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PubMed2006

Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activity.

RPE65 is the isomerohydrolase in the retinoid visual cycle essential for recycling of 11-cis retinal, the chromophore for visual pigments in both rod and cone photoreceptors. Mutations in the RPE65 gene are associated with inherited retinal dystrophies with unknown mechanisms. Here we show that two point mutations of RPE65, R91W and Y368H, identified in patients with retinal dystrophies both abolished the isomerohydrolase activity of RPE65 after a subretinal injection into the Rpe65-/- mice and in the in vitro isomerohydrolase activity assay, independent of their protein levels. Further, the R91W and Y368H mutants showed significantly decreased protein levels but unchanged mRNA levels when compared with the wild-type RPE65 (wtRPE65). Protein stability analysis showed that wtRPE65 is a fairly stable protein, with an apparent half-life longer than 10 h, when expressed in 293A cells. Under the same conditions, mutants R91W and Y368H both showed substantially decreased protein stabilities, with half-lives less than 2 and 6 h, respectively. Subcellular fractionation and Western blot analysis demonstrated that wtRPE65 predominantly exists in the membrane fraction, while both of the mutants are primarily distributed in the cytosolic fraction, suggesting that these mutations disrupt the membrane association of RPE65. However, palmitoylation assay showed that wtRPE65 and both of the mutants were palmitoylated. These results suggest that these mutations may result in critical structural alterations of RPE65 protein, disrupt its membrane association, and consequently impair its isomerohydrolase activity, leading to retinal degeneration.

Animals↗

PubMed2005

Cluster synchronization in an ensemble of neurons interacting through chemical synapses.

In networks of periodically firing spiking neurons that are interconnected with chemical synapses, we analyze a cluster state, where an ensemble of neurons are subdivided into a few clusters, in each of which neurons exhibit perfect synchronization. To clarify stability of the cluster state, we decompose linear stability of the solution into two types of stabilities, stability of a mean state and stabilities of clusters. Computing Floquet matrices for these stabilities, we clarify the total stability of the cluster state for any type of neuron and any strength of interaction even if the size of networks is infinitely large. First, we apply this stability analysis to investigating synchronization in the large ensemble of integrate-and-fire (IF) neurons. In one-cluster state we find the change of stability of a cluster, which elucidates that in-phase synchronization of IF neurons occurs with only inhibitory synapses. Then, we investigate entrainment of two clusters of IF neurons with different excitability. IF neurons with fast decaying synapses show low entrainment capability, which is explained by a pitchfork bifurcation appearing in the two-cluster state with change of synapse decay time constant. Second, we analyze a one-cluster state of Hodgkin-Huxley (HH) neurons and discuss the difference in synchronization properties between IF neurons and HH neurons.

Action Potentials↗

PubMed2002

Advantages of continuous over batch reactors for the kinetic analysis of enzymes inhibited by an unknown substrate impurity.

A new experimental technique, employing a continuous stirred-tank reactor, for studying enzyme kinetics in the presence of inhibitor-contaminated substrate is described. The proposed method is simulated mathematically for competitive, uncompetitive, and mixed-type noncompetitive inhibition. The step-by-step experimental procedure is described, as is the necessary data analysis for determining the kinetic parameters. Differences in system response for enzyme inhibition by excess substrate and by an impurity are illustrated, and a stability analysis of the system is performed.

Bioreactors↗

PubMed2002

Analytical properties and optimization of time-delayed feedback control.

Time-delayed feedback control is an efficient method for stabilizing unstable periodic orbits of chaotic systems. If the equations governing the system dynamics are known, the success of the method can be predicted by a linear stability analysis of the desired orbit. Unfortunately, the usual procedures for evaluating the Floquet exponents of such systems are rather intricate. We show that the main stability properties of the system controlled by time-delayed feedback can be simply derived from a leading Floquet exponent defining the system behavior under proportional feedback control. Optimal parameters of the delayed feedback controller can be evaluated without an explicit integration of delay-differential equations. The method is valid for low-dimensional systems whose unstable periodic orbits are originated from a period doubling bifurcation and is demonstrated for the Rössler system and the Duffing oscillator.

Journal Article↗

PubMedDate not supplied

24-42 month stability of internal blood standards for glycated hemoglobin analysis.

