Radiation Hormesis in Barley Manifests as Changes in Growth Dynamics Coordinated with the Expression of PM19L-like, CML31-like, and AOS2-like.

The stimulation of growth and development of crops using ionising radiation (radiation hormesis) has been reported by many research groups. However, specific genes contributing to the radiation stimulation of plant growth are largely unknown. In this work, we studied the impact of the low-dose γ-irradiation of barley seeds on the growth dynamics and gene expression of eight barley cultivars in a greenhouse experiment. Our findings confirmed that candidate genes of the radiation growth stimulation, previously established in barley seedlings (PM19L-like, CML31-like, and AOS2-like), are significant in radiation hormesis throughout ontogeny. In γ-stimulated cultivars, the expression of these genes was aligned with the growth dynamics, yield parameters, and physiological conditions of plants. We identified contrasting cultivars for future gene editing and found that the γ-stimulated cultivar possessed some specific abiotic stress-responsive elements in the promotors of candidate genes, possibly revealing a new level of radiation hormesis effect execution. These results can be used in creating new productive barley cultivars, ecological toxicology of radionuclides, and eustress biology studies.

Role of asymmetry and external noise in the development and synchronization of oscillations in the analog Hopfield neural networks with time delay.

The analog Hopfield neural network with time delay and random connections has been studied for its similarities in activity to human electroencephalogram and its usefulness in other areas of the applied sciences such as speech recognition, image analysis, and electrocardiogram modeling. Our goal here is to understand the mechanisms that affect the rhythmic activity in the neural network and how the addition of a Gaussian noise contributes to the network behavior. The neural network studied is composed of ten identical neurons. We investigated the excitatory and inhibitory networks with symmetric (square matrix) and asymmetric (triangular matrix) connections. The differential equations that model the network are solved numerically using the stochastic second-order Runge-Kutta method. Without noise, the neural networks with symmetric and asymmetric matrices possessed different synchronization properties: fully connected networks were synchronized both in time and in amplitude, while asymmetric networks were synchronized in time only. Saturation outputs of the excitatory neural networks do not depend on the time delay, whereas saturation oscillation amplitudes of inhibitory networks increase with the time delay until the steady state. The addition of the Gaussian noise is shown to significantly amplify small-amplitude oscillations, dramatically accelerates the rate of amplitude growth to saturation, and changes synchronization properties of the neural network outputs.

Caveolae-associated cAMP/Ca2+-mediated mechano-chemical signal transduction in mouse atrial myocytes.

Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca2+ signaling in atrial cardiomyocytes. In Langendorff-perfused mouse hearts, atrial pressure/volume overload stretched atrial myocytes and decreased caveolae density. In isolated cells, caveolae were disrupted through hypotonic challenge that induced a temporal (<10 min) augmentation of Ca2+ transients and caused a rise in Ca2+ spark activity. Similar changes in Ca2+ signaling were observed after chemical (methyl-ß-cyclodextrin) and genetic ablation of caveolae in cardiac-specific conditional caveolin-3 knock-out mice. Acute disruption of caveolae, both mechanical and chemical, led to the elevation of cAMP level in the cell interior, and cAMP-mediated augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at Ser2030 and Ser2808). Caveolae-mediated stimulatory effects on Ca2+ signaling were abolished via inhibition of cAMP production by adenyl cyclase antagonists MDL12330 and SQ22536, or reduction of PKA activity by H-89. A compartmentalized mathematical model of mouse atrial myocytes linked the observed changes to a microdomain-specific decrease in phosphodiesterase activity, which disrupted cAMP signaling and augmented PKA activity. Our findings add a new dimension to cardiac mechanobiology and highlight caveolae-associated cAMP/PKA-mediated phosphorylation of Ca2+ handling proteins as a novel component of mechano-chemical feedback in atrial myocytes.

Comparative analysis of epigenetic variability in two pine species exposed to chronic radiation in the Chernobyl and Fukushima affected zones.

