Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Deterministic and Stochastic Cellular Mechanisms Contributing to Carbon Monoxide Induced Ventricular Arrhythmias.

ABSTRACT: Chronic exposure to low levels of Carbon Monoxide is associated with an increased risk of cardiac arrhythmia. Microelectrode recordings from rat and guinea pig single isolated ventricular myocytes exposed to CO releasing molecule CORM-2 and excited at 0.2/s show repolarisation changes that develop over hundreds of seconds: action potential prolongation by delayed repolarisation, EADs, multiple EADs and oscillations around the plateau, leading to irreversible repolarisation failure. The measured direct effects of CO on currents in these cells, and ion channels expressed in mammalian systems showed an increase in prolonged late Na⁺, and a decrease in the maximal T- and L-type Ca⁺⁺. peak and late Na⁺, ultra-rapid delayed, delayed rectifier, and the inward rectifier K⁺ currents. Incorporation of these CO induced changes in maximal currents in ventricular cell models; (Gattoni et al., J. Physiol., 2016, 594, 4193-4224) (rat) and (Luo and Rudy, Circ. Res., 1994, 74, 1071-1096) (guinea-pig) and human endo-, mid-myo- and epi-cardial (O'Hara et al., PLoS Comput. Biol., 2011, 7, e1002061) models, by changes in maximal ionic conductance reproduces these repolarisation abnormalities. Simulations of cell populations with Gaussian distributions of maximal conductance parameters predict a CO induced increase in APD and its variability. Incorporation of these predicted CO induced conductance changes in human ventricular cell electrophysiology into ventricular tissue and wall models give changes in indices for the probability of the initiation of re-entrant arrhythmia.

SUBMITTER: Al-Owais MM

PROVIDER: S-EPMC8113948 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Patterning the insect eye: From stochastic to deterministic mechanisms.

Project description:While most processes in biology are highly deterministic, stochastic mechanisms are sometimes used to increase cellular diversity. In human and Drosophila eyes, photoreceptors sensitive to different wavelengths of light are distributed in stochastic patterns, and one such patterning system has been analyzed in detail in the Drosophila retina. Interestingly, some species in the dipteran family Dolichopodidae (the "long legged" flies, or "Doli") instead exhibit highly orderly deterministic eye patterns. In these species, alternating columns of ommatidia (unit eyes) produce corneal lenses of different colors. Occasional perturbations in some individuals disrupt the regular columns in a way that suggests that patterning occurs via a posterior-to-anterior signaling relay during development, and that specification follows a local, cellular-automaton-like rule. We hypothesize that the regulatory mechanisms that pattern the eye are largely conserved among flies and that the difference between unordered Drosophila and ordered dolichopodid eyes can be explained in terms of relative strengths of signaling interactions rather than a rewiring of the regulatory network itself. We present a simple stochastic model that is capable of explaining both the stochastic Drosophila eye and the striped pattern of Dolichopodidae eyes and thereby characterize the least number of underlying developmental rules necessary to produce both stochastic and deterministic patterns. We show that only small changes to model parameters are needed to also reproduce intermediate, semi-random patterns observed in another Doli species, and quantification of ommatidial distributions in these eyes suggests that their patterning follows similar rules.

| S-EPMC6264902 | biostudies-literature

Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8).

Project description:Ca(2+) flux through l-type CaV1.2 channels shapes the waveform of the ventricular action potential (AP) and is essential for excitation-contraction (EC) coupling. Timothy syndrome (TS) is a disease caused by a gain-of-function mutation in the CaV1.2 channel (CaV1.2-TS) that decreases inactivation of the channel, which increases Ca(2+) influx, prolongs APs, and causes lethal arrhythmias. Although many details of the CaV1.2-TS channels are known, the cellular mechanisms by which they induce arrhythmogenic changes in intracellular Ca(2+) remain unclear. We found that expression of CaV1.2-TS channels increased sarcolemmal Ca(2+) "leak" in resting TS ventricular myocytes. This resulted in higher diastolic [Ca(2+)]i in TS ventricular myocytes compared to WT. Accordingly, TS myocytes had higher sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) spark activity, larger amplitude [Ca(2+)]i transients, and augmented frequency of Ca(2+) waves. The large SR Ca(2+) release in TS myocytes had a profound effect on the kinetics of CaV1.2 current in these cells, increasing the rate of inactivation to a high, persistent level. This limited the amount of influx during EC coupling in TS myocytes. The relationship between the level of expression of CaV1.2-TS channels and the probability of Ca(2+) wave occurrence was non-linear, suggesting that even low levels of these channels were sufficient to induce maximal changes in [Ca(2+)]i. Depolarization of WT cardiomyocytes with a TS AP waveform increased, but did not equalize [Ca(2+)]i, compared to depolarization of TS myocytes with the same waveform. We propose that CaV1.2-TS channels increase [Ca(2+)] in the cytosol and the SR, creating a Ca(2+)overloaded state that increases the probability of arrhythmogenic spontaneous SR Ca(2+) release.

| S-EPMC3903114 | biostudies-literature

Deterministic versus stochastic model of reprogramming: new evidence from cellular barcoding technique.

Project description:Factor-mediated reprogramming of somatic cells towards pluripotency is a low-efficiency process during which only small subsets of cells are successfully reprogrammed. Previous analyses of the determinants of the reprogramming potential are based on average measurements across a large population of cells or on monitoring a relatively small number of single cells with live imaging. Here, we applied lentiviral genetic barcoding, a powerful tool enabling the identification of familiar relationships in thousands of cells. High-throughput sequencing of barcodes from successfully reprogrammed cells revealed a significant number of barcodes from related cells. We developed a computer model, according to which a probability of synchronous reprogramming of sister cells equals 10-30%. We conclude that the reprogramming success is pre-established in some particular cells and, being a heritable trait, can be maintained through cell division. Thus, reprogramming progresses in a deterministic manner, at least at the level of cell lineages.

| S-EPMC5413903 | biostudies-literature

Mechanisms of ventricular arrhythmias: from molecular fluctuations to electrical turbulence.