The stability of fresh and out-of-date Blood Bank standards for quality control of glycated hemoglobin testing was extensively documented. Eight blood standards were prepared as aliquots of washed erythrocytes, stored at -70 degrees C, and assayed in duplicate repeatedly for 24 to 42 months. Significant differences over time were noted only occasionally, and exhibited no consistent trend. Ambient room temperature, 'season of the year', and various mini-column lot numbers had no consistent effect on any blood standard values. In conclusion, washed erythrocytes from controls and patients with IDDM can be stored for future analysis for at least 24 months at -70 degrees C. Out-of-date blood from the Blood Bank can be used with equal stability for at least 18 months.

Diabetes Mellitus↗

PubMed1983

Analysis of a model of a vertically transmitted disease.

A model is presented of a disease that can be transmitted directly from parent to offspring (vertical transmission) as well as through contact with infectives. A global stability analysis is given for the basic model and the epidemiological effects of vertical transmission are discussed. The effects of the addition of maturation and incubation delays as well as spatial diffusion are analyzed in some special cases.

Communicable Diseases↗

PubMed2002

Weakly nonlinear analysis of the electrohydrodynamic instability of a charged membrane.

The effect of nonlinear interactions on the linear instability of shape fluctuations of a flat charged membrane immersed in a fluid is analyzed using a weakly nonlinear stability analysis. There is a linear instability when the surface tension reduces below a critical value for a given charge density, because a displacement of the membrane surface causes a fluctuation in the counterion density at the surface, resulting in an additional Maxwell normal stress at the surface which is opposite in direction to the stress caused by surface tension. The nonlinear analysis shows that at low surface charge densities, the nonlinear interactions saturate the growth of perturbations resulting in a new steady state with a fluctuation amplitude determined by the balance between the destabilizing electrodynamic force and surface tension. As the surface charge density is increased, the nonlinear terms destabilize the perturbations, and the bifurcation is subcritical. There is also a significant difference in the predictions of the approximate Debye-Huckel and more exact Poisson-Boltzmann equations at high charge densities, with the former erroneously predicting that the bifurcation is supercritical at all charge densities.

Biophysical Phenomena↗

PubMed2006

Model based analysis of sleep disordered breathing in congestive heart failure.

We employed a computational model of the respiratory control system to examine which of several factors, in isolation and in combination, can contribute to or explain the development of Cheyne-Stokes breathing (CSB). Our approach uses a graphical method for stability analysis similar, in concept, to the phase plane. The results from the computer simulations indicate that a postulated three-fold increase in the chemosensitivity of the central chemoreflex (CCR) loop may, by itself, explain development of CSB. By contrast, a similar increase in the chemosensitivity of the peripheral chemoreflex (PCR) loop cannot, by itself, account for CSB. The analysis reveals that the system is more readily destabilized by increasing the gain of only one chemoreflex loop than by a combined increase in gain of both loops. Reduction in the cardiac output or cardiomegaly decreases the size of the stability region. We conclude that development of CSB is the result of a complex interaction between CCR and PCR loops which may, in turn, interact with decreased cardiac output and cardiomegaly.

Blood Gas Analysis↗

PubMed1989

[The use of DNA from phage M13 for the analysis of interindividual polymorphism of human DNA as demonstrated by a population study in Krasnodar city].

Hypervariable "minisatellite" regions detected in human genome by wild-type M13 DNA were found to have high polymorphism and somatic stability. Analysis of individual specific patterns of 34 human DNAs from Krasnodar population is presented. The observed length of fragments ranged from 2 to 6 kb. The mean frequency of a fragment in the population under study is p = 0.247 +/- 0.171, the mean number of fragments per individual being x = 9.35 +/- 1.95. The mean probability of individual identification is calculated to be 1-2.10(-6) = 0.999998.

Coliphages↗

PubMed2006

Evidence that alkyl substitution provides little stabilization to radicals: the C-C bond test and the nonbonded interaction contradiction.

Although the C-H bond dissociation energies of alkanes have been widely employed as measures of radical stability, it is shown here that the assumptions needed for that conclusion are incompatible with experimental and computational data related to C-C bond dissociation energies. Calculations at the QCISD(T)/6-311+G(d,p) level on model systems show that 1,3 nonbonded interactions in alkanes are repulsive, whereas the conventional radical stabilization analysis of bond dissociation energies requires that they become more attractive with increasing steric bulk. This result puts a severe limit on the role that radical stabilization can play and indicates that another factor must be responsible for the observed variation in the C-H bond dissociation energies of alkanes.