Comparative analysis of epigenetic variability in two pine species affected as a result of the Chernobyl and Fukushima accidents is presented. The absorbed dose rate within the affected Chernobyl sites varies over a wider range (1.5-24.6 µGy/h) than within the Fukushima sites (3.5-6.5 µGy/h). It was shown that chronic irradiation can change the level of whole genome methylation in pine populations, but in different ways. The genomes of Japanese red pines are hypomethylated, and the degree of methylation and hydroxymethylation decreases with an increase in the level of radiation exposure. In contrast, the percentages of genome methylation and hydroxymethylation in Scots pine populations exceed the reference levels. The observed discrepancy in the patterns of genome-wide DNA methylation can be attributed partly to the design of the study (differences in the climate, radiation dose, age and species of the pines) which could affect the results. In the frame of IRAP analysis, a larger number of different bands was observed in the Chernobyl populations compared to the Japanese populations. Both the Japanese and Chernobyl populations are characterized by significant genetic variability. However, the main part of this variability is observed within populations. The dendrograms, based on presence/absence of IRAP fragments and Nei's genetic distances, revealed subdivisions of the Chernobyl and Japanese populations according to the level of radioactive contamination. Analysis of the results presented will improve our understanding of the mechanisms underlying the responses of pine trees to chronic radiation exposure.

Differential gene expression in chronically irradiated herbaceous species from the Chernobyl exclusion zone.

PURPOSE: Transcriptional activity of genes related to ionizing radiation responses in chronically irradiated plant populations at radioactively contaminated territories can be a cost-effective and precise approach for stress response evaluation. However, there are limits to studying non-model plants in field conditions. The work studies the transcriptional activity of candidate genes of adaptation to chronic radiation exposure in plant populations from radioactively contaminated territories of the Chernobyl. MATERIALS AND METHODS: In this work, we studied plant species with different sensitivity to acute irradiation: Trifolium repens L., Taraxacum officinale Wigg., and Dactylis glomerata L., sampled in the Chernobyl exclusion zone. The differential expression of several candidate genes of adaptation to chronic radiation exposure in the leaves of these species was analyzed, including homologs of Arabidopsis thaliana genes SLAC1, APX1, GPX2, CAB1, NTRB, PP2-B11, RBOH-F, HY5, SnRK2.4, PDS1, CIPK20, SIP1, PIP1, TIP1. RESULTS AND CONCLUSIONS: All studied species were characterized by upregulation of the CAB1 homolog, encoding chlorophyll a/b binding protein, at radioactively contaminated plots. An increase in the expression of genes associated with water and hydrogen peroxide transport, intensity of photosynthesis, and stress responses (homolog of aquaporin TIP1 for T. repens; homologs of aquaporin PIP1 and transcription factor HY5 for D. glomerata; homolog of CBL-interacting serine/threonine protein kinase CIPK20 for T. officinale) was revealed. The methodological approach for studying gene expression in non-model plant species is described, which may allow large-scale screening studies of candidate genes in various plant species abundant in radioactively contaminated areas.

A compartmentalized mathematical model of the ß1- and ß2-adrenergic signaling systems in ventricular myocytes from mouse in heart failure.

Mouse models of heart failure are extensively used to research human cardiovascular diseases. In particular, one of the most common is the mouse model of heart failure resulting from transverse aortic constriction (TAC). Despite this, there are no comprehensive compartmentalized mathematical models that describe the complex behavior of the action potential, [Ca2+]i transients, and their regulation by ß1- and ß2-adrenergic signaling systems in failing mouse myocytes. In this paper, we develop a novel compartmentalized mathematical model of failing mouse ventricular myocytes after TAC procedure. The model describes well the cell geometry, action potentials, [Ca2+]i transients, and ß1- and ß2-adrenergic signaling in the failing cells. Simulation results obtained with the failing cell model are compared with those from the normal ventricular myocytes. Exploration of the model reveals the sarcoplasmic reticulum Ca2+ load mechanisms in failing ventricular myocytes. We also show a larger susceptibility of the failing myocytes to early and delayed afterdepolarizations and to a proarrhythmic behavior of Ca2+ dynamics upon stimulation with isoproterenol. The mechanisms of the proarrhythmic behavior suppression are investigated and sensitivity analysis is performed. The developed model can explain the existing experimental data on failing mouse ventricular myocytes and make experimentally testable predictions of a failing myocyte's behavior.

Outcomes of deep brain stimulation surgery for substance use disorder: a systematic review.

