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PubMed2004

Simultaneous surface plasmon resonance and quartz crystal microbalance with dissipation monitoring measurements of biomolecular adsorption events involving structural transformations and variations in coupled water.

Simultaneous quartz crystal microbalance with dissipation monitoring (QCM-D) and surface plasmon resonance (SPR) measurements are used to analyze the surface kinetics of two biomacromolecular systems, one lipid and one protein based, undergoing surface-induced conformational changes. First we establish a theoretical platform, which allows quantitative analysis of the combined SPR and QCM-D data. With this theoretical base, new information can be extracted, not obtainable with either technique alone. As an example we demonstrate how time-resolved measurements with these two techniques in combination--yielding three independent measured quantities--add new information about (i) kinetics, i.e. number of adsorbed molecules per unit area versus time, and (ii) temporal variation in the mass fraction of coupled water versus coverage. In particular, it is demonstrated for the first time, how the kinetics of the process during which adsorbed vesicles are spontaneously transformed into a supported phospholipid bilayer (SPB) on SiO(2) can be quantitatively separated into its two dominating states: adsorbed vesicles and supported planar bilayer patches. In addition, the relevance of dynamically coupled water for interpretation and modeling of the QCM-D response during bilayer formation is discussed and further illustrated with a second model system: streptavidin adsorption on a biotin-modified SPB. A very strong coverage dependence in the number of water molecules per protein sensed by the QCM is demonstrated, with strong implications for the use of QCM as a tool for quantitative determination of protein mass uptake kinetics.

Adsorption↗
PubMed2005

Architectural and synaptic mechanisms underlying coherent spontaneous activity in V1.

To investigate the existence and the characteristics of possible cortical operating points of the primary visual cortex, as manifested by the coherent spontaneous ongoing activity revealed by real-time optical imaging based on voltage-sensitive dyes, we studied numerically a very large-scale ( approximately 5 x 10(5)) conductance-based, integrate-and-fire neuronal network model of an approximately 16-mm(2) patch of 64 orientation hypercolumns, which incorporates both isotropic local couplings and lateral orientation-specific long-range connections with a slow NMDA component. A dynamic scenario of an intermittent desuppressed state (IDS) is identified in the computational model, which is a dynamic state of (i) high conductance, (ii) strong inhibition, and (iii) large fluctuations that arise from intermittent spiking events that are strongly correlated in time as well as in orientation domains, with the correlation time of the fluctuations controlled by the NMDA decay time scale. Our simulation results demonstrate that the IDS state captures numerically many aspects of experimental observation related to spontaneous ongoing activity, and the specific network mechanism of the IDS may suggest cortical mechanisms and the cortical operating point underlying observed spontaneous activity.

Animals↗
PubMed1997

The effects of a pool of dispersers on host-parasitoid systems.

When individuals migrate in a multi-patch environment, a considerable proportion of their lifetime might be spent in transit between patches. We investigate the effects such a pool of dispersers can have on local stability and dynamics for a variety of multi-patch host-parasitoid models. When an arbitrary number of patches with internal Lotka-Volterra dynamics is coupled via a global pool of dispersers, the equilibrium is globally stable. The global pool is stabilising if dispersal is by hosts only, by parasitoids only, or by both hosts and parasitoids. If dispersal is local such that individuals first enter a pool close to the patch where they originate and then disperse to adjacent pools, the equilibrium is locally stable. We also analyse the situation where the functional response of parasitoids within a patch is Holling type II which is known to destabilise host-parasitoid systems. Coupling this single patch to a pool of dispersers can produce a locally stable interaction, provided the handling time of hosts is not too long. However, the pool provides a biologically realistic example of an interaction that is locally stable but not permanent. The longer the handling time, the smaller the region of population densities within which populations converge to the equilibrium state. In a multi-patch environment with a global disperser pool, the dynamics of the system are not qualitatively different from the single patch case (i.e. the equilibrium can be locally stable but the system is not permanent). In a multi-patch environment with local disperser pools, true spatial interactions between patches can develop. In contrast to the global pool, local pools can destabilise the stable equilibrium of the single patch case. Limit cycles develop around this unstable equilibrium that lead to extremely complicated dynamics. In contrast to the global pool, a system of local pools can exhibit bounded fluctuations so that populations do not go extinct.

