in terms of Cl-/HCO3- exchange.

Animals↗
PubMed1989

Na+ and Cl- transport across rabbit nonciliated bronchiolar epithelial (Clara) cells.

Radioisotopic flux measurements were performed on rabbit Clara cell epithelium cultured in serum-free hormone-supplemented medium to identify the major ion transport pathways in the cell type. Clara cells cultured in serum-free hormone-supplemented medium exhibit a large short-circuit current compared with cells maintained in serum-containing medium (45 microA/cm2 vs. 15 microA/cm2). The responses to amiloride and isoproterenol, however, are similar for cells grown in the two media. A net amiloride-sensitive movement of Na+ in the mucosal (M)-to-serosal (S) direction undershort- and open-circuit conditions is detected (1.48 and 0.67 mueq.h-1.cm-2, respectively). No statistically significant difference in the unidirectional fluxes of Cl- is apparent in the basal state, but a net flux of Cl- in the S-to-M direction is observed after exposure of the apical membrane to amiloride (0.93 mueq.h-1.cm-2). The partial ionic conductances for Na+ and Cl- estimated from the fluxes measured in the passive directions (JNaS----M, JClM----S) exceed the total tissue conductance by 20%. Ussing flux ratio analyses of Cl- movements at clamped potentials between -60 and +20 mV show that Cl- movements are not strictly through passive conductive pathways at negative potentials. The movement of Cl- can be modeled by passive diffusion combined with Cl- -Cl- exchange equal to 20% of total passive fluxes of Na+ and Cl-. These observations indicate that 1) Na+ absorption is the major active ion transport pathway across cultured Clara cells, 2) active Cl- secretion is minimal in the basal state, and 3) approximately 20% of the unidirectional Cl- fluxes occur via nonconductive pathways.

Amiloride↗
PubMed2002

Arterial ultrastructure influences transport of locally delivered drugs.

An incomplete understanding of the transport forces and local tissue structures that modulate drug distribution has hampered local pharmacotherapies in many organ systems. These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release. Local delivery produces tremendous drug concentration gradients and although these are in part derived from transport forces, differences in deposition from tissue to tissue imply that tissue ultrastructure also plays an important role. We measured the equilibrium drug uptake and the penetration and diffusivity of dextrans (a model hydrophilic drug similar to heparin) and albumin in orthogonal planes in arteries explanted from different vascular beds. We found significant variations in drug distribution with geometric orientation and arterial connective tissue content. Drug diffusivities parallel to the connective tissue sheaths were one to two orders of magnitude greater than across these sheaths. This diffusivity difference remained relatively constant for drugs up to 70 kDa before decreasing for larger drugs. Drugs also distributed better into elastic arteries, especially at lower molecular weights, with almost 66% greater transfer into the thoracic aorta than into the carotid artery. Arterial drug transport is thus highly anisotropic and dependent on arterial tissue content. The role of the local composition and geometric organization of arterial tissue in influencing vascular pharmacokinetics is likely to become a critical consideration for local vascular drug delivery.

Animals↗
PubMed2004

Dip-pen nanolithography with poly(diallyl dimethyl ammonium) chloride.

Poly(diallyl dimethyl ammonium) chloride (PDAC), a high molecular weight cationic polyelectrolyte, was used as ink for dip-pen nanolithography. Line patterns were generated on bare silicon wafers directly with PDAC-coated tips. Widths and heights of lines increased with decreasing scan rates. At the same scan rate, widths and heights of patterning decreased with increasing PDAC molecular weight. The dependence of line width on inverse writing speed was found to be consistent with a modified diffusion model.

Computer Simulation↗
PubMed1997

Effect of hematocrit and albumin concentration on hepatic clearance of tacrolimus (FK506) during rabbit liver perfusion.