Long has the standard of care for substance use disorder (SUD) been pharmacotherapy, psychotherapy, or rehabilitation with varying success. Deep brain stimulation (DBS) may have a beneficial reduction in the addiction-reward pathway. Recent studies have found reduced relapse and improvements in quality of life following DBS stimulation of the nucleus accumbens. We aim to identify positive outcomes and adverse effects to assess the viability of DBS as a treatment of addiction. A PubMed search following PRISMA guidelines was conducted to identify the entirety of reports reporting DBS as a treatment for SUD. Outcomes were extracted from the literature to be summarized, and a review of the quality of publications was also performed. From 2305 publications, 14 studies were found to fit the inclusion criteria published between 2007 and 2019. All studies targeted the nucleus accumbens (NAc) and remission rates at 6 months, 1 year, 2 years, and more than 6 years were 61% (20/33), 53% (17/32), 43% (14/30), and 50% (3/6), respectively. Not all studies detailed the stimulation settings or coordinates. The most common adverse effect across studies was a weight change of at least 2 kg. DBS shows potential as a long-term treatment of SUD in refractory patients. Further studies with controlled double-blind paradigms are needed for evaluation of the efficacy and safety of this treatment. Future studies should also investigate other brain regions for stimulation and optimal device stimulation parameters.

Visceral fat in different locations assessed by ultrasound: Correlation with computed tomography and cut-off values in patients with metabolic syndrome.

The aim of this study was to evaluate the correlation between ultrasound measurements of visceral adipose tissue (VAT) in different locations and visceral fat area parameters estimated by computed tomography (CT), as well as to determine the cut-off values of ultrasound measurements in patients with metabolic syndrome and in normal controls. Altogether, 304 patients aged 18 to 65 years were enrolled in the study. Ultrasound measurements of visceral fat volume were performed using a number of already described techniques. The correlations of ultrasound indices of VAT and СТ (104 patients) ranged from 0.420 to 0.726. For the most effective diagnostic VAT ultrasound indices, the cut-off values in metabolic syndrome were (200 patients): 21.12 cm2 for the inferior part of perirenal fat (AUC = 0.983); and 47.00, 61.3 and 72.7 mm for the distance between the internal surface of the rectus abdominis muscle and the anterior wall of the aorta, the posterior wall of the aorta and the lumbar vertebra (AUC = 0.960, 0.966, 0.968, respectively). Ultrasound VAT measurements highly correlated with CT results. Cut-off VAT values, determined by ultrasound for the patients with metabolic syndrome, yielded good diagnostic operational characteristics.

Synthesis, structure and properties of layered Pr2MoO6-based oxymolybdates doped with Mg.

Undoped and Mg-doped Pr2MoO6 oxymolybdate polycrystals and single crystals have been prepared by solid-state reactions and flux growth. The compounds have been characterized by powder X-ray diffraction, energy-dispersive spectroscopy, inductively coupled plasma mass spectrometry, scanning transmission electron microscopy, single crystal X-ray structure analysis, differential scanning calorimetry and thermogravimetry. The (MgO)x(Pr2O3)y(MoO3)z (x + y + z = 1) solid solution series has been shown to extend to x = 0.03. The structure of the Mg-doped Pr2MoO6 single crystals can be represented as superimposed lattices of the main matrix (Pr2MoO6) and lattices in which Mo atoms are partially replaced by Mg. The incorporation of Mg atoms into the structure of Pr2MoO6 results in the disordering of the praseodymium and oxygen lattices. Both the polycrystalline and single-crystal Mg-doped samples are hygroscopic.

A compartmentalized mathematical model of mouse atrial myocytes.

Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca2+]i transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca2+]i dynamics, and ß-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system. The model consists of three compartments related to ß-adrenergic signaling (caveolae, extracaveolae, and cytosol) and employs local control of Ca2+ release. It also simulates ionic mechanisms of action potential generation and describes atrial-specific Ca2+ handling as well as frequency dependences of the action potential and [Ca2+]i transients. The model showed that the T-type Ca2+ current significantly affects the later stage of the action potential, with little effect on [Ca2+]i transients. The block of the small-conductance Ca2+-activated K+ current leads to a prolongation of the action potential at high intracellular Ca2+. Simulation results obtained from the atrial model cells were compared with those from ventricular myocytes. The developed model represents a useful tool to study complex electrical properties in the mouse atria and could be applied to enhance the understanding of atrial physiology and arrhythmogenesis.NEW & NOTEWORTHY A new compartmentalized mathematical model of mouse right atrial myocytes was developed. The model simulated action potential and Ca2+ dynamics at baseline and after stimulation of the ß-adrenergic signaling system. Simulations showed that the T-type Ca2+ current markedly prolonged the later stage of atrial action potential repolarization, with a minor effect on [Ca2+]i transients. The small-conductance Ca2+-activated K+ current block resulted in prolongation of the action potential only at the relatively high intracellular Ca2+.