Animals↗
PubMed2002

Drifting pattern domains in a reaction-diffusion system with nonlocal coupling.

Drifting pattern domains (DPDs), i.e., moving localized patches of traveling waves embedded in a stationary (Turing) pattern background and vice versa, are observed in simulations of a reaction-diffusion model with nonlocal coupling. Within this model, a region of bistability between Turing patterns and traveling waves arises from a codimension-2 Turing-wave bifurcation (TWB). DPDs are found within that region in a substantial distance from the TWB. We investigated the dynamics of single interfaces between Turing and wave patterns. It is found that DPDs exist due to a locking of the interface velocities, which is imposed by the absence of space-time defects near these interfaces.

Journal Article↗
PubMed1976

Spatial properties of horizontal cell responses in the turtle retina.

1. Intracellular recordings were made from horizontal cells in the retina of the turtle Pseudemys scripta elegans. Spatial properties of the responses were determined using brief flashes of monochromatic light. 2. For a light stimulus in the form of a long narrow slit the peak response decayed approximately exponentially with displacement from the centred position. 3. With variation in the area of a centred circular patch, the peak response increased in a graded manner with stimulus area but was not proportional to area. 4. The model of electrical coupling in the horizontal cell layer proposed by Naka & Rushton (1976) was applied to the results. For the case of dim illumination a simplification is applicable, and the voltage distribution for circular and slit-shaped patches of light can be expressed in terms of two unknowns: the voltage resulting from diffuse illumination and a characteristic 'length constant'. 5. The measured variation of response amplitude was well described by the theory. Measured length constants were distributed from less than 100 mum to greater than 1 mm, and in a given cell the values determined by the slit displacement method and the area variation method were in reasonable agreement. 6. It is concluded that with dim illumination the model provides an accurate description of the voltage spread in the cells. Deviations were found to occur at higher intensities and possible reasons are discussed. 7. The implications of the model on the measurement of resistance changes during illunination are discussed.

Action Potentials↗
PubMed2001

A methodology for achieving high-speed rates for artificial conductance injection in electrically excitable biological cells.

We present a novel approach to implementing the dynamic-clamp protocol (Sharp et al., 1993), commonly used in neurophysiology and cardiac electrophysiology experiments. Our approach is based on real-time extensions to the Linux operating system. Conventional PC-based approaches have typically utilized single-cycle computational rates of 10 kHz or slower. In thispaper, we demonstrate reliable cycle-to-cycle rates as fast as 50 kHz. Our system, which we call model reference current injection (MRCI); pronounced merci is also capable of episodic logging of internal state variables and interactive manipulation of model parameters. The limiting factor in achieving high speeds was not processor speed or model complexity, but cycle jitter inherent in the CPU/motherboard performance. We demonstrate these high speeds and flexibility with two examples: 1) adding action-potential ionic currents to a mammalian neuron under whole-cell patch-clamp and 2) altering a cell's intrinsic dynamics via MRCI while simultaneously coupling it via artificial synapses to an internal computational model cell. These higher rates greatly extend the applicability of this technique to the study of fast electrophysiological currents such fast a currents and fast excitatory/inhibitory synapses.

Animals↗
PubMed2006

Desensitization of mechano-gated K2P channels.

The neuronal mechano-gated K2P channels TREK-1 and TRAAK show pronounced desensitization within 100 ms of membrane stretch. Desensitization persists in the presence of cytoskeleton disrupting agents, upon patch excision, and when channels are expressed in membrane blebs. Mechanosensitive currents evoked with a variety of complex stimulus protocols were globally fit to a four-state cyclic kinetic model in detailed balance, without the need to introduce adaptation of the stimulus. However, we show that patch stress can be a complex function of time and stimulation history. The kinetic model couples desensitization to activation, so that gentle conditioning stimuli do not cause desensitization. Prestressing the channels with pressure, amphipaths, intracellular acidosis, or the E306A mutation reduces the peak-to-steady-state ratio by changing the preexponential terms of the rate constants, increasing the steady-state current amplitude. The mechanical responsivity can be accounted for by a change of in-plane area of approximately 2 nm2 between the closed and open conformations. Desensitization and its regulation by chemical messengers is predicted to condition the physiological role of K2P channels.