Journal Article↗

PubMed2006

Mathematical analysis of a free-boundary model for lung branching morphogenesis.

Lung branching morphogenesis has been widely studied in the field of developmental biology. Lung airway trees consist of relatively regular-sized distal branches, but how this regular branched pattern is formed is not well understood. In the present study, we undertake a detailed mathematical analysis of the model proposed in (Hartmann & Miura (2006), which numerically captures branching morphogenesis of the simplest possible experimental system in vitro. We investigate analytically the stability of 1D travelling waves with respect to periodic perturbations in two dimensions. This linear stability analysis leads to the so-called dispersion relations, predicting that a certain representative length dominates in this model. As the analytical analysis is restricted to travelling waves, we generalize the linear analysis to any 1D solution by numerical simulations. Both results predict how the representative lengths will change by experimentally changing specific parameters. Finally, we discuss the importance of the analytical results from a biological point of view and propose an experimental scheme for a quantitative comparison between experiments and theory.

Algorithms↗

PubMed2006

Dynamics of two-dimensional coherent structures in nonlocal nonlinear media.

We study stability and dynamics of the single cylindrically symmetric solitary structures and dipolar solitonic molecules in spatially nonlocal media. The main properties of the solitons, vortex solitons, and dipolar solitons are investigated analytically and numerically. The vortices and higher-order solitons show the transverse symmetry-breaking azimuthal instability below some critical power. We find the threshold of the vortex soliton stabilization using the linear stability analysis and direct numerical simulations. The higher-order solitons, which have a central peak and one or more surrounding rings, are also demonstrated to be stabilized in nonlocal nonlinear media. Using direct numerical simulations, we find a class of radially asymmetric, dipolelike solitons and show that, at sufficiently high power, these structures are stable.

Journal Article↗

PubMed2005

Interaction of RNA-binding proteins HuR and AUF1 with the human ATF3 mRNA 3'-untranslated region regulates its amino acid limitation-induced stabilization.

ATF3 expression is induced in cells exposed to a variety of stress conditions, including nutrient limitation. Here we demonstrated that the mechanism by which the ATF3 mRNA content is increased following amino acid limitation of human HepG2 hepatoma cells is mRNA stabilization. Analysis of ATF3 mRNA turnover revealed that the half-life was increased from about 1 h in control cells to greater than 8 h in the histidine-deprived state, demonstrating mRNA stabilization in response to nutrient deprivation. Treatment of HepG2 cells with thapsigargin, which causes endoplasmic reticulum stress, also increased the half-life of ATF3 mRNA. HuR is an RNA-binding protein that regulates both the stability and cytoplasmic/nuclear localization of mRNA species containing AU-rich elements. Another RNA-binding protein, AUF1, regulates target mRNA molecules by enhancing their decay. Amino acid limitation caused a slightly elevated mRNA level for HuR and AUF1 mRNA. The nuclear HuR protein content was unchanged, and AUF1 protein increased slightly after amino acid limitation, whereas the cytoplasmic levels of both HuR and AUF1 protein increased. Immunoprecipitation of HuR-RNA complexes followed by reverse transcriptase-PCR analysis showed that HuR interacted with ATF3 mRNA in vivo and that this interaction increased following amino acid limitation. In contrast, the interaction of AUF1 with the ATF3 mRNA is decreased in histidine-deprived cells relative to control cells. Suppression of HuR expression by RNA interference partially blocked the accumulation of ATF3 mRNA following amino acid deprivation. The results demonstrated that coordinated regulation of mRNA stability by HuR and AUF1 proteins contributes to the observed increase in ATF3 expression following amino acid limitation.

3' Untranslated Regions↗

PubMed2003

Hydrodynamic instability of a thin viscous film between two drops.

Linear stability analysis is employed to derive analytical expressions for the growth rate of disturbances applied to a thin plane-parallel film trapped between two drops. From these expressions, the band of unstable wavenumbers and the "most dangerous" wavenumber are identified for systems in the absence and presence of insoluble surfactant. Marangoni effects are shown to exert a stabilizing influence and reasonably good agreement with experimental observations is found. Subsequent nonlinear analysis indicated amplification of the disturbance growth rate beyond that suggested by linear theory as the film proceeded toward rupture.

