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Boundaries of two-tone rate suppression of cochlear-nerve activity.

Two-tone rate suppression was examined in the responses of single cochlear-nerve fibers in Mongolian gerbils. The iso-rate tracking algorithm developed by Kiang and Moxon (Kiang, N.Y.-S. and Moxon, E.C. (1974): J. Acoust Soc. Am. 55, 620-630) for obtaining tuning curves was modified to track iso-rate suppression boundaries as a function of frequency with the excitor tone fixed at the characteristic frequency (CF) of the fiber. Lower threshold boundaries of the areas of suppression flanking the tuning curve above and below CF were outlined for fibers over a large CF range. It was found that the boundaries of rate suppression obtained below CF were very stable in their absolute positions on the intensity-frequency plane. This stability was evident both as a function of fiber CF (0.6-15 kHz) and as a function of the shape of the tuning curve at a given CF. In other words, the suppression boundary obtained below CF was largely independent of the tuning curve. In a second series of experiments tuning curves were taken in the presence of a fixed tone placed in the suppression area located above the fiber CF. The fixed tone by itself was not excitatory. These tuning curves were compared to tuning curves obtained with a single tone. It was found that frequencies around the fiber CF were most affected (suppressed) by the presence of the second tone, and that the low-frequency tail of the tuning curve tended to shift toward the boundary of the suppression area below CF. Because this suppression boundary lies below the threshold of the normal tail of the tuning curve for many mid- and high-CF fibers, these fibers often became hypersensitive at low frequencies in the presence of the second tone above CF.

Acoustic Stimulation↗

Comparison of calculation and experiment implicates significant electrostatic contributions to the binding stability of barnase and barstar.

The contributions of electrostatic interactions to the binding stability of barnase and barstar were studied by the Poisson-Boltzmann model with three different protocols: a), the dielectric boundary specified as the van der Waals (vdW) surface of the protein along with a protein dielectric constant (epsilon (p)) of 4; b), the dielectric boundary specified as the molecular (i.e., solvent-exclusion (SE)) surface along with epsilon (p) = 4; and c), "SE + epsilon (p) = 20." The "vdW + epsilon (p) = 4" and "SE + epsilon (p) = 20" protocols predicted an overall electrostatic stabilization whereas the "SE + epsilon (p) = 4" protocol predicted an overall electrostatic destabilization. The "vdW + epsilon (p) = 4" protocol was most consistent with experiment. It quantitatively reproduced the observed effects of 17 mutations neutralizing charged residues lining the binding interface and the measured coupling energies of six charge pairs across the interface and reasonably rationalized the experimental ionic strength and pH dependences of the binding constant. In contrast, the "SE + epsilon (p) = 4" protocol predicted significantly larger coupling energies of charge pairs whereas the "SE + epsilon (p) = 20" protocol did not predict any pH dependence. This study calls for further scrutiny of the different Poisson-Boltzmann protocols and demonstrates potential danger in drawing conclusions on electrostatic contributions based on a particular calculation protocol.

Bacterial Proteins↗

Pore-network study of the characteristic periods in the drying of porous materials.

We study the periods that develop in the drying of capillary porous media, particularly the constant rate (CRP) and the falling rate (FRP) periods. Drying is simulated with a 3-D pore-network model that accounts for the effect of capillarity and buoyancy at the liquid-gas interface and for diffusion through the porous material and through a boundary layer over the external surface of the material. We focus on the stabilizing or destabilizing effects of gravity on the shape of the drying curve and the relative extent of the various drying periods. The extents of CRP and FRP are directly associated with various transition points of the percolation theory, such as the breakthrough point and the main liquid cluster disconnection point. Our study demonstrates that when an external diffusive layer is present, the constant rate period is longer.

Desiccation↗

Foam and wetting films: electrostatic and steric stabilization.

