Modeling of Glucose-Induced cAMP Oscillations in Pancreatic β Cells: cAMP Rocks when Metabolism Rolls

Recent advances in imaging technology have revealed oscillations of cyclic adenosine monophosphate (cAMP) in insulin-secreting cells. These oscillations may be in phase with cytosolic calcium oscillations or out of phase. cAMP oscillations have previously been modeled as driven by oscillations in calcium, based on the known dependence of the enzymes that generate cAMP (adenylyl cyclase) and degrade it (phosphodiesterase). However, cAMP oscillations have also been reported to occur in the absence of calcium oscillations. Motivated by similarities between the properties of cAMP and metabolic oscillations in pancreatic β cells, we propose here that in addition to direct control by calcium, cAMP is controlled by metabolism. Specifically, we hypothesize that AMP inhibits adenylyl cyclase. We incorporate this hypothesis into the dual oscillator model for β cells, in which metabolic (glycolytic) oscillations cooperate with modulation of ion channels and metabolism by calcium. We show that the combination of oscillations in AMP and calcium in the dual oscillator model can account for the diverse oscillatory patterns that have been observed, as well as for experimental perturbations of those patterns. Predictions to further test the model are provided.     

On the mechanisms of glycolytic oscillations in yeast

This work concerns the cause of glycolytic oscillations in yeast. We analyse experimental data as well as models in two distinct cases: the relaxation-like oscillations seen in yeast extracts, and the sinusoidal Hopf oscillations seen in intact yeast cells. In the case of yeast extracts, we use flux-change plots and model analyses to establish that the oscillations are driven by on/off switching of phosphofructokinase. In the case of intact yeast cells, we find that the instability leading to the appearance of oscillations is caused by the stoichiometry of the ATP-ADP-AMP system and the allosteric regulation of phosphofructokinase, whereas frequency control is distributed over the reaction network. Notably, the NAD+/NADH ratio modulates the frequency of the oscillations without affecting the instability. This is important for understanding the mutual synchronization of oscillations in the individual yeast cells, as synchronization is believed to occur via acetaldehyde, which in turn affects the frequency of oscillations by changing this ratio.     

Enhancing oscillations in intracranial electrophysiological recordings with data-driven spatial filters

In invasive electrophysiological recordings, a variety of neural oscillations can be detected across the cortex, with overlap in space and time. This overlap complicates measurement of neural oscillations using standard referencing schemes, like common average or bipolar referencing. Here, we illustrate the effects of spatial mixing on measuring neural oscillations in invasive electrophysiological recordings and demonstrate the benefits of using data-driven referencing schemes in order to improve measurement of neural oscillations. We discuss referencing as the application of a spatial filter. Spatio-spectral decomposition is used to estimate data-driven spatial filters, a computationally fast method which specifically enhances signal-to-noise ratio for oscillations in a frequency band of interest. We show that application of these data-driven spatial filters has benefits for data exploration, investigation of temporal dynamics and assessment of peak frequencies of neural oscillations. We demonstrate multiple use cases, exploring between-participant variability in presence of oscillations, spatial spread and waveform shape of different rhythms as well as narrowband noise removal with the aid of spatial filters. We find high between-participant variability in the presence of neural oscillations, a large variation in spatial spread of individual rhythms and many non-sinusoidal rhythms across the cortex. Improved measurement of cortical rhythms will yield better conditions for establishing links between cortical activity and behavior, as well as bridging scales between the invasive intracranial measurements and noninvasive macroscale scalp measurements.     

Single cell studies and simulation of cell-cell interactions using oscillating glycolysis in yeast cells

The observation of oscillations in the concentrations of NADH and other intermediates in glycolysis in dense yeast cell suspensions is generally believed to be the result of synchronization of such oscillations between individual cells. The synchrony is believed to be a property of cell density and the question is: does metabolism in each individual yeast cell continue to oscillate, but out of phase, in the absence of synchronization? Here we have used high-sensitivity fluorescence microscopy to measure NADH in single isolated yeast cells under conditions where we observe oscillations of glycolysis in dense cell suspensions. However, we have not been able to detect intracellular oscillations in NADH in these isolated cells, which cannot synchronize their metabolism with other cells. However, addition of acetaldehyde to a single cell as pulses with a frequency similar to the oscillations in dense cell suspensions will induce oscillations in that cell. Ethanol, another product of glycolysis, which has been proposed as a synchronizing agent of glycolysis in cells, was not able to induce oscillations when added as pulses. The experiments support the notion that the intracellular oscillations are associated with the cell density of the yeast cell suspension and mediated by acetaldehyde and perhaps also other substances.     

