Non-oscillatory Responses Research Articles

Calcium Oscillations in Human Pulmonary Artery Smooth Muscle Cells: Developing a Hierarchical Clustering Method for Analysis and the Effects of IL‐1b

RationaleAcute respiratory distress syndrome (ARDS) is characterized by lung inflammation, edema, and severe hypoxemia. In previous work, we showed that IL‐1b is required for the development of severe hypoxemia in a murine model of acute lung injury, independent of measures of inflammation and edema. We hypothesized that IL‐1b is altering the regulation of pulmonary blood flow to cause severe V/Q mismatching in acute lung injury. To explore possible mechanisms for this, we studied the effects of IL‐1b on calcium flux in human pulmonary artery smooth muscle cells (hPASMCs) in response to the vasoconstrictor endothelin‐1 (ET‐1).MethodshPASMCs were grown on glass bottom dishes to confluence and some dishes were treated with IL‐1b (10ng/mL) for 3h. Cells were loaded with 5mM Cal‐520 and stimulated with ET‐1 (10nM) during fluorescent imaging on a Zeiss LSM confocal microscope. All cells from each field were individually selected using Fiji image analysis software. By visual inspection, we noticed that a marked number of cells showed oscillations in calcium flux after ET‐1. To quantify oscillatory from non‐oscillatory responses, we used a mixture of information theoretic and machine learning algorithms and developed a custom classifier tool. We applied this tool to our control and IL‐1b‐treated data (Figure 1) and created a contingency table for the effects of IL‐1b on the induction of oscillatory responses. χ2 confidence intervals and statistical significance were computed by bootstrap simulation with 105 replicates using custom scripts in R(v3.4.1).ResultsIn control dishes (n = 6), there were a total of 444 non‐oscillators cells and 379 oscillator cells. In dishes treated with IL‐1b (n = 2), there were 50 non‐oscillator cells and 211 oscillators total. A bootstrap simulation based χ2 test was performed and a strong relationship was found between IL‐1b treatment and the presence of oscillatory responses, χ2 = 96.7 (71.2, 125.5; 95% C.I.), p < 10−5.Support or Funding InformationNat'l Heart, Lung & Blood Inst.K08HL125806This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Midfrontal conflict-related theta-band power reflects neural oscillations that predict behavior

Action monitoring and conflict resolution require the rapid and flexible coordination of activity in multiple brain regions. Oscillatory neural population activity may be a key physiological mechanism underlying such rapid and flexible network coordination. EEG power modulations of theta-band (4-8 Hz) activity over the human midfrontal cortex during response conflict have been proposed to reflect neural oscillations that support conflict detection and resolution processes. However, it has remained unclear whether this frequency-band-specific activity reflects neural oscillations or nonoscillatory responses (i.e., event-related potentials). Here, we show that removing the phase-locked component of the EEG did not reduce the strength of the conflict-related modulation of the residual (i.e., non-phase-locked) theta power over midfrontal cortex. Furthermore, within-subject regression analyses revealed that the non-phase-locked theta power was a significantly better predictor of the conflict condition than was the time-domain phase-locked EEG component. Finally, non-phase-locked theta power showed robust and condition-specific (high- vs. low-conflict) cross-trial correlations with reaction time, whereas the phase-locked component did not. Taken together, our results indicate that most of the conflict-related and behaviorally relevant midfrontal EEG signal reflects a modulation of ongoing theta-band oscillations that occurs during the decision process but is not phase-locked to the stimulus or to the response.