Tacrolimus is an immunosuppressive agent used for organ transplantation. Studies were performed to examine the influence of different perfusate hematocrits and albumin concentrations on hepatic extraction of tacrolimus. In vitro binding, efflux and influx between red blood cells (RBCs) and buffer or plasma, and rabbit liver perfusion with use of human erythrocytes were studied. In the range of hematocrits from 0.05 to 0.4, plasma concentrations of tacrolimus were not affected by increased albumin content. Increased hematocrit caused decreases in whole blood:plasma (buffer) concentration ratios. The binding capacity of drug with RBCs was independent of hematocrit, with a value of 440 ng/ml of RBCs; the binding affinity was 0.876 ng/ml using plasma or buffer. Diffusion of tacrolimus from RBCs to buffer was rapid with a clearance of 0.940 ml/min, and equilibration was achieved within 2 min. Diffusion in the opposite direction (buffer-RBCs) was slower with a clearance of 0.576 ml/min. In such diffusion studies, plasma produced a greater difference between efflux (1.70 ml/min) and influx (0.276 ml/min) clearances. During liver perfusion, the major factor regulating elimination of tacrolimus was hematocrit. Both well-stirred and parallel-tube models reflected a low extraction ratio drug with values of 0.15 and 0.17 for the 0.05 and 0.2 hematocrits. Intrinsic clearances were 8.43 and 17.44 ml/min for the well-stirred and parallel-tube models. Albumin had a negligible influence on liver extraction of drug. A model-building process of characterizing nonlinear RBC binding, RBC diffusion rates, and liver perfusion parameters allows the complexities of tacrolimus hepatic clearance to be dissected and shows that strong RBC binding can be artificially perceived as causing a high clearance of the drug.

Animals↗
PubMed1984

Application of reaction-diffusion models to cell patterning in Xenopus retina. Initiation of patterns and their biological stability.

We have examined the behavior of two reaction-diffusion models, originally proposed by Gierer & Meinhardt (1972) and by Kauffman, Shymko & Trabert (1978), for biological pattern formation. Calculations are presented for pattern formation on a disc (approximating the geometry of a number of embryonic anlagen including the frog eye rudiment), emphasizing the sensitivity of patterns to changes in initial conditions and to perturbations in the geometry of the morphogen-producing space. Analysis of the linearized equations from the models enabled us to select appropriate parameters and disc size for pattern growth. A computer-implemented finite element method was used to solve the non-linear model equations reiteratively. For the Gierer-Meinhardt model, initial activation (varying in size over two orders of magnitude) of one point on the disc's edge was sufficient to generate the primary gradient. Various parts of the disc were removed (remaining only as diffusible space) from the morphogen-producing cycle to investigate the effects of cells dropping out of the cycle due to cell death or malfunction (single point removed) or differentiation (center removed), as occur in the Xenopus eye rudiment. The resulting patterns had the same general shape and amplitude as normal gradients. Nor did a two-fold increase in disc size affect the pattern-generating ability of the model. Disc fragments bearing their primary gradient patterns were fused (with gradients in opposite directions, but each parallel to the fusion line). The resulting patterns generated by the model showed many similarities to results of "compound eye" experiments in Xenopus. Similar patterns were obtained with the model of Kauffman's group (1978), but we found less stability of the pattern subject to simulations of central differentiation. However, removal of a single point from the morphogen cycle (cell death) did not result in any change. The sensitivity of the Kauffman et al. model to shape perturbations is not surprising since the model was originally designed to use shape and increasing size during growth to generate a sequence of transient patterns. However, the Gierer-Meinhardt model is remarkably stable even when subjected to a wide range of perturbations in the diffusible space, thus allowing it to cope with normal biological variability, and offering an exciting range of possibilities for reaction-diffusion models as mechanisms underlying the spatial patterns of tissue structures.

Animals↗
PubMed1996

Self-organizing multi-resolution grid for motion planning and control.