Foam films and wetting films on quartz, obtained from aqueous solutions of two different surfactants [cetyltrimethylammonium bromide (CTAB) and PEO-PPO-PEO triblock copolymer (F108)] with NaCl as a background electrolyte, are considered as convenient models to compare the properties of symmetric (free thin liquid films) and asymmetric (thin liquid films on solid substrate) films with the same air/solution interface. Microinterferometric methodology of assessment of foam and wetting films is used to allow precise determination of the film thickness. In the case of CTAB films, experimental data for the potential phi(0) of the diffuse electric layer at the solution/air interface and the potential phi(1) at the solution/quartz interface are used to analyze the stability of the films studied. A conclusion drawn is that electrostatic interaction forces stabilize both kinds of films studied. It is shown that with increasing CTAB concentration a charge reversal occurs at both the solution/air and solution/quartz interfaces that determines the stability/instability of the foam and wetting films. Concentration ranges where both types of films produce stable (equilibrium) films are found. There are also concentration ranges where the films either rupture or are metastable (quasi-equilibrium). The CTAB concentration ranges, which provide formation of unstable (rupturing and metastable) and stable films, are different for symmetric (foam) and asymmetric (wetting) thin liquid films. It is only at high CTAB concentrations (>2 x 10(-4) mol dm(-3)) that both cases render formation of stable equilibrium films. In the case of F108 films, the comparison of foam films and wetting films on quartz indicates film stability that is either electrostatic or steric in origin. On the basis of the effect of electrolyte concentration on film thickness, the transition from electrostatic to steric stabilization is demonstrated for both kinds of films. The critical electrolyte concentration at which this transition occurs is determined. Foam films are found to be always stable (equilibrium). Formation of either unstable (rupturing and metastable) or stable (equilibrium) wetting films on quartz is established depending on the solution composition. The effects are similar for both hydrophilic and hydrophobic quartz surfaces. The results obtained show certain similarity between foam and wetting films. In both cases, electrostatic forces below the critical electrolyte concentration, and above it steric forces govern film stability. Some specific properties of the wetting films are induced by the asymmetric boundary conditions as distinct from symmetric foam films.

Journal Article↗

Yeast chorismate mutase in the R state: simulations of the active site.

The isomerization of chorismate to prephenate by chorismate mutase in the biosynthetic pathway that forms Tyr and Phe involves C5---O (ether) bond cleavage and C1---C9 bond formation in a Claisen rearrangement. Development of negative charge on the ether oxygen, stabilized by Lys-168 and Glu-246, is inferred from the structure of a complex with a transition state analogue (TSA) and from the pH-rate profile of the enzyme and the E246Q mutant. These studies imply a protonated Glu-246 well above pH 7. Here, several 500-ps molecular dynamics simulations test the stability of enzyme-TSA complexes by using a solvated system with stochastic boundary conditions. The simulated systems are (i) protonated Glu-246 (stable), (ii) deprotonated Glu-246 (unstable), (iii) deprotonated Glu-246 plus one H2O between Glu-246 and the ether oxygen (unstable), (iv) the E246Q mutant (stable), and (v) addition of OH- between protonated Glu-246 and the ether oxygen. In (v), a local conformational change of Lys-168 displaced the OH- into the solvent region, suggesting a possible rate-determining step that precedes the catalytic step. In a 500-ps simulation of the enzyme complexed with the reactant chorismate or the product prephenate, no water molecule remained near the oxygen of the ligand. Calculations using the linearized Poisson-Boltzmann equation show that the effective pKa of Glu-246 is shifted from 5.8 to 8.1 as the negative charge on the ether oxygen of the TSA is changed from -0.56 electron to -0.9 electron. Altogether, these results support retention of a proton on Glu-246 to high pH and the absence of a water molecule in the catalytic steps.

Binding Sites↗

Cdc7p-Dbf4p kinase binds to chromatin during S phase and is regulated by both the APC and the RAD53 checkpoint pathway.