Mathematical model for ß1-adrenergic regulation of the mouse ventricular myocyte contraction.

The ß1-adrenergic regulation of cardiac myocyte contraction plays an important role in regulating heart function. Activation of this system leads to an increased heart rate and stronger myocyte contraction. However, chronic stimulation of the ß1-adrenergic signaling system can lead to cardiac hypertrophy and heart failure. To understand the mechanisms of action of ß1-adrenoceptors, a mathematical model of cardiac myocyte contraction that includes the ß1-adrenergic system was developed and studied. The model was able to simulate major experimental protocols for measurements of steady-state force-calcium relationships, cross-bridge release rate and force development rate, force-velocity relationship, and force redevelopment rate. It also reproduced quite well frequency and isoproterenol dependencies for intracellular Ca2+ concentration ([Ca2+]i) transients, total contraction force, and sarcomere shortening. The mathematical model suggested the mechanisms of increased contraction force and myocyte shortening on stimulation of ß1-adrenergic receptors is due to phosphorylation of troponin I and myosin-binding protein C and increased [Ca2+]i transient resulting from activation of the ß1-adrenergic signaling system. The model was used to simulate work-loop contractions and estimate the power during the cardiac cycle as well as the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The developed mathematical model can be used further for simulations of contraction of ventricular myocytes from genetically modified mice and myocytes from mice with chronic cardiac diseases.NEW & NOTEWORTHY A new mathematical model of mouse ventricular myocyte contraction that includes the ß1-adrenergic system was developed. The model simulated major experimental protocols for myocyte contraction and predicted the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The model also allowed for simulations of work-loop contractions and estimation of the power during the cardiac cycle.

A Mathematical Model of the Human Cardiac Na+ Channel.

Sodium ion channel is a membrane protein that plays an important role in excitable cells, as it is responsible for the initiation of action potentials. Understanding the electrical characteristics of sodium channels is essential in predicting their behavior under different physiological conditions. We investigated several Markov models for the human cardiac sodium channel NaV1.5 to derive a minimal mathematical model that describes the reported experimental data obtained using major voltage clamp protocols. We obtained simulation results for peak current-voltage relationships, the voltage dependence of normalized ion channel conductance, steady-state inactivation, activation and deactivation kinetics, fast and slow inactivation kinetics, and recovery from inactivation kinetics. Good agreement with the experimental data provides us with the mechanisms of the fast and slow inactivation of the human sodium channel and the coupling of its inactivation states to the closed and open states in the activation pathway.

Mathematical modeling physiological effects of the overexpression of ß2-adrenoceptors in mouse ventricular myocytes.

Transgenic (TG) mice overexpressing ß2-adrenergic receptors (ß2-ARs) demonstrate enhanced myocardial function, which manifests in increased basal adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo. To gain insights into the mechanisms of these effects, we developed a comprehensive mathematical model of the mouse ventricular myocyte overexpressing ß2-ARs. We found that most of the ß2-ARs are active in control conditions in TG mice. The simulations describe the dynamics of major signaling molecules in different subcellular compartments, increased basal adenylyl cyclase activity, modifications of action potential shape and duration, and the effects on L-type Ca2+ current and intracellular Ca2+ concentration ([Ca2+]i) transients upon stimulation of ß2-ARs in control, after the application of pertussis toxin, upon stimulation with a specific ß2-AR agonist zinterol, and upon stimulation with zinterol in the presence of pertussis toxin. The model also describes the effects of the ß2-AR inverse agonist ICI-118,551 on adenylyl cyclase activity, action potential, and [Ca2+]i transients. The simulation results were compared with experimental data obtained in ventricular myocytes from TG mice overexpressing ß2-ARs and with simulation data on wild-type mice. In conclusion, a new comprehensive mathematical model was developed that describes multiple experimental data on TG mice overexpressing ß2-ARs and can be used to test numerous hypotheses. As an example, using the developed model, we proved the hypothesis of the major contribution of L-type Ca2+ current to the changes in the action potential and [Ca2+]i transient upon stimulation of ß2-ARs with zinterol. NEW & NOTEWORTHY We developed a new mathematical model for transgenic mouse ventricular myocytes overexpressing ß2-adrenoceptors that describes the experimental findings in transgenic mice. The model reveals mechanisms of the differential effects of stimulation of ß2-adrenoceptors in wild-type and transgenic mice overexpressing ß2-adrenoceptors.