Journal Article↗

PubMed2002

Instability for shearing of an electrified Kelvin fluid sheet with or without supporting surface charges.

The present study demonstrates the instability of streaming in a fluid layer sandwiched between two other bounded fluids under the influence of a vertical periodic electric field. The fluids are of a viscoelastic nature where the constitutive equation is Kelvin type. Due to the inclusion of streaming flow and the influence of a periodic force, a mathematical simplification is urged. Equation of motion is solved in light of the weakness effect for the viscoelastic properties. The instabilization of the problem is examined in view of the linearization of the perturbation approach. The boundary value problem is discussed for a charged or uncharged fluid sheet. Both cases are lead to derive linear coupled Mathieu equations with complex coefficients and damping terms. Stability analysis is discussed through a simplified configuration for the system of Mathieu equations. It is found that the elasticity parameters as well as the viscosity parameters have a stabilizing influence. The field frequency plays a destabilizing role in the presence of surface charges and a dual role in the absence of surface charges. The presence of surface charges retards the stabilizing influence of the viscoelastic effects. This calculation shows that the fluid velocity retards the destabilizing influence for the electric field. The increase of the thickness of the fluid sheet plays two different roles. A stabilizing role in the presence of surface charges and a destabilizing influence in their absence.

Journal Article↗

PubMed1992

Oscillations in a model of repression with external control.

A mathematical model for control by repression by an extracellular substance is developed, including diffusion and time delays. The model examines how active transport of a nutrient can produce either oscillatory or stable responses depending on a variety of parameters, such as diffusivity, cell size, or nutrient concentration. The system of equations for the mathematical model is reduced to a system of delay differential equations and linear Volterra equations. After linearizing these equations and forming the limiting Volterra equations, the resulting linear system no longer has any spatial dependence. Local stability analysis of the radially symmetric model shows that the system of equations can undergo Hopf bifurcations for certain parameter values, while other ranges of the parameters guarantee asymptotic stability. One numerical study shows that the model can exhibit intracellular biochemical oscillations with increasing extracellular concentrations of the nutrient, which suggests a possible trigger mechanism for morphogenesis.

Bacterial Physiological Phenomena↗

PubMed2004

Stable adaptive neurocontrol for nonlinear discrete-time systems.

This paper presents a novel approach in designing neural network based adaptive controllers for a class of nonlinear discrete-time systems. This type of controllers has its simplicity in parallelism to linear generalized minimum variance (GMV) controller design and efficiency to deal with complex nonlinear dynamics. A recurrent neural network is introduced as a bridge to compensation simplify controller design procedure and efficiently to deal with nonlinearity. The network weight adaptation law is derived from Lyapunov stability analysis and the connection between convergence of the network weight and the reconstruction error of the network is established. A theorem is presented for the conditions of the stability of the closed-loop systems. Two simulation examples are provided to demonstrate the efficiency of the approach.

Neural Networks, Computer↗

PubMed1998

Mutational analysis of p50E4F suggests that DNA binding activity is mediated through an alternative structure in a zinc finger domain that is regulated by phosphorylation.

p50E4F is a cellular transcription factor whose DNA binding activity is stimulated in a phosphorylation-dependent manner by products of the adenovirus E1A oncogene. Although p50E4F does not contain a bZIP DNA binding motif, it binds a tandemly repeated palindromic sequence in the adenovirus E4 promoter that is recognized by a large number of bZIP proteins, but with much greater stability. Analysis of deletions in the p50E4F sequence identified the regions that are responsible for its unique DNA binding properties. Sequence-specific DNA binding and factor dimerization were localized to a C-terminal region containing two C2H2and one CCHC zinc finger motifs; the phosphorylation site critical for DNA binding activity was also localized to this domain. The high stability of p50E4F binding also required residues within the first 83 amino acids of the N-terminus. Analysis of single and double amino acid substitutions in the C-terminal zinc finger domain demonstrated that while the second C2H2zinc finger was required for DNA binding activity, the putative structures of the first C2H2and the CCHC zinc fingers were not. Instead, residues from these other zinc finger motifs appeared to participate in an alternative structure that mediates DNA binding activity and is regulated by phosphorylation.

Amino Acid Sequence↗