A fully self-organizing neural network approach to low-dimensional control problems is described. We consider the problem of learning to control an object and solving the path planning problem at the same time. Control is based on the path planning model that follows the gradient of the stationary solution of a diffusion process working in the state space. Previous works are extended by introducing a self-organizing multigrid-like discretizing structure to represent the external world. Diffusion is simulated within a recurrent neural network built on this multigrid system. The novelty of the approach is that the diffusion on the multigrid is fast. Moreover, the diffusion process on the multigrid fits well the requirements of the path planning: it accelerates the diffusion in large free space regions while still keeps the resolution in small bottleneck-like labyrinths along the path. Control is achieved in the usual way: associative learning identifies the inverse dynamics of the system in a direct fashion. To this end there are introduced interneurons between neighboring discretizing units that detect the strength of the steady-state diffusion and forward control commands to the control neurons via modifiable connections. This architecture forms the Multigrid Position-and-Direction-to-Action (MPDA) map. The architecture integrates reactive path planning and continuous motion control. It is also shown that the scheme leads to population coding for the actual command vector.

Algorithms↗
PubMed2003

Comparison of standard CPR versus diffuse and stacked hand position interposed abdominal compression-CPR in a swine model.

Interposed abdominal compression cardiopulmonary resuscitation (IAC-CPR) is an innovative basic life support technique requiring no mechanical adjuncts. Optimizing its performance remains a challenge. Hand-position technique over the abdomen during interposed abdominal compression (IAC) may be important. The purpose of this study was to determine if there is a difference in efficacy depending on the type of abdominal hand-position used. Two different hand positions were studied: open hands, placed side by side, resulting in diffuse abdominal compression and stacked hands, with one on top of the other, producing a more focal compression of the abdomen. Thirty swine were cannulated with micromanometer-tipped pressure transducers in the ascending aorta (Ao) and right atrium (RA), and Millar Doppler-tipped catheters in the descending aorta and inferior vena cava (IVC) to determine flow patterns during cardiopulmonary resuscitation (CPR), During CPR there were no differences in aortic systolic or right atrial systolic pressures. Both forms of IAC-CPR produced greater aortic diastolic and right atrial diastolic pressures then standard CPR (STD-CPR) (P<0.05). Coronary perfusion pressures (CPP), however, were not different. Blood flow directions and velocity patterns showed that STD-CPR chest compressions produce caudally directed blood flow in both the descending aorta and the IVC, and that such flows reverse (becoming cranially directed) during the relaxation phase of chest compression. IAC-CPR produced similar blood flow patterns in the aorta and IVC, as seen with STD-CPR. There were no differences in blood flow patterns between the different forms of IAC-CPR. No CPR-produced trauma difference was found. Abdominal hand position (diffuse or stacked) did not affect blood flow in either the aorta or IVC or resuscitation success in this experimental model. There was a trend towards better outcomes with stacked hands IAC-CPR with 90 versus 70% survival with STD-CPR.

Abdomen↗
PubMedDate not supplied

Entamoeba histolytica: diffuse liver inflammation in gerbils (Meriones unguiculatus) with experimentally induced amebic liver abscess.

The histopathological changes that occur in the uninfected liver lobes of gerbils with a localized amebic liver abscess (left lobe) were studied from 5 to 60 days after inoculation. Early parenchymal changes (10 days) in the right and median liver lobes showed a lymphocytic infiltrate and bile duct proliferation in the portal areas. Maximum alterations occurred at 20 to 30 days after inoculation and were characterized by a dense portal infiltrate, hepatocyte degeneration, granulocytic infiltrate and marked glycogen depletion. In drug-treated infections with metronidazole, the diffuse liver inflammation was terminated. The results of this study suggest that the diffuse liver injury was directly or indirectly induced by the presence of a proliferating amebic liver abscess and that the pathology caused by amebic liver abscess is more extensive than previously thought.

Animals↗
PubMed2003

Structural effects of quinacrine binding in the open channel of the acetylcholine receptor.