Dynamic Modeling of Damping Effects in Highly Damped Compliant Fingers for Applications Involving Contacts

In many industries, it is often required to transfer objects using compliant fingers capable of accommodating a limited range of object shapes/sizes without causing damage to the products being handled. This paper presents a coupled computational and experimental method in time domain to characterize the damping coefficient of a continuum structure, particularly, its applications for analyzing the damping effect of a highly damped compliant finger on contact-induced forces and stresses. With the aid of Rayleigh damping and explicit dynamic finite element analysis (FEA), this method relaxes several limitations of commonly used damping identification methods (such as log-decrement and half-power methods) that are valid for systems with an oscillatory response and generally estimate the damping ratio for a lumped parameter model. This damping identification method implemented using off-the-shelf commercial FEA packages has been validated by comparing results against published data; both oscillatory and nonoscillatory responses are considered. Along with a detailed discussion on practical issues commonly encountered in explicit dynamic FEA for damping identification, the effects of damping coefficients on contact between a rotating compliant finger and an elliptical object has been numerically investigated and experimentally validated. The findings offer a better understanding for improving grasper designs for applications where joint-less compliant fingers are advantageous.

Elucidating the digital control mechanism for DNA damage repair with the p53–Mdm2 system: single cell data analysis and ensemble modelling

Recent experimental evidence about DNA damage response using the p53-Mdm2 system has raised some fundamental questions about the control mechanism employed. In response to DNA damage, an ensemble of cells shows a damped oscillation in p53 expression whose amplitude increases with increased DNA damage--consistent with 'analogue' control. Recent experimental results, however, show that the single cell response is a series of discrete pulses in p53; and with increase in DNA damage, neither the height nor the duration of the pulses change, but the mean number of pulses increase--consistent with 'digital' control. Here we present a system engineering model that uses published data to elucidate this mechanism and resolve the dilemma of how digital behaviour at the single cell level can manifest as analogue ensemble behaviour. First, we develop a dynamic model of the p53-Mdm2 system that produces non-oscillatory responses to a stress signal. Second, we develop a probability model of the distribution of pulses in a cell population, and combine the two with the simplest digital control algorithm to show how oscillatory responses whose amplitudes grow with DNA damage can arise from single cell behaviour in which each single pulse response is independent of the extent of DNA damage. A stochastic simulation of the hypothesized control mechanism reproduces experimental observations remarkably well.

Tuning of Passivity-Preserving Controllers for Switched-Mode Power Converters

Nonlinear passivity-based control (PBC) algorithms for power converters have proved to be an interesting alternative to other, mostly linear, control techniques. The control objective is usually achieved through an energy reshaping process and by injecting damping to modify the dissipation structure of the system. However, a key question that arises during the implementation of the controller is how to tune the various control parameters. From a circuit theoretic perspective, a PBC forces the closed-loop dynamics to behave as if there are artificial resistors-the control parameters-connected in series or in parallel to the real circuit elements. In this paper, a solution to the tuning problem is proposed that uses the classical Brayton-Moser equations. The method is based on the study of a certain "mixed-potential function" which results in quantitative restrictions on the control parameters. These restrictions seem to be practically relevant in terms stability, overshoot and nonoscillatory responses. The theory is exemplified using the elementary single-switch buck and boost converters.

Ca2+-stimulated Ca2+ Oscillations Produced by the Ca2+-sensing Receptor Require Negative Feedback by Protein Kinase C

We examined the role of protein kinase C (PKC) in the mechanism and regulation of intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations elicited by an increase in the extracellular concentration of Ca(2+) ([Ca(2+)](e)) in human embryonic kidney 293 cells expressing the Ca(2+)-sensing receptor (CaR). Exposure to the PKC inhibitors bisindolylmaleimide I (GF I) or Ro-31-8220 converted oscillatory responses to transient, non-oscillatory responses, significantly reducing the percentage of cells that showed [Ca(2+)](i) oscillations but without decreasing the overall response to increase in [Ca(2+)](e). Exposure to 100 nm phorbol 12,13-dibutyrate, a direct activator of PKC, eliminated [Ca(2+)](i) oscillations. Addition of phorbol 12,13-dibutyrate at lower concentrations (3 and 10 nm) did not eliminate the oscillations but greatly reduced their frequency in a dose-dependent manner. Co-expression of CaR with constitutively active mutants of PKC (either epsilon or beta(1) isoforms) also reduced [Ca(2+)](i) oscillation frequency. Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor.