Oscillatory Transpiration and Water Uptake of Avena Plants I. Preliminary Observations

Oscillations in transpiration and water uptake of individual, young oat plants have been studied. The free-running period of these oscillations was about 30 minutes. Conditions were reached under which the oscillations were sustained for about two days. Short perturbations were given to the transpiration oscillations, the perturbations consisting of a short time increase or decrease in the illumination. The phase shifts of the oscillations as well as the amplitude effects caused by these perturbations were investigated. Simultaneous recordings of transpiration and water uptake of a single plant showed that these functions were oscillating in phase. Both oscillations disappeared if the leaf was excised.     

Citrate oscillates in liver and pancreatic beta cell mitochondria and in INS-1 insulinoma cells

Oscillations in citric acid cycle intermediates have never been previously reported in any type of cell. Here we show that adding pyruvate to isolated mitochondria from liver, pancreatic islets, and INS-1 insulinoma cells or adding glucose to intact INS-1 cells causes sustained oscillations in citrate levels. Other citric acid cycle intermediates measured either did not oscillate or possibly oscillated with a low amplitude. In INS-1 mitochondria citrate oscillations are in phase with NAD(P) oscillations, and in intact INS-1 cells citrate oscillations parallel oscillations in ATP, suggesting that these processes are co-regulated. Oscillations have been extensively studied in the pancreatic beta cell where oscillations in glycolysis, NAD(P)/NAD(P)H and ATP/ADP ratios, plasma membrane electrical activity, calcium levels, and insulin secretion have been well documented. Because the mitochondrion is the major site of ATP synthesis and NADH oxidation and the only site of citrate synthesis, mitochondria need to be synchronized for these factors to oscillate. In suspensions of mitochondria from various organs, most of the citrate is exported from the mitochondria. In addition, citrate inhibits its own synthesis. We propose that this enables citrate itself to act as one of the cellular messengers that synchronizes mitochondria. Furthermore, because citrate is a potent inhibitor of the glycolytic enzyme phosphofructokinase, the pacemaker of glycolytic oscillations, citrate may act as a metabolic link between mitochondria and glycolysis. Citrate oscillations may coordinate oscillations in mitochondrial energy production and anaplerosis with glycolytic oscillations, which in the beta cell are known to parallel oscillations in insulin secretion.     

Sensitivity and flexibility of regular and chaotic calcium oscillations

Sensitivity and flexibility are important properties of biological systems. These properties are here investigated for intracellular calcium oscillations. For a particular model, we comparatively investigate sensitivity and flexibility of regular and chaotic Ca(2+) oscillations. For this model, we obtain two main results. First, sensitivity of the model system to parameter shifting does not depend on the complexity of Ca(2+) oscillations. We observe, however, that both regular and chaotic Ca(2+) oscillations are highly sensitive in regions close to bifurcation points. Second, also flexibility of Ca(2+) oscillations does not significantly depend on the type of Ca(2+) oscillations. Our results show that regular as well as chaotic Ca(2+) oscillations in the studied model are highly flexible in regimes with weak dissipation. Both results are discussed in the sense of possible biological importance.     

Novel mechanism for oscillations in catchbonded motor-filament complexes

Generation of mechanical oscillations is ubiquitous to a wide variety of intracellular processes, ranging from activity of muscle fibers to oscillations of the mitotic spindle. The activity of motors plays a vital role in maintaining the integrity of the mitotic spindle structure and generating spontaneous oscillations. Although the structural features and properties of the individual motors are well characterized, their implications on the functional behavior of motor-filament complexes are more involved. We show that force-induced allosteric deformations in dynein, which result in catchbonding behavior, provide a generic mechanism to generate spontaneous oscillations in motor-cytoskeletal filament complexes. The resultant phase diagram of such motor-filament systems—characterized by force-induced allosteric deformations—exhibits bistability and sustained limit-cycle oscillations in biologically relevant regimes, such as for catchbonded dynein. The results reported here elucidate the central role of this mechanism in fashioning a distinctive stability behavior and oscillations in motor-filament complexes such as mitotic spindles.     