Eukaryotic cells coordinate chromosome duplication by assembly of protein complexes at origins of DNA replication and by activation of cyclin-dependent kinase and Cdc7p-Dbf4p kinase. We show in Saccharomyces cerevisiae that although Cdc7p levels are constant during the cell division cycle, Dbf4p and Cdc7p-Dbf4p kinase activity fluctuate. Dbf4p binds to chromatin near the G(1)/S-phase boundary well after binding of the minichromosome maintenance (Mcm) proteins, and it is stabilized at the non-permissive temperature in mutants of the anaphase-promoting complex, suggesting that Dbf4p is targeted for destruction by ubiquitin-mediated proteolysis. Arresting cells with hydroxyurea (HU) or with mutations in genes encoding DNA replication proteins results in a more stable, hyper-phosphorylated form of Dbf4p and an attenuated kinase activity. The Dbf4p phosphorylation in response to HU is RAD53 dependent. This suggests that an S-phase checkpoint function regulates Cdc7p-Dbf4p kinase activity. Cdc7p may also play a role in adapting from the checkpoint response since deletion of CDC7 results in HU hypersensitivity. Recombinant Cdc7p-Dbf4p kinase was purified and both subunits were autophosphorylated. Cdc7p-Dbf4p efficiently phosphorylates several proteins that are required for the initiation of DNA replication, including five of the six Mcm proteins and the p180 subunit of DNA polymerase alpha-primase.

Cell Cycle Proteins↗

mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor.

Nonsense mutations in a gene can accelerate the decay rate of the mRNA transcribed from that gene, a phenomenon we describe as nonsense-mediated mRNA decay. Using amber (UAG) mutants of the yeast PGK1 gene as a model system, we find that nonsense-mediated mRNA decay is position dependent, that is, nonsense mutations within the initial two-thirds of the PGK1-coding region accelerate the decay rate of the PGK1 transcript < or = 12-fold, whereas nonsense mutations within the carboxy-terminal third of the coding region have no effect on mRNA decay. Moreover, we find that this position effect reflects (1) a requirement for sequences 3' to the nonsense mutation that may be necessary for translational reinitiation or pausing, and (2) the presence of an additional sequence that, when translated, inactivates the nonsense-mediated mRNA decay pathway. This stabilizing element is positioned within the coding region such that it constitutes the boundary between nonsense mutations that do or do not affect mRNA decay. Rapid decay of PGK1 nonsense-containing transcripts is also dependent on the status of the UPF1 gene. Regardless of the position of an amber codon in the PGK1 gene, deletion of the UPF1 gene restores wild-type decay rates to nonsense-containing PGK1 transcripts.

Base Sequence↗

The boundary layer of swimming fish.

Tangential and normal velocity profiles of the boundary layer surrounding live swimming fish were determined by digital particle tracking velocimetry, DPTV. Two species were examined: the scup Stenotomus chrysops, a carangiform swimmer, and the smooth dogfish Mustelus canis, an anguilliform swimmer. Measurements were taken at several locations over the surfaces of the fish and throughout complete undulatory cycles of their propulsive motions. The Reynolds number based on length, Re, ranged from 3x10(3) to 3x10(5). In general, boundary layer profiles were found to match known laminar and turbulent profiles including those of Blasius, Falkner and Skan and the law of the wall. In still water, boundary layer profile shape always suggested laminar flow. In flowing water, boundary layer profile shape suggested laminar flow at lower Reynolds numbers and turbulent flow at the highest Reynolds numbers. In some cases, oscillation between laminar and turbulent profile shapes with body phase was observed. Local friction coefficients, boundary layer thickness and fluid velocities at the edge of the boundary layer were suggestive of local oscillatory and mean streamwise acceleration of the boundary layer. The behavior of these variables differed significantly in the boundary layer over a rigid fish. Total skin friction was determined. Swimming fish were found to experience greater friction drag than the same fish stretched straight in the flow. Nevertheless, the power necessary to overcome friction drag was determined to be within previous experimentally measured power outputs. No separation of the boundary layer was observed around swimming fish, suggesting negligible form drag. Inflected boundary layers, suggestive of incipient separation, were observed sporadically, but appeared to be stabilized at later phases of the undulatory cycle. These phenomena may be evidence of hydrodynamic sensing and response towards the optimization of swimming performance.

Animals↗

Computer simulation of the toroidal equilibrium and stability of a plasma in three dimensions.

A computer program has been written to solve the equations for sharp boundary magnetohydrodynamic equilibrium of a toroidal plasma in three dimensions without restriction to axial symmetry. The numerical method is based on a variational principle that indicates whether the equilibria obtained are stable. Applications have been made to Tokamak, Stellarator, and Scyllac configurations.

Journal Article↗

The quaternary structure of bovine alpha-crystallin. Effects of variation in alkaline pH, ionic strength, temperature and calcium ion concentration.