Non-oscillation criteria for hypoelastic models under simple shear deformation

Ten objective rates, spinning or non-spinning, are critically examined from the viewpoint of Sturm's theorems in ordinary differential equations. Upon developing implication relations of oscillatory, non-oscillatory, and disconjugate behavior, we establish oscillation and non-oscillation criteria which pick out the objective stress rates that lead to oscillatory and non-oscillatory responses in simple shear deformation, respectively. Among the hypoelastic equations associated with the spinning objective rates examined, the Jaumann equation is an oscillatory minorant, the homogeneous Xiao–Bruhns–Meyers equation is a non-oscillatory majorant, and the homogeneous Green–Naghdi equation is a disconjugate majorant. If (Sturm comparable) non-spinning objective rates are also taken into consideration, then the Durban–Baruch equation becomes an oscillatory minorant, but the other two equations remain to play the same roles. The Jaumann equation is a Sturm majorant for all the other nine homogeneous hypoelastic equations, and the homogeneous Szabo–Balla-2 equation is a Sturm minorant for all the other nine homogeneous hypoelastic equations. Most of the solutions of the zeroth-grade hypoelastic equations at simple shear have already been published, except for those of Szabo and Balla, to which the closed-form solutions are derived here. Moreover, all solutions are extended to include the effect of initial stresses.

Digital tracking control for PWM systems with unacceptable zeros

Perfect output tracking, which requires inversion of the input-output dynamics, is not always a practical control objective. Difficulties are encountered for systems with zeros which are unstable, or stable but lightly damped. When the zeros are unacceptable in the above sense, perfect output tracking would require the control to be either unbounded, or bounded but highly oscillatory. In this paper, an approximate output tracking control design method is introduced for pulsewidth modulated (PWM) systems with unacceptable zeros. The design method is applied to the nonlinear sampled-data model of the PWM system, and is based on output redefinition. Although the new approach leads to approximate rather than perfect output tracking, it guarantees bounded and nonoscillatory responses.

Inhibition of sustained gamma oscillations (35-80 Hz) by fast transient responses in cat visual cortex.

Interactions between stimulus-induced oscillations (35-80 Hz) and stimulus-locked nonoscillatory responses were investigated in the visual cortex areas 17 and 18 of anaesthetized cats. A single square-wave luminance grating was used as a visual stimulus during simultaneous recordings from up to seven electrodes. The stimulus movement consisted of a superposition of a smooth movement with a sequence of dynamically changing accelerations. Responses of local groups of neurons at each electrode were studied on the basis of multiple unit activity and local slow field potentials (13-120 Hz). Oscillatory and stimulus-locked components were extracted from multiple unit activity and local slow field potentials and quantified by a combination of temporal and spectral correlation methods. We found fast stimulus-locked components primarily evoked by sudden stimulus accelerations, whereas oscillatory components (35-80 Hz) were induced during slow smooth movements. Oscillations were gradually reduced in amplitude and finally fully suppressed with increasing amplitudes of fast stimulus-locked components. It is argued that suppression of oscillations is necessary to prevent confusion during sequential processing of stationary and fast changing retinal images.

Veratridine‐induced oscillations of cytosolic calcium and membrane potential in bovine chromaffin cells.