Animals↗
PubMed2006

Evidence for association of GABA(B) receptors with Kir3 channels and regulators of G protein signalling (RGS4) proteins.

Many neurotransmitters and hormones signal by stimulating G protein-coupled neurotransmitter receptors (GPCRs), which activate G proteins and their downstream effectors. Whether these signalling proteins diffuse freely within the plasma membrane is not well understood. Recent studies have suggested that direct protein-protein interactions exist between GPCRs, G proteins and G protein-gated inwardly rectifying potassium (GIRK or Kir3) channels. Here, we used fluorescence resonance energy transfer (FRET) combined with total internal reflection fluorescence microscopy to investigate whether proteins within this signalling pathway move within 100 A of each other in the plasma membrane of living cells. GABA(B) R1 and R2 receptors, Kir3 channels, Galphao subunits and regulators of G protein signalling (RGS4) proteins were each fused to cyan fluorescent protein (CFP) or yellow fluorescent protein (YFP) and first assessed for functional expression in HEK293 cells. The presence of the fluorophore did not significantly alter the signalling properties of these proteins. Possible FRET was then investigated for different protein pair combinations. As a positive control, FRET was measured between tagged GABA(B) R1 and R2 subunits ( approximately 12% FRET), which are known to form heterodimers. We measured significant FRET between tagged RGS4 and GABA(B) R1 or R2 subunits ( approximately 13% FRET), and between Galphao and GABA(B) R1 or R2 subunits ( approximately 10% FRET). Surprisingly, FRET also occurred between tagged Kir3.2a/Kir3.4 channels and GABA(B) R1 or R2 subunits ( approximately 10% FRET). FRET was not detected between Kir3.2a and RGS4 nor between Kir3.2a and Galphao. These data are discussed in terms of a model in which GABA(B) receptors, G proteins, RGS4 proteins and Kir3 channels are closely associated in a signalling complex.

Cell Line↗
PubMed2000

The effects of metapopulation structure on indirect interactions in host-parasitoid assemblages.

The interaction between two species that do not compete for resources but share a common natural enemy is known as apparent competition. In the absence of other limiting factors, such three-species interactions are impermanent, with one species being excluded from the assemblage by the natural enemy. Here, the effects of metapopulation structure are explored in a system of two hosts that experience apparent competition through a shared parasitoid. A coupled-map lattice model is developed and used to explore species coexistence and patterns of patch occupancy at the metapopulation scale. Linking local and regional dynamics favours coexistence by uncoupling the dynamics of the three species in space. Coexistence is promoted by the inferior species being either a fugitive or a sedentary species. The occurrence of these two mutually exclusive mechanisms of coexistence is influenced by the relative dispersal of the inferior apparent competitor.

Animals↗
PubMed1986

An analysis of a dendritic neuron model with an active membrane site.

We formulate and analyze a mathematical model that couples an idealized dendrite to an active boundary site to investigate the nonlinear interaction between these passive and active membrane patches. The active site is represented mathematically as a nonlinear boundary condition to a passive cable equation in the form of a space-clamped FitzHugh-Nagumo (FHN) equation. We perform a bifurcation analysis for both steady and periodic perturbation at the active site. We first investigate the uncoupled space-clamped FHN equation alone and find that for periodic perturbation a transition from phase locked (periodic) to phase pulling (quasiperiodic) solutions exist. For the model coupling a passive cable with a FHN active site at the boundary, we show for steady perturbation that the interval for repetitive firing is a subset of the interval for the space-clamped case and shrinks to zero for strong coupling. The firing rate at the active site decreases as the coupling strength increases. For periodic perturbation we show that the transition from phase locked to phase pulling solutions is also dependent on the coupling strength.