The stability of the native quaternary structure of bovine alpha-crystallin was studied, by sedimentation analysis and electron microscopy, as a function of pH (7--11), ionic strength (0.01--0.5), temperature (6--60 degrees C) and calcium ion concentration (0 and 10 mM). Three successive transitions are distinguished at 20 degrees C. Firstly, a slow transconformation step, which is independent of pH, ionic strength or calcium ions. Secondly, an irreversible primary dissociation step, favoured by increasing pH above 8 and/or a lower ionic strength, with formation of 'alkali-modified alpha-crystallin', which is spherically shaped like the native protein but has a smaller average diameter, sedimentation coefficient and molecular weight. Thirdly, with further increase of pH above 9, a rapidly reversible dissociation of alkali-modified alpha-crystallin characterized by a single reaction boundary in sedimentation velocity analysis. In the presence of calcium ions the quaternary structure is stabilized to the extent that no dissociation is observed up to at least pH 10.3. Upon increase of temperature, at pH 7.3, a slow irreversible dissociation and swelling run parallel until a limit is reached around 37 degrees C with formation of 'temperature-modified alpha-crystallin', which is indistinguishable from the native protein by electron microscopy, but has a higher relative viscosity and lower sedimentation coefficient and molecular weight. Calcium ions have little or no effect on this transition. Above 37 degrees C a reversal of this transition or aggregation is indicated. These findings, together with previous structural data on microheterogeneity, reassociation from urea, and aging of alpha-crystallin in vivo, are incorporated into a hypothetical scheme of transitions, based on a three-layer model for the quaternary structure.

Animals↗

Resonance frequency assessment of dental implant stability with various bone qualities: a numerical approach.

Resonance frequency analysis (RFA) has been used by several investigators to assess the boundary conditions of dental implants. The goal of the current study was to determine the vibrating behavior of a dental implant under various surrounding bone conditions. A 3D finite element (FE) model of a cylinder-type titanium implant was developed. In this model, the implant was embedded into a cubic section of bone. The model was first validated using a series of modal testing experiments. The effects of bony conditions on the resonance frequencies of the implant were computed with different bone types and bone densities. Our results show that the resonance frequency of the implant with type III surrounding bone decreased linearly (r = -0.996, P < 0.01) from 17.9 kHz (without loss in bone density) to 0.6 kHz (90% loss in bone density) when the bone densities were decreased. On the other hand, without bone loss, the highest resonance frequency value (36.1 kHz) was found when the implant was placed into type I surrounding bone. In contrast, the resonance frequency of the implant with type IV bone quality was found to be 9.9 kHz, which is almost four-fold less than that found in the type I model. These results suggest that RFA could serve as a non-invasive diagnostic tool for detecting the stability of dental implants during the healing stages and in subsequent routine follow-up care after treatment.

Animals↗

Stabilization of protein crystals by electrostatic interactions as revealed by a numerical approach.

We developed a novel algorithm to solve numerically the Poisson-Boltzmann equations under a periodic boundary condition. By employing this algorithm to calculate the electrostatic potentials in two different types of protein crystals, a bovine pancreatic trypsin inhibitor (BPTI) orthorhombic crystal and a pig-insulin cubic crystal, the energy contributions of the electrostatic interactions to the crystals' stability were evaluated. At a high ionic strength, the condensed state of proteins in the crystal was stabilized electrostatically compared with that isolated in dilute solution because the attractive electrostatic interactions between neighboring protein molecules overcame the repulsive forces that originated from the same net charges of the equivalent protein molecules. On the other hand, at a low ionic strength the electrostatic interactions destabilized the crystalline state of both proteins, although a different dependence on the ionic strength was found between them. Here, the insulin crystal was more stable than the BPTI one because of the higher charge density in the BPTI crystal. In all of the solvent ionic strengths investigated, the attractive electrostatic interactions between charge pairs separated by less than 5 A on the respective protein molecules prominently stabilize the protein crystals. Therefore, two protein molecules in the crystals are oriented to compensate each other for their opposite charges on the surfaces. We also found a specific role for bound phosphate ions in the stabilization of the BPTI crystal, based on comparison of the electrostatic energies of the two crystals with and without the ions. By determining the contribution of each atomic charge in the crystals to the electrostatic energy, it was revealed that several electrostatic pairs specifically contributed to the crystal's stability. On the basis of our numerical calculation results, we propose a new method to design protein molecules that adopt stable crystals by replacing destabilizing residues with stabilizing ones and by introducing specific hydrogen bonds or salt bridges between neighboring protein molecules.