Noncompetitive inhibitors of the nicotinic acetylcholine (ACh) receptors suppress cation flux directly by binding in and blocking the open channel or indirectly by stabilizing closed states of the receptor. The lidocaine derivative QX-314 and the acridine derivative quinacrine act directly as open channel blockers, but can act indirectly as well. The binding site for quinacrine in the open channel of mouse-muscle ACh receptor was mapped in cysteine-substituted mutants of the alpha subunit expressed with wild-type beta, gamma, and delta subunits. In the open state, substituted cysteines in the inner half of the second membrane-spanning segment (M2), but not in the outer half, were protected by quinacrine from reaction with 2-aminoethyl methanethiosulfonate. In addition, an alkylating derivative, quinacrine mustard, affinity labeled a subset of the substituted cysteines in M2, but only in the open state. These results, mapped onto a model of the open channel surrounded by five alpha-helical M2s, imply that quinacrine binds midway down M2 in the same site previously mapped for QX-314. A cysteine substituted for a residue in the outer third of alphaM1, which reacted with 2-aminoethyl methanethiosulfonate only in the presence of ACh, reacted faster in the additional presence of quinacrine or QX-314. It is proposed that channel opening involves both the opening of the resting gate at the inner end of M2 and the removal of an obstruction formed by the outer end of M1 that retards diffusion of blockers into the closed channel. Blocker binding in the open channel causes a further change in structure.

Amino Acid Substitution↗
PubMed2001

Simulation study of the structure and dynamics of the Alzheimer's amyloid peptide congener in solution.

The amyloid Abeta(10-35)-NH2 peptide is simulated in an aqueous environment on the nanosecond time scale. One focus of the study is on the validation of the computational model through a direct comparison of simulated statistical averages with experimental observations of the peptide's structure and dynamics. These measures include (1) nuclear magnetic resonance spectroscopy-derived amide bond order parameters and temperature-dependent H(alpha) proton chemical shifts, (2) the peptide's radius of gyration and end-to-end distance, (3) the rates of peptide self-diffusion in water, and (4) the peptide's hydrodynamic radius as measured by quasielastic light scattering experiments. A second focus of the study is the identification of key intrapeptide interactions that stabilize the central structural motif of the peptide. Particular attention is paid to the structure and fluctuation of the central LVFFA hydrophobic cluster (17-21) region and the VGSN turn (24-27) region. There is a strong correlation between preservation of the structure of these elements and interactions between the cluster and turn regions in imposing structure on the peptide monomer. The specific role of these interactions in relation to proposed mechanisms of amyloidosis is discussed.

Alzheimer Disease↗
PubMed2004

Dependence of the spin-spin relaxation time of water in collagen gels on collagen fiber directions.

In this study, we investigated the effect of structural differences in collagen fibers in relation to the spin-spin (T2) relaxation time of surrounding water molecules. We propose a simple experimental model of the magic angle effect based on magnetically oriented collagen gels. Experiments were performed with a 4.7T magnetic resonance imaging (MRI) system with a quadrature radio frequency coil operated at 200 MHz for 1H resonance. Collagen gels were polymerized from collagen solutions exposed to a 4.7T magnetic field for 120 min. The T2 relaxation time was measured with the Carr-Purcell-Meiboom-Gill (CPMG) sequence. The apparent diffusion coefficient (ADC) was measured with the stimulated echo acquisition mode (STEAM) sequence with a motion-probing gradient (MPG). Orienting the collagen fibers at an angle of about 55 degrees to the main magnetic field caused an increase in the T2 relaxation times of water molecules in the collagen gels. The ADC in the direction parallel to the fibers was larger than that in the direction perpendicular to the fibers. The increase in the T2 relaxation time and ADC are attributed to a change in the magnetic interaction between the water molecules and collagen fibers.

Anisotropy↗
PubMed1975

An experimental model of Pseudomonas aeruginosa renal infection in rats.

The model of experimental pyocyanic renal infection in rats based on direct inoculation of bacteria to the renal parenchyma is described. The authors describe in detail the procedure and evaluation of the results with respect to microbiology, histology and reproducibility. The method produced a focal supurrative inflammation with a significant bacteriologica finding in renal tissue for 8 weeks at the least. The inflammation has a tendency to form focal cicatrices not accompanied by diffuse shrinkage of the kidney. The method is well reproducible and its technique is relatively simple thus permitting to induce infection in a large series of animals within a short period of time. In the second part of the paper, the use of this method in testing the therapeutical efficacy of gentamicin, carbenicillin and their combination is reported. The results showed gentamicin to be more effective than carbenicillin and the combination of the two to have the highest therapeutical effect. Moreover, their combination made it possible to reduce the dosage of the antibiotics and thereby reduce their potential undesirable effect. Further, the results showed the described model of experimental renal infection to be well suited for testing the efficacy of chemotherapeutics and resolving some problems of the treatment of infectious diseases.