Animals↗
PubMed2000

A neuronal network model of macaque primary visual cortex (V1): orientation selectivity and dynamics in the input layer 4Calpha.

In this paper, we offer an explanation for how selectivity for orientation could be produced by a model with circuitry that is based on the anatomy of V1 cortex. It is a network model of layer 4Calpha in macaque primary visual cortex (area V1). The model consists of a large number of integrate-and-fire conductance-based point neurons, both excitatory and inhibitory, which represent dynamics in a small patch of 4Calpha-1 mm(2) in lateral area-which contains four orientation hypercolumns. The physiological properties and coupling architectures of the model are derived from experimental data for layer 4Calpha of macaque. Convergent feed-forward input from many neurons of the lateral geniculate nucleus sets up an orientation preference, in a pinwheel pattern with an orientation preference singularity in the center of the pattern. Recurrent cortical connections cause the network to sharpen its selectivity. The pattern of local lateral connections is taken as isotropic, with the spatial range of monosynaptic excitation exceeding that of inhibition. The model (i) obtains sharpening, diversity in selectivity, and dynamics of orientation selectivity, each in qualitative agreement with experiment; and (ii) predicts more sharpening near orientation preference singularities.

Animals↗
PubMed1997

Anxiolytic activity of glycine-B antagonists and partial agonists--no relation to intrinsic activity in the patch clamp.

On the basis of animal models, anxiety was one of the first suggested clinical applications of partial agonists of the glycineB site coupled to the NMDA receptor. It is not certain, however, whether these findings can be extended to full glycineB antagonists and what is the relation between intrinsic activity (degree of NMDA receptor antagonism) and anxiolytic effect. In the present study several NMDA receptor antagonists, including several glycineB antagonists/partial agonists, were tested for anxiolytic activity in the Vogel conflict test and the elevated plus-maze. Additionally, the intrinsic activities of the glycineB partial agonists used [ACPC, (R,+)-HA-966 and D-cycloserine] were compared in patch-clamp experiments in cultured neurones. In the plus-maze the most striking increase in the time spent in open arms (index of anxiolytic effect) was seen after diazepam and D-cycloserine (at doses that did not change locomotion). Also reliable (dose-dependent), although weaker, anxiolytic activity was produced by the uncompetitive NMDA receptor antagonist (+)MK-801 and the competitive antagonist CGP 39551. Modest anxiolytic-like effect in the plus-maze was also observed after the glycineB antagonist L-701,324 and the partial agonist (+,R)-HA-966. Uncompetitive antagonists memantine and amantadine, the glycineB partial agonist ACPC (up to 600 mg/kg) or the full antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 had no effect. In the Vogel conflict test neither memantine, nor any of the full glycineB antagonists tested (L-701,324 and MRZ 2/576), showed anxiolytic activity. Patch-clamp studies revealed that the intrinsic activity of (+,R)-HA-966, D-cycloserine and ACPC was 13, 57 and 92%, respectively, as compared to that of glycine itself (100%). In conclusion, for the agents tested there is no clear relation between the levels of intrinsic activity, i.e. degree of NMDA receptor inhibition, and anxiolytic activity. Moreover, L-701,324 and MRZ-type glycineB full antagonists do not exchibit anxiolytic activity in the elevated plus-maze and Vogel conflict test.

Animals↗
PubMedDate not supplied

The kinetics of tracer movement through homologous gap junctions in the rabbit retina.