Complex calcium oscillations and the role of mitochondria and cytosolic proteins

Intracellular calcium oscillations, which are oscillatory changes of cytosolic calcium concentration in response to agonist stimulation, are experimentally well observed in various living cells. Simple calcium oscillations represent the most common pattern and many mathematical models have been published to describe this type of oscillation. On the other hand, relatively few theoretical studies have been proposed to give an explanation of complex intracellular calcium oscillations, such as bursting and chaos. In this paper, we develop a new possible mechanism for complex calcium oscillations based on the interplay between three calcium stores in the cell: the endoplasmic reticulum (ER), mitochondria and cytosolic proteins. The majority ( approximately 80%) of calcium released from the ER is first very quickly sequestered by mitochondria. Afterwards, a much slower release of calcium from the mitochondria serves as the calcium supply for the intermediate calcium exchanges between the ER and the cytosolic proteins causing bursting calcium oscillations. Depending on the permeability of the ER channels and on the kinetic properties of calcium binding to the cytosolic proteins, different patterns of complex calcium oscillations appear. With our model, we are able to explain simple calcium oscillations, bursting and chaos. Chaos is also observed for calcium oscillations in the bursting mode.     

Oscillations of voltage and resistance in Malpighian tubules of Aedes aegypti

The transepithelial voltage (V(t)) of isolated Malpighian tubules of the yellow fever mosquito Aedes aegypti spontaneously oscillates in more than half the tubules. Typically, V(t) decreases and then rises at a frequency of 2 oscillations/min with a duration of 16 s. In 6 isolated perfused tubules studied in detail, V(t) oscillates between 50.5 mV and 15.7 mV in parallel with (1) oscillations of the transepithelial resistance (R(t)) between 7.61 kOmegacm and 3.63 kOmegacm, (2) oscillations of the basolateral membrane voltage of principal cells between -56.7 mV and -72.2 mV, and (3) oscillations of the apical membrane voltage between 107.2 mV and 87.8 mV. The oscillations are dependent on the Cl concentration in the extracellular solutions. As R(t) decreases during the oscillations V(t) goes to the transepithelial equilibrium potential of Cl (E(cl)) indicating transient changes in transepithelial Cl conductance as the mechanism of voltage and resistance oscillations. Since the largest voltage oscillations take place across the whole epithelium and not across cell membranes, oscillating Cl conductances are localized to a single transepithelial Cl diffusion barrier such as the paracellular pathway. This conclusion is supported by the analysis of electrically equivalent circuits that identify the shunt pathway as the site of oscillating Cl conductances.     

Calcium oscillations: phenomena, mechanisms and significance

Many hormones that mobilise intracellular calcium via inositol 1,4,5 trisphosphate induce oscillations in cytoplasmic free Ca. Two basic oscillatory patterns occur: quasi-sinusoidal oscillations and repetitive free Ca transients. The mechanisms responsible for generating these oscillations are not clear; calcium-induced calcium release, interplay between two intracellular calcium pools and repetitive generation of InsP3 are discussed. The significance of different oscillatory patterns induced by different agonists in the same cell is emphasised, and mechanisms by which the oscillators may retain-receptor specific information are proposed, such as negative feedback onto receptors or G-proteins by protein kinase C. Reasons why cells generate free Ca oscillations and possible consequences such as oscillations in downstream pathways are explored. The possibility that pathological conditions such as aluminium toxicity are exerted through distortion of oscillatory free Ca signalling is raised.     