1. Veratridine (VTD) induced large oscillations of the cytosolic Ca2+ concentration ([Ca2+]i) and the membrane potential (Vm) in otherwise silent bovine chromaffin cells loaded with fura-2. 2. Depletion of the intracellular Ca2+ stores by thapsigargin or ryanodine did not affect these oscillations. Caffeine had a complex effect, decreasing them in cells with high activity but increasing them in cells with low activity. 3. The [Ca2+]i oscillations required extracellular Ca2+ and Na+ and were blocked by Ni2+ or tetrodotoxin. They were antagonized by high external concentrations of Mg2+ and/or Ca2+. 4. The oscillations of Vm had three phases: (i) slow depolarization (20 mV in 10-40 s); (ii) further fast depolarization (30 mV in 1 s); and (iii) rapid (5 s) repolarization. [Ca2+]i decreased during (i), increased quickly during (ii) with a 1 s delay with regard to the peak depolarization, and decreased during (iii). 5. Slight depolarizations increased the frequency of the oscillations whereas large depolarizations decreased it. 6. The Ca(2+)-dependent K+ channel blocker apamin increased the duration and decreased the frequency of the oscillations. 7. We propose the following mechanism for the oscillations: (i) the membrane depolarizes slowly by a decrease of potassium conductance (gK), perhaps due to a gradual decrease of [Ca2+]i; (ii) the threshold for activation of Na+ channels (decreased by VTD) is reached, producing further depolarization and recruiting Ca2+ channels, and inactivation of both Ca2+ and VTD-poisoned Na+ channels is slow; and (iii) gK increases, aided by activation of Ca(2+)-dependent K+ channels by the increased [Ca2+]i, and the membrane repolarizes. The contribution of the Na+ channels seems essential for the generation of the oscillations. 8. Bovine chromaffin cells have the machinery required for [Ca2+]i oscillations even though the more physiological stimulus tested here (high K+, field electrical stimulation, nicotinic or muscarinic agonists) produced mainly non-oscillatory responses.

Calcium signaling in endothelin- and platelet-derived growth factor-stimulated chondrocytes.

In bovine articular chondrocytes, endothelin (ET) and platelet-derived growth factor (PDGF) receptors mediate agonist-induced increases in inositol phosphate hydrolysis, cytoplasmic calcium concentration ([Ca2+]i), and mitogenesis. In most cells, ET stimulated nonoscillatory [Ca2+]i elevations with dose-dependent increases in both spike and plateau amplitudes. However, about 15% of cells showed oscillatory Ca2+ responses with a constant frequency and variable shape and duration of spiking. ET-1 and ET-2 were more potent than ET-3 in stimulating [Ca2+]i responses in inhibiting the specific binding of 125I-ET-1 and 125I-ET-3 and in promoting internalization of the receptor-ligand complex, consistent with actions through endothelin ETA receptors. Similar nonoscillatory and oscillatory patterns of Ca2+ responses were observed in PDGF-stimulated cells. In cells showing nonoscillatory Ca2+ responses to ET-1, subsequent stimulation with PDGF was frequently followed by the development of an oscillatory Ca2+ response. Nonoscillatory responses to both agonists were only slightly reduced in Ca(2+)-deficient medium, but the oscillatory responses were critically dependent on Ca2+ entry. Ca2+ spiking was not altered in the presence of the voltage-sensitive Ca2+ channel blocker, nifedipine; also, depolarization of chondrocytes by high K+ did not induce [Ca2+]i responses, confirming that voltage-sensitive calcium channels are not expressed in these cells. At high agonist concentrations, ET- but not PDGF-stimulated cells underwent rapid desensitization. Activation of ETA and PDGF receptors was associated with differential stimulation of thymidine incorporation; ET-1 induced a low-amplitude bell-shaped dose-response curve; PDGF induced a sustained sigmoidal and dose-dependent rise. These data indicate that two distinct types of Ca(2+)-mobilizing receptors initiate similar patterns of [Ca2+]i responses but have different capacities to maintain and reinitiate the Ca2+ signaling, as well as to promote mitogenesis.