Bacteriuria↗
PubMed2002

Polymerization of monolignols by redox shuttle-mediated enzymatic oxidation: a new model in lignin biosynthesis I.

Lignin is one of the most abundant biopolymers, and it has a complex racemic structure. It may be formed by a radical polymerization initiated by redox enzymes, but much remains unknown about the process, such as how molecules as large as enzymes can generate the compact structure of the lignified plant cell wall. We have synthesized lignin oligomers according to a new concept, in which peroxidase is never in direct contact with the lignin monomers coniferaldehyde and coniferyl alcohol. Instead, manganese oxalate worked as a diffusible redox shuttle, first being oxidized from Mn(II) to Mn(III) by a peroxidase and then being reduced to Mn(II) by a simultaneous oxidation of the lignin monomers to radicals that formed covalent linkages of the lignin type. Furthermore, a high molecular mass polymer was generated by oxidation of coniferyl alcohol by Mn(III) acetate in a dioxane and water mixture. This polymer was very similar to natural spruce wood lignin, according to its NMR spectrum. The possible involvement of a redox shuttle/peroxidase system in lignin biosynthesis is discussed.

Acrolein↗
PubMed2002

Enhanced self-termination of re-entrant arrhythmias as a pharmacological strategy for antiarrhythmic action.

Ventricular tachycardia and fibrillation are potentially lethal cardiac arrhythmias generated by high frequency, irregular spatio-temporal electrical activity. Re-entrant propagation has been demonstrated as a mechanism generating these arrhythmias in computational and in vitro animal models of these arrhythmias. Re-entry can be idealised in homogenous isotropic virtual cardiac tissues as spiral and scroll wave solutions of reaction-diffusion equations. A spiral wave in a bounded medium can be terminated if its core reaches a boundary. Ventricular tachyarrhythmias in patients are sometimes observed to spontaneously self-terminate. One possible mechanism for self-termination of a spiral wave is meander of its core to an inexcitable boundary. We have previously proposed the hypothesis that the spatial extent of meander of a re-entrant wave in the heart can be directly related to its probability of self-termination, and so inversely related to its lethality. Meander in two-dimensional virtual ventricular tissues based on the Oxsoft family of cell models, with membrane excitation parameters simulating the inherited long Q-T syndromes has been shown to be consistent with this hypothesis: the largest meander is seen in the syndrome with the lowest probability of death per arrhythmic episode. Here we extend our previous results to virtual tissues based on the Luo-Rudy family of models. Consistent with our hypothesis, for both families of models, whose different ionic mechanisms produce different patterns of meander, the LQT virtual tissue with the larger meander simulates the syndrome with the lower probability of death per episode. Further, we search the parameter space of the repolarizing currents to find their conductance parameter values that give increased meander of spiral waves. These parameters may provide targets for antiarrhythmic drugs designed to act by increasing the likelihood of self-termination of re-entrant arrhythmias. (c) 2002 American Institute of Physics.

Journal Article↗
PubMed1989

Malignant melanoma of the iris in xeroderma pigmentosum.

Xeroderma pigmentosum is an autosomal recessive, precancerous dermatosis caused by defective repair of ultraviolet-damaged DNA. Characterized clinically by progressive cutaneous pigmentary alterations and tumorigenesis, it serves as a model for ultraviolet carcinogenesis. We describe the clinical and histopathologic findings in a 31-year-old woman with xeroderma pigmentosum and a massive iris melanoma of the left eye. Histologic examination following enucleation revealed diffuse iris replacement by spindle and epithelioid cells with extension into the trabecular meshwork. Evidence of direct extraocular extension was absent, and a metastatic evaluation showed no abnormalities. To our knowledge, this is the first reported case of xeroderma pigmentosum complicated by melanoma of the iris. It provides further evidence suggesting a role for sunlight exposure in the pathogenesis of uveal melanoma.

Adult↗