Observation of the spread of biotinylated or fluorescent tracers following injection into a single cell has become one of the most common methods of demonstrating the presence of gap junctions. Nevertheless, many of the fundamental features of tracer movement through gap junctions are still poorly understood. These include the relative roles of diffusion and iontophoretic current, and under what conditions the size of the stained mosaic will increase, asymptote, or decline. Additionally, the effect of variations in amount of tracer introduced, as produced by variation in electrode resistance following cell penetration, is not obvious. To examine these questions, Neurobiotin was microinjected into the two types of horizontal cell of the rabbit retina and visualized with streptavidin-Cy3. Images were digitally captured using a confocal microscope. The spatial distribution of Neurobiotin across the patches of coupled cells was measured. Adequate fits to the data were obtained by fitting to a model with terms for diffusion and amount of tracer injected. Results indicated that passive diffusion is the major source of tracer movement through gap junctions, whereas iontophoretic current played no role over the range tested. Fluorescent visualization, although slightly less sensitive than peroxidase reactions, produced staining intensities with a more useful dynamic range. The rate constants for movement of Neurobiotin between A-type horizontal cells was about ten times greater than that for B-type horizontal cells. Although direct extrapolation to ion conductances cannot be assumed, tracer movement can be used to give an estimate of relative coupling rates across cell types, retinal location, or modulation conditions in intact tissue.

Animals↗
PubMed1992

Membrane currents of horizontal cells isolated from turtle retina.

1. Membrane currents of horizontal cells isolated from the retina of the turtle, Pseudemys, were characterized by the whole-cell patch-clamp technique. 2. Four membrane currents were identified: an anomalous rectifier blocked by barium, a transient A-current, a sustained L-type calcium current enhanced by Bay K 8644, and a fast, tetrodotoxin-sensitive sodium current. Each of these four currents was found in both horizontal cell somata and axon terminals. 3. The current-voltage relations of axon terminals and somata were similar, but, in the normal operating range of the cell (-30 to -50 mV), the mean slope resistance of the axon terminal was higher (1.38 G omega) than that of the soma (0.26 G omega). 4. Exposure to either glutamate, kainate, or quisqualate induced a sustained inward current in horizontal cell axon terminals. The reversal potential for this current was -3 mV when tested with voltage steps and +9.1 mV when measured by a voltage ramp. The same horizontal cells were insensitive to N-methyl-D-aspartate. 5. A continuum model was developed to compute the degree of signal transfer between a horizontal cell body and its axon terminal. The model consisted of a network of electrically coupled somata that communicates with a network of electrically coupled axon terminals through the connecting axons. The specific membrane resistances used for the model derived from the patch-clamp measures. 6. We computed the voltage change elicited in either the layer of somata or of axon terminals by a static light stimulus of arbitrary dimensions. The amplitude of a spot response as a function of its radius was given by the weighted sum of two Bessel functions with different space constants. 7. The computed responses of the cell body were dominated by the Bessel function with the smaller space constant, whereas those of the axon terminal depended primarily on the Bessel function with the larger space constant. 8. The model predicts that, in contrast to the findings in teleost retina, there is little signal transfer between the somata and axon terminals of horizontal cell in the turtle retina.

Animals↗
PubMed2004

Performance of piezoelectric fiber-reinforced composites for active structural-acoustic control of laminated composite plates.

This paper deals with the active structural acoustic control of thin laminated composite plates using piezoelectric fiber-reinforced composite (PFRC) material for the constraining layer of active constrained layer damping (ACLD) treatment. A finite element model is developed for the laminated composite plates integrated with the patches of ACLD treatment to describe the coupled structural-acoustic behavior of the plates enclosing an acoustic cavity. The performance of the PFRC layers of the patches has been investigated for active control of sound radiated from thin symmetric and antisymmetric cross-ply and antisymmetric angle-ply laminated composite plates into the acoustic cavity. The significant effect of variation of piezoelectric fiber orientation in the PFRC layer on controlling the structure-borne sound radiated from thin laminated plates has been investigated to determine the fiber angle in the PFRC layer for which the structural-acoustic control authority of the patches becomes maximum.

Journal Article↗
PubMed1999

GAT1 (GABA:Na+:Cl-) cotransport function. Steady state studies in giant Xenopus oocyte membrane patches.