Algorithms↗

The nonlinear dynamics of speech categorization.

Little is known about the processes underlying the nonlinear relationship between acoustics and speech perception. In Experiment 1, we explored the effects of systematic variation of a single acoustic parameter (silent gap duration between a natural utterance of s and a synthetic vowel ay) on judgements of speech category. The resulting shifts in category boundary between say and stay showed rich dynamics, including hysteresis, contrast, and critical boundary effects. We propose a dynamical model to account for the observed patterns. Experiment 2 evaluated one prediction of the model, that changing the relative stability of the two percepts allows categorical switching. In agreement with the model; an increase in the number of stimulus repetitions maximized the frequency of judgments of category change near the boundary. Thus, a dynamical approach affords the rudiments for a theory of the effects of temporal context on speech categorization.

Acoustic Stimulation↗

A hierarchy of global coupling induced cluster patterns during the oscillatory H2-electrooxidation reaction on a Pt ring-electrode.

We report experimental results on spatiotemporal pattern formation during the oscillatory hydrogen electrooxidation reaction on a Pt ring-electrode under negative (desynchronizing) global coupling (GC). Spatially one-dimensional profiles of the interfacial potential drop along the angular direction of the ring electrode are recorded by means of a potential probe. The dynamics is investigated as a function of two control parameters, the applied voltage U and the strength of the global coupling. The latter is adjusted either by varying the distance between the working electrode (WE) and the reference electrode (RE) or by inserting a negative impedance device in series with the WE. In the absence of global coupling, uniform oscillations were destabilized by migration coupling, and electrochemical turbulence developed at large values of U (H. Varela, C. Beta, A. Bonnefont and K. Krischer, Phys. Rev. Lett., 2005, 94, 174104; ). Already low global coupling strengths sufficed to suppress turbulence. Instead, regular two-phase clusters formed. At higher coupling strength, a second type of two-phase cluster was observed as well as two types of irregular cluster patterns, which were connected with an irregular motion of the cluster boundaries and the emergence and disappearance of clusters through splitting and merging of the boundaries, respectively. Upon increasing the coupling strength even further, five-phase clusters were stabilized and at the highest coupling strength applied the cluster patterns transformed into strongly modulated pulses. The two types of two-phase clusters and the five-phase clusters are analyzed employing several signal processing techniques.

Journal Article↗

Simulation of the gyroid phase in off-lattice models of pure diblock copolymer melts.

Particle-based molecular simulations of pure diblock copolymer (DBC) systems were performed in continuum space via dissipative particle dynamics and Monte Carlo methods for a bead-spring chain model. This model consisted of chains of soft repulsive particles often used with dissipative particle dynamics. The gyroid phase was successfully simulated in DBC melts at selected conditions provided that the simulation box size was commensurate with the gyroid lattice spacing. Simulations were concentrated at conditions where the gyroid phase is expected to be stable which allowed us to outline approximate phase boundaries. When more than one phase was observed by varying simulation box size, thermodynamic stability was discerned by comparing the Helmholtz free energy of the competing phases. For this purpose, chemical potentials were efficiently simulated via an expanded ensemble that gradually inserts/deletes a target chain to/from the system. These simulations employed a novel combination of Bennett's [J. Comput. Phys. 22, 245 (1976)] acceptance-ratio method to estimate free-energy differences and a recently proposed method to get biasing weights that maximize the number of times that the target chain is regrown. The analysis of the gyroid nodes revealed clear evidence of packing frustration in the form of an (entropically) unfavorably overstretching of chains, a phenomenon that has been suggested to provide the structural basis for the limited region of stability of the gyroid phase in the DBC phase diagram. Finally, the G phase and nodal chain stretching were also found in simulations with a completely different DBC particle-based model.