视觉注意与神经振荡

人脑每时每刻都要接收大量视觉信息，由于人脑加工信息的能力有限，所以在较大视野内将注意分配给相关信息，同时抑制引起注意分散的不相关信息，对执行目标导向的行为至关重要。这种对视觉信息的选择性和主动性加工以适应当前目标的过程被称作视觉注意（visual attention），且视觉注意可分为自上而下的注意与自下而上的注意两种不同功能。由于来自大脑电信号的神经振荡活动在认知加工中发挥重要作用，已有研究综述了视觉注意与神经振荡（neural oscillation）的密切关系，但并未涉及不同的注意功能与神经振荡的关系。本文系统性调查了不同注意功能与神经振荡的关系，发现额-顶区域的theta频带振荡活动反映了自上而下的认知控制，而后部脑区的theta振荡与自下而上的注意相关。顶-枕区域alpha振荡的偏侧化有助于注意分配，而alpha频带的大规模同步促成了注意对视皮层自上而下的影响。Beta振荡介导了自上而下的信息与自下而上的信息之间的互动，作为信息载体促进了视觉信息处理。Gamma振荡则可能与自上而下和自下而上的注意间整合相关。本文就视觉注意功能与神经振荡关系的研究现状展开综述，旨在揭示不同的神经振荡活动在特定的视觉注意功能中的作用。     

Microelectrode Recording of Tissue Neural Oscillations for a Bionic Olfactory Biosensor

In olfactory research,neural oscillations exhibit excellent temporal regularity,which are functional and necessary at the physiological and cognitive levels.In this paper,we employed a bionic tissue biosensor which treats intact epithelium as sensing element to record the olfactory oscillations extracellularly.After being stimulated by odorant of butanedione,the olfactory receptor neurons generated different kinds of oscillations,which can be described as pulse firing oscillation,transient firing oscillation,superposed firing oscillation,and sustained firing oscillation,according to their temporal appearances respectively.With a time-frequency analysis of sonogram,the oscillations also demonstrated different frequency properties,such as δ,θ,α,β and γ oscillations.The results suggest that the bionic biosensor cooperated with sonogram analysis can well improve the investigation of olfactory oscillations,and provide a novel model for artificial olfaction sensor design.     

Sustained oscillations in glycolysis: an experimental and theoretical study of chaotic and complex periodic behavior and of quenching of simple oscillations

We report sustained oscillations in glycolysis conducted in an open system (a continuous-flow, stirred tank reactor; CSTR) with inflow of yeast extract as well as glucose. Depending on the operating conditions, we observe simple or complex periodic oscillations or chaos. We report the response of the system to instantaneous additions of small amounts of several substrates as functions of the amount added and the phase of the addition. We simulate oscillations and perturbations by a kinetic model based on the mechanism of glycolysis in a CSTR. We find that the response to particular perturbations forms an efficient tool for elucidating the mechanism of biochemical oscillations.     

Synchronized ATP oscillations have a critical role in prechondrogenic condensation during chondrogenesis

The skeletal elements of embryonic limb are prefigured by prechondrogenic condensation in which secreted molecules such as adhesion molecules and extracellular matrix have crucial roles. However, how the secreted molecules are controlled to organize the condensation remains unclear. In this study, we examined metabolic regulation of secretion in prechondrogenic condensation, using bioluminescent monitoring systems. We here report on ATP oscillations in the early step of chondrogenesis. The ATP oscillations depended on both glycolysis and mitochondrial respiration, and their synchronization among cells were achieved via gap junctions. In addition, the ATP oscillations were driven by Ca²⁺ oscillations and led to oscillatory secretion in chondrogenesis. Blockade of the ATP oscillations prevented cellular condensation. Furthermore, the degree of cellular condensation increased with the frequency of ATP oscillations. We conclude that ATP oscillations have a critical role in prechondrogenic condensation by inducing oscillatory secretion.     

Regulation of oscillations in filamentous actin content in polymorphonuclear leukocytes stimulated with leukotriene B(4) and platelet-activating factor.