Characterization of Cytosolic Calcium Oscillations Induced by Phenylephrine and Vasopressin in Single Fura-2-loaded Hepatocytes

Changes of cytosolic free Ca2+ [( Ca2+]i) in response to receptor activation were studied at the single cell level by using digital imaging fluorescence microscopy of fura-2-loaded primary cultured hepatocytes. In response to phenylephrine and vasopressin, individual hepatocytes displayed dose-dependent oscillations of [Ca2+]i similar to those observed in aequorin-injected hepatocytes by Woods et al. (Woods, N. M., Cuthbertson, K. S. R., and Cobbold, P. H. (1986) Nature 329, 719-721). With increasing agonist concentration, the frequency of oscillations increased and the latent period decreased. For a given cell, peak [Ca2+]i was independent of applied agonist concentration. However, there was considerable variation from cell to cell in the absolute value of peak [Ca2+]i. There was also marked intercellular heterogeneity in the latency, frequency, and overall pattern of the Ca2+ responses. Such asynchronous responses can be explained in part by the apparent differential agonist sensitivity of individual cells for latency and frequency. At high doses, phenylephrine maintained an oscillatory pattern, whereas vasopressin produced a complex mixture of spiking and sustained [Ca2+]i responses. Vasopressin and phenylephrine also displayed differently shaped [Ca2+]i oscillations at submaximal doses, due primarily to a slower rate of decay with vasopressin. Despite the large cell-cell variation in the patterns of [Ca2+]i oscillations, successive readditions of the same agonist elicited identical cell-specific patterns of oscillation. In the absence of extracellular Ca2+ the frequency but not the magnitude of [Ca2+]i oscillations was decreased. Buffering of [Ca2+]i by increasing the fura-2 load of single hepatocytes also decreased the frequency of oscillations without affecting the peak Ca2+ level. These data provide further support for the importance of frequency modulation in agonist-induced Ca2+ responses and suggest that Ca2+ itself plays an important role in regulating the frequency of [Ca2+]i oscillations. Furthermore, the data demonstrate a broad heterogeneity in hepatocyte [Ca2+]i oscillations which may underlie the nonoscillatory responses of cell populations.

The effect of area and intensity on the response of cat retinal ganglion cells to brief light flashes.

1. The action potentials of single optic tract axons were recorded in cats anaesthetized by pentobarbital. The receptive fields were stimulated with brief light flashes (20 or 25 msec) of variable area (0.18 less than or equal to A less than or equal to 11.8 degrees) and stimulus intensity (0.36 less than or equal to I less than or equal to 360 cd-m-2). 2. Retinal on-center and off-center neurons responded in one of two ways to brief light flashes: oscillatory responses (O-response) to certain stimulus combinations or non-oscillatory responses (N-response) for all stimulus combinations. 3. The O-respnse of on-center neurons was characterized in its PST-histogram by up to five peaks. Neurons exhibiting an O-response at medium and/or strong stimulus intensities responded at low AxI-values with an N-response. Other neurons, however, exhibited for all stimulus combinations an N-response, in which the instantaneous neuronal impulse rate decreased after an initial peak approximately expronentially with time. 4. The O-response of off-center neurons exhibited with medium AxI-values up to four peaks in the PST-histograms. N-type off-center neurons had at low and medium AxI-values a short primary inhibition period which was followed by a fast rising and slowly decaying activity period. 5. Ricco's law was only valid for small AxI-values not more than one 10log unit above threshold. For higher stimulus values (especially in the O-response) an increment of the stimulus intensity was usually more effective than an equal increment of the stimulus area. 6. On-center and off-center neurons located in about the same region of the retina had a strong tendency to discharge alternately with each other. 7. A superposition model is proposed as an explanation of the experimental data. 8. Possible correlations between the neurophysiological findings and the fast oscillatory after-images seen in corresponding psychophysical experiments are discussed.

Geometric criterion for the design of a non-oscillatory dynamical system†

The paper deals with responses of a non-linear multiple lumped dynamical system bounded in a large neighbourhood of the single, asymptotically stable equilibrium point. The sufficient, analytic criteria for the non-oscillation of such responses have been introduced in previous work (cf. Skowronaki and Shannon 1972). On the basis of the latter, the author discusses a geometric interpretation of necessary and sufficient criteria for non-oscillatory responses applied to the synthetic design of the relevant systems.