Journal Article↗

Pulse bifurcations and instabilities in an excitable medium: computations in finite ring domains.

We investigate the instabilities and bifurcations of traveling pulses in a model excitable medium; in particular, we discuss three different scenarios involving either the loss of stability or disappearance of stable pulses. In numerical simulations beyond the instabilities we observe replication of pulses ("backfiring") resulting in complex periodic or spatiotemporally chaotic dynamics as well as modulated traveling pulses. We approximate the linear stability of traveling pulses through computations in a finite albeit large domain with periodic boundary conditions. The critical eigenmodes at the onset of the instabilities are related to the resulting spatiotemporal dynamics and "act" upon the back of the pulses. The first scenario has been analyzed earlier [M. G. Zimmermann et al., Physica D 110, 92 (1997)] for high excitability (low excitation threshold): it involves the collision of a stable pulse branch with an unstable pulse branch in a so-called T point. In the framework of traveling wave ordinary differential equations, pulses correspond to homoclinic orbits and the T point to a double heteroclinic loop. We investigate this transition for a pulse in a domain with finite length and periodic boundary conditions. Numerical evidence of the proximity of the infinite-domain T point in this setup appears in the form of two saddle node bifurcations. Alternatively, for intermediate excitation threshold, an entire cascade of saddle nodes causing a "spiraling" of the pulse branch appears near the parameter values corresponding to the infinite-domain T point. Backfiring appears at the first saddle-node bifurcation, which limits the existence region of stable pulses. The third case found in the model for large excitation threshold is an oscillatory instability giving rise to "breathing," traveling pulses that periodically vary in width and speed.

Journal Article↗

Family goals as indicants of adaptation during chronic illness.

Families that successfully adapt to new situations have been found not only to appraise the situations as manageable but also to possess the necessary resources to meet the challenges. The purpose of this study was to determine the goals that families in which the mother had chronic illness identified for themselves and how these goals related to family functioning. A five-occasion, 15-month, descriptive longitudinal design was used to collect data. Data from occasions 2 and 3 were used to generate the coding scheme. This coding scheme was used to analyze the fourth-occasion data set, which is presented here. The sample at the fourth occasion consisted of 103 families in which the mother was diagnosed with breast cancer, diabetes, or fibrocystic breast disease. Content analysis of responses revealed 10 mutually exclusive categories of family goals: viability of children, cohesion, adaptation, boundary alterations, health maintenance, conflict management, individual achievements and pursuits, acquisition of possessions, financial stability, and family relocation. Types of goals identified did not significantly differ by disease type. The results suggest that family-system goals are relatively enduring and not readily discarded in response to health or illness disruption.

Adaptation, Psychological↗

Interaction of pyridinium bis-retinoid (A2E) with bilayer lipid membranes.

The accumulation of lipofuscin granules within the retinal pigment epithelium (RPE) cells is correlated with the progression of age-related macular degeneration. One of the fluorophores contained in lipofiscin granules is pyridinium bis-retinoid (A2E). To test its membrane-toxic effect, the interaction of A2E with bilayer lipid membranes (BLM) was studied. The incorporation of charged A2E molecules into the membranes has been detected as a change of either zeta-potential of multilayer liposomes or boundary potential of BLM. It was shown that the presence of up to 25mol% of A2E did not destabilize the bilayers made of saturated phosphatidylcholine (PC). However, the destabilizing effect became very significant when BLM contained negatively charged lipids such as cardiolipin or phosphatidylserine. The electrical breakdown measurements revealed that the A2E-induced decrease of BLM stability was primarily associated with the growing probability of lipid pore formation. It was found from the measurements of boundary potential of BLM that exposure of A2E to light initiates its transformation into at least two products. One of them is epoxy-A2E, which, being hydrophilic, moves from the membrane into water solution. The other product is a non-identified hydrophobic substance. Illumination of A2E-containing BLM made from unsaturated PC by visible light caused the membrane damage presumably due to oxidation of these lipids by singlet oxygen generated by excited A2E molecules. However, this effect was very weak compared to the effect of known photosensitizers. The illumination of BLM with A2E also leads to the damage of gramicidin incorporated into the membrane, as was detected by measuring the conductance of channels formed by this peptide.

Electrochemistry↗