Stimulation of neutrophils with LTB(4) or PAF results in the production of a rapidly oscillating actin polymerization/depolymerization response. Treatment of neutrophils with inhibitors of PKC prior to stimulation with ligand resulted in a masking of the F-actin oscillations. Because myosin has been shown to be a substrate for neutrophil PKC, this protein was investigated as a potential downstream mediator of F-actin oscillations. Stimulation of neutrophils with LTB(4) resulted in myosin light chain being serine phosphorylated in a PKC-dependent manner. This phosphorylation was shown to occur in a manner that is kinetically distinct from the myosin phosphorylation induced by FMLP, a potent activator of actin polymerization that alone does not induce F-actin oscillations. Additionally, disruption of intracellular actin-myosin interactions resulted in inhibition of LTB(4)- as well as PAF-induced F-actin oscillations. These data suggest that PKC and downstream phosphorylation of myosin as well as actin-myosin interaction may play roles in mediating the production of neutrophil F-actin oscillations.     

ATP oscillations mediate inductive action of FGF and Shh signalling on prechondrogenic condensation

Skeletal patterns are prefigured by prechondrogenic condensation. Morphogens such as fibroblast growth factor (FGF) and sonic hedgehog (Shh) specify the skeletal patterns in limb development. However, how morphogens regulate prechondrogenic condensation has remained unclear. Recently, it was demonstrated that synchronized Adenosine triphosphate (ATP) oscillations play a critical role in prechondrogenic condensation. Thus, the present study has focused on whether ATP oscillations mediate the actions of major developmental morphogens such as FGF and Shh on prechondrogenic condensation. It has been shown that both FGF and Shh signalling promoted cellular condensation but not chondrogenic differentiation and also induced ATP oscillations. In addition, blockage of FGF and Shh signalling prevented both ATP oscillations and prechondrogenic condensation. Furthermore, it was found that inhibition of ATP oscillations suppressed FGF/Shh‐induced prechondrogenic condensation. These results indicate that ATP oscillations mediate the actions of FGF and Shh signalling on prechondrogenic condensation. This study proposes that morphogens organize skeletal patterns via ATP oscillations. Copyright © 2012 John Wiley & Sons, Ltd.     

The rhythm of yeast

Although yeast are unicellular and comparatively simple organisms, they have a sense of time which is not related to reproduction cycles. The glycolytic pathway exhibits oscillatory behaviour, i.e. the metabolite concentrations oscillate around phosphofructokinase. The frequency of these oscillations is about 1 min when using intact cells. Also a yeast cell extract can oscillate, though with a lower frequency. With intact cells the macroscopic oscillations can only be observed when most of the cells oscillate in concert. Transient oscillations can be observed upon simultaneous induction; sustained oscillations require an active synchronisation mechanism. Such an active synchronisation mechanism, which involves acetaldehyde as a signalling compound, operates under certain conditions. How common these oscillations are in the absence of a synchronisation mechanism is an open question. Under aerobic conditions an oscillatory metabolism can also be observed, but with a much lower frequency than the glycolytic oscillations. The frequency is between one and several hours. These oscillations are partly related to the reproductive cycle, i.e. the budding index also oscillates; however, under some conditions they are unrelated to the reproductive cycle, i.e. the budding index is constant. These oscillations also have an active synchronisation mechanism, which involves hydrogen sulfide as a synchronising agent. Oscillations with a frequency of days can be observed with yeast colonies on plates. Here the oscillations have a synchronisation mechanism which uses ammonia as a synchronising agent.     

Is a constant low-entropy process at the root of glycolytic oscillations?

We measured temporal oscillations in thermodynamic variables such as temperature, heat flux, and cellular volume in suspensions of non-dividing yeast cells which exhibit temporal glycolytic oscillations. Oscillations in these variables have the same frequency as oscillations in the activity of intracellular metabolites, suggesting strong coupling between them. These results can be interpreted in light of a recently proposed theoretical formalism in which isentropic thermodynamic systems can display coupled oscillations in all extensive and intensive variables, reminiscent of adiabatic waves. This interpretation suggests that oscillations may be a consequence of the requirement of living cells for a constant low-entropy state while simultaneously performing biochemical transformations, i.e., remaining metabolically active. This hypothesis, which is in line with the view of the cellular interior as a highly structured and near equilibrium system where energy inputs can be low and sustain regular oscillatory regimes, calls into question the notion that metabolic processes are essentially dissipative.