Neurotransmitter transporters are reported to mediate transmembrane ion movements that are poorly coupled to neurotransmitter transport and to exhibit complex "channel-like" behaviors that challenge the classical "alternating access" transport model. To test alternative models, and to develop an improved model for the Na+- and Cl--dependent gamma-aminobutyric acid (GABA) transporter, GAT1, we expressed GAT1 in Xenopus oocytes and analyzed its function in detail in giant membrane patches. We detected no Na+- or Cl--dependent currents in the absence of GABA, nor did we detect activating effects of substrates added to the trans side. Outward GAT1 current ("reverse" transport mode) requires the presence of all three substrates on the cytoplasmic side. Inward GAT1 current ("forward" transport mode) can be partially activated by GABA and Na+ on the extracellular (pipette) side in the nominal absence of Cl-. With all three substrates on both membrane sides, reversal potentials defined with specific GAT1 inhibitors are consistent with the proposed stoichiometry of 1GABA:2Na+:1Cl-. As predicted for the "alternating access" model, addition of a substrate to the trans side (120 mM extracellular Na+) decreases the half-maximal concentration for activation of current by a substrate on the cis side (cytoplasmic GABA). In the presence of extracellular Na+, the half-maximal cytoplasmic GABA concentration is increased by decreasing cytoplasmic Cl-. In the absence of extracellular Na+, half-maximal cytoplasmic substrate concentrations (8 mM Cl-, 2 mM GABA, 60 mM Na+) do not change when cosubstrate concentrations are reduced, with the exception that reducing cytoplasmic Cl- increases the half-maximal cytoplasmic Na+ concentration. The forward GAT1 current (i.e., inward current with all extracellular substrates present) is inhibited monotonically by cytoplasmic Cl- (Ki, 8 mM); cytoplasmic Na+ and cytoplasmic GABA are without effect in the absence of cytoplasmic Cl-. In the absence of extracellular Na+, current-voltage relations for reverse transport current (i.e., outward current with all cytoplasmic substrates present) can be approximated by shallow exponential functions whose slopes are consistent with rate-limiting steps moving 0.15-0.3 equivalent charges. The slopes of current-voltage relations change only little when current is reduced four- to eightfold by lowering each cosubstrate concentration; they increase twofold upon addition of 100 mM Na+ to the extracellular (pipette) side.

Algorithms↗
PubMed2003

Ion fluxes in giant excised cardiac membrane patches detected and quantified with ion-selective microelectrodes.

We have used ion-selective electrodes (ISEs) to quantify ion fluxes across giant membrane patches by measuring and simulating ion gradients on both membrane sides. Experimental conditions are selected with low concentrations of the ions detected on the membrane side being monitored. For detection from the cytoplasmic (bath) side, the patch pipette is oscillated laterally in front of an ISE. For detection on the extracellular (pipette) side, ISEs are fabricated from flexible quartz capillary tubing (tip diameters, 2-3 microns), and an ISE is positioned carefully within the patch pipette with the tip at a controlled distance from the mouth of the patch pipette. Transport activity is then manipulated by solution changes on the cytoplasmic side. Ion fluxes can be quantified by simulating the ion gradients with appropriate diffusion models. For extracellular (intrapatch pipette) recordings, ion diffusion coefficients can be determined from the time courses of concentration changes. The sensitivity and utility of the methods are demonstrated with cardiac membrane patches by measuring (a) potassium fluxes via ion channels, valinomycin, and Na/K pumps; (b) calcium fluxes mediated by Na/Ca exchangers; (c) sodium fluxes mediated by gramicidin and Na/K pumps; and (d) proton fluxes mediated by an unknown electrogenic mechanism. The potassium flux-to-current ratio for the Na/K pump is approximately twice that determined for potassium channels and valinomycin, as expected for a 3Na/2K pump stoichiometery (i.e., 2K/charge moved). For valinomycin-mediated potassium currents and gramicidin-mediated sodium currents, the ion fluxes calculated from diffusion models are typically 10-15% smaller than expected from the membrane currents. As presently implemented, the ISE methods allow reliable detection of calcium and proton fluxes equivalent to monovalent cation currents <1 pA in magnitude, and they allow detection of sodium and potassium fluxes equivalent to <5 pA currents. The capability to monitor ion fluxes, independent of membrane currents, should facilitate studies of both electrogenic and electroneutral ion-coupled transporters in giant patches.

Cell Culture Techniques↗