Bursting dynamics in the normal and failing hearts.

A failing heart differs from healthy hearts by an array of symptomatic characteristics, including impaired Ca2+ transients, upregulation of Na+/Ca2+ exchanger function, reduction of Ca2+ uptake to sarcoplasmic reticulum, reduced K+ currents, and increased propensity to arrhythmias. While significant efforts have been made in both experimental studies and model development to display the causes of heart failure, the full process of deterioration from a healthy to a failing heart yet remains deficiently understood. In this paper, we analyze a highly detailed mathematical model of mouse ventricular myocytes to disclose the key mechanisms underlying the continual transition towards a state of heart failure. We argue that such a transition can be described in mathematical terms as a sequence of bifurcations that the healthy cells undergo while transforming into failing cells. They include normal action potentials and [Ca2+]i transients, action potential and [Ca2+]i alternans, and bursting behaviors. These behaviors where supported by experimental studies of heart failure. The analysis of this model allowed us to identify that the slow component of the fast Na+ current is a key determining factor for the onset of bursting activity in mouse ventricular myocytes.

Distinct physiological effects of ß1- and ß2-adrenoceptors in mouse ventricular myocytes: insights from a compartmentalized mathematical model.

The ß1- and ß2-adrenergic signaling systems play different roles in the functioning of cardiac cells. Experimental data show that the activation of the ß1-adrenergic signaling system produces significant inotropic, lusitropic, and chronotropic effects in the heart, whereas the effects of the ß2-adrenergic signaling system is less apparent. In this paper, a comprehensive compartmentalized experimentally based mathematical model of the combined ß1- and ß2-adrenergic signaling systems in mouse ventricular myocytes is developed to simulate the experimental findings and make testable predictions of the behavior of the cardiac cells under different physiological conditions. Simulations describe the dynamics of major signaling molecules in different subcellular compartments; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; and [Ca2+]i and [Na+]i dynamics upon stimulation of ß1- and ß2-adrenergic receptors (ß1- and ß2-ARs). The model reveals physiological conditions when ß2-ARs do not produce significant physiological effects and when their effects can be measured experimentally. Simulations demonstrated that stimulation of ß2-ARs with isoproterenol caused a marked increase in the magnitude of the L-type Ca2+ current, [Ca2+]i transient, and phosphorylation of phospholamban only upon additional application of pertussis toxin or inhibition of phosphodiesterases of type 3 and 4. The model also made testable predictions of the changes in magnitudes of [Ca2+]i and [Na+]i fluxes, the rate of decay of [Na+]i concentration upon both combined and separate stimulation of ß1- and ß2-ARs, and the contribution of phosphorylation of PKA targets to the changes in the action potential and [Ca2+]i transient.

Simulation of the effects of moderate stimulation/inhibition of the ß1-adrenergic signaling system and its components in mouse ventricular myocytes.

The ß1-adrenergic signaling system is one of the most important protein signaling systems in cardiac cells. It regulates cardiac action potential duration, intracellular Ca(2+) concentration ([Ca(2+)]i) transients, and contraction force. In this paper, a comprehensive experimentally based mathematical model of the ß1-adrenergic signaling system for mouse ventricular myocytes is explored to simulate the effects of moderate stimulations of ß1-adrenergic receptors (ß1-ARs) on the action potential, Ca(2+) and Na(+) dynamics, as well as the effects of inhibition of protein kinase A (PKA) and phosphodiesterase of type 4 (PDE4). Simulation results show that the action potential prolongations reach saturating values at relatively small concentrations of isoproterenol (∼0.01 µM), while the [Ca(2+)]i transient amplitude saturates at significantly larger concentrations (∼0.1-1.0 µM). The differences in the response of Ca(2+) and Na(+) fluxes to moderate stimulation of ß1-ARs are also observed. Sensitivity analysis of the mathematical model is performed and the model limitations are discussed. The investigated model reproduces most of the experimentally observed effects of moderate stimulation of ß1-ARs, PKA, and PDE4 inhibition on the L-type Ca(2+) current, [Ca(2+)]i transients, and the sarcoplasmic reticulum Ca(2+) load and makes testable predictions for the action potential duration and [Ca(2+)]i transients as functions of isoproterenol concentration.

Enhancement of COPD biological networks using a web-based collaboration interface.

The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest stage. COPD network models are important tools to better understand the biological components and processes underlying initial disease development. With the increasing amounts of literature that are now available, crowdsourcing approaches offer new forms of collaboration for researchers to review biological findings, which can be applied to the construction and verification of complex biological networks. We report the construction of 50 biological network models relevant to lung biology and early COPD using an integrative systems biology and collaborative crowd-verification approach. By combining traditional literature curation with a data-driven approach that predicts molecular activities from transcriptomics data, we constructed an initial COPD network model set based on a previously published non-diseased lung-relevant model set. The crowd was given the opportunity to enhance and refine the networks on a website ( https://bionet.sbvimprover.com/) and to add mechanistic detail, as well as critically review existing evidence and evidence added by other users, so as to enhance the accuracy of the biological representation of the processes captured in the networks. Finally, scientists and experts in the field discussed and refined the networks during an in-person jamboree meeting. Here, we describe examples of the changes made to three of these networks: Neutrophil Signaling, Macrophage Signaling, and Th1-Th2 Signaling. We describe an innovative approach to biological network construction that combines literature and data mining and a crowdsourcing approach to generate a comprehensive set of COPD-relevant models that can be used to help understand the mechanisms related to lung pathobiology. Registered users of the website can freely browse and download the networks.

A compartmentalized mathematical model of the ß1-adrenergic signaling system in mouse ventricular myocytes.

The ß1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca(2+)]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of ß1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the ß1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol). The model describes biochemical reactions that occur during stimulation of ß1-adrenoceptors, changes in ionic currents, and modifications of Ca(2+) handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca(2+) handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca(2+)]i transients; changes in intracellular and transmembrane Ca(2+) fluxes; and [Na(+)]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of ß1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca(2+)]i transients. In particular, the model includes two subpopulations of the L-type Ca(2+) channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca(2+)]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of mathematical models for other species or for pathological conditions.

Microtubule-associated protein tau in bovine retinal photoreceptor rod outer segments: comparison with brain tau.

Recent studies have suggested a possible involvement of abnormal tau in some retinal degenerative diseases. The common view in these studies is that these retinal diseases share the mechanism of tau-mediated degenerative diseases in brain and that information about these brain diseases may be directly applied to explain these retinal diseases. Here we collectively examine this view by revealing three basic characteristics of tau in the rod outer segment (ROS) of bovine retinal photoreceptors, i.e., its isoforms, its phosphorylation mode and its interaction with microtubules, and by comparing them with those of brain tau. We find that ROS contains at least four isoforms: three are identical to those in brain and one is unique in ROS. All ROS isoforms, like brain isoforms, are modified with multiple phosphate molecules; however, ROS isoforms show their own specific phosphorylation pattern, and these phosphorylation patterns appear not to be identical to those of brain tau. Interestingly, some ROS isoforms, under the normal conditions, are phosphorylated at the sites identical to those in Alzheimer's patient isoforms. Surprisingly, a large portion of ROS isoforms tightly associates with a membranous component(s) other than microtubules, and this association is independent of their phosphorylation states. These observations strongly suggest that tau plays various roles in ROS and that some of these functions may not be comparable to those of brain tau. We believe that knowledge about tau in the entire retinal network and/or its individual cells are also essential for elucidation of tau-mediated retinal diseases, if any.

A mathematical model of the mouse ventricular myocyte contraction.

Mathematical models of cardiac function at the cellular level include three major components, such as electrical activity, Ca(2+) dynamics, and cellular shortening. We developed a model for mouse ventricular myocyte contraction which is based on our previously published comprehensive models of action potential and Ca(2+) handling mechanisms. The model was verified with extensive experimental data on mouse myocyte contraction at room temperature. In the model, we implemented variable sarcomere length and indirect modulation of the tropomyosin transition rates by Ca(2+) and troponin. The resulting model described well steady-state force-calcium relationships, dependence of the contraction force on the sarcomere length, time course of the contraction force and myocyte shortening, frequency dependence of the contraction force and cellular contraction, and experimentally measured derivatives of the myocyte length variation. We emphasized the importance of the inclusion of variable sarcomere length into a model for ventricular myocyte contraction. Differences in contraction force and cell shortening for epicardial and endocardial ventricular myocytes were investigated. Model applicability for the experimental studies and model limitations were discussed.