Project description:Ventricular arrhythmias have complex causes and mechanisms. Despite extensive investigation involving many clinical, experimental, and computational studies, effective biological therapeutics are still very limited. In this article, we review our current understanding of the mechanisms of ventricular arrhythmias by summarizing the state of knowledge spanning from the molecular scale to electrical wave behavior at the tissue and organ scales and how the complex nonlinear interactions integrate into the dynamics of arrhythmias in the heart. We discuss the challenges that we face in synthesizing these dynamics to develop safe and effective novel therapeutic approaches.

| S-EPMC4342983 | biostudies-literature

Disentangling mechanisms that mediate the balance between stochastic and deterministic processes in microbial succession.

Project description:Ecological succession and the balance between stochastic and deterministic processes are two major themes within microbial ecology, but these conceptual domains have mostly developed independent of each other. Here we provide a framework that integrates shifts in community assembly processes with microbial primary succession to better understand mechanisms governing the stochastic/deterministic balance. Synthesizing previous work, we devised a conceptual model that links ecosystem development to alternative hypotheses related to shifts in ecological assembly processes. Conceptual model hypotheses were tested by coupling spatiotemporal data on soil bacterial communities with environmental conditions in a salt marsh chronosequence spanning 105 years of succession. Analyses within successional stages showed community composition to be initially governed by stochasticity, but as succession proceeded, there was a progressive increase in deterministic selection correlated with increasing sodium concentration. Analyses of community turnover among successional stages--which provide a larger spatiotemporal scale relative to within stage analyses--revealed that changes in the concentration of soil organic matter were the main predictor of the type and relative influence of determinism. Taken together, these results suggest scale-dependency in the mechanisms underlying selection. To better understand mechanisms governing these patterns, we developed an ecological simulation model that revealed how changes in selective environments cause shifts in the stochastic/deterministic balance. Finally, we propose an extended--and experimentally testable--conceptual model integrating ecological assembly processes with primary and secondary succession. This framework provides a priori hypotheses for future experiments, thereby facilitating a systematic approach to understand assembly and succession in microbial communities across ecosystems.

| S-EPMC4371938 | biostudies-literature

Deterministic characterization of stochastic genetic circuits.

Project description:For cellular biochemical reaction systems where the numbers of molecules is small, significant noise is associated with chemical reaction events. This molecular noise can give rise to behavior that is very different from the predictions of deterministic rate equation models. Unfortunately, there are few analytic methods for examining the qualitative behavior of stochastic systems. Here we describe such a method that extends deterministic analysis to include leading-order corrections due to the molecular noise. The method allows the steady-state behavior of the stochastic model to be easily computed, facilitates the mapping of stability phase diagrams that include stochastic effects, and reveals how model parameters affect noise susceptibility in a manner not accessible to numerical simulation. By way of illustration we consider two genetic circuits: a bistable positive-feedback loop and a negative-feedback oscillator. We find in the positive feedback circuit that translational activation leads to a far more stable system than transcriptional control. Conversely, in a negative-feedback loop triggered by a positive-feedback switch, the stochasticity of transcriptional control is harnessed to generate reproducible oscillations.

| S-EPMC1863463 | biostudies-literature

High complexity cellular barcoding and clonal tracing reveals stochastic and deterministic parameters of radiation resistance

Project description:It is elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. With high resolution clonal barcoding and tracking of over 400.000 HNSCC patient-derived tumor cells the clonal dynamics of tumor cells in response to IR was analysed. Fractionated IR induced a strong selective pressure for clonal reduction. This significantly exceeded uniform clonal survival probabilities indicative for a strong clone-to clone difference within tumor cells. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. The ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype was found at a frequency of 0.6-3.3%. With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for evaluating the contribution of stochastic and deterministic clonal selection processes in response to IR.

2021-09-07 | E-MTAB-9693 | biostudies-arrayexpress

Deterministic and stochastic control of kirigami topology.

Project description:Kirigami, the creative art of paper cutting, is a promising paradigm for mechanical metamaterials. However, to make kirigami-inspired structures a reality requires controlling the topology of kirigami to achieve connectivity and rigidity. We address this question by deriving the maximum number of cuts (minimum number of links) that still allow us to preserve global rigidity and connectivity of the kirigami. A deterministic hierarchical construction method yields an efficient topological way to control both the number of connected pieces and the total degrees of freedom. A statistical approach to the control of rigidity and connectivity in kirigami with random cuts complements the deterministic pathway, and shows that both the number of connected pieces and the degrees of freedom show percolation transitions as a function of the density of cuts (links). Together, this provides a general framework for the control of rigidity and connectivity in planar kirigami.

| S-EPMC7060672 | biostudies-literature

Dual pathways of carbon monoxide-mediated vasoregulation: modulation by redox mechanisms.

Project description:RationaleVascular tissues produce carbon monoxide (CO) via HO-dependent and HO-independent mechanisms; the former in tandem with biliverdin and iron and the latter as a lone product. CO has been shown to function as both a vasoconstrictor and vasodilator; however, factors that dictate the vasoregulatory phenotype of this gas are unknown.ObjectiveWe investigated whether CO-mediated vasoconstriction is mechanistically linked to enhanced reactive oxygen species production that masks vasodilatory pathways.Methods and resultsSprague-Dawley rat interlobar and interlobular arteries were examined in terms of superoxide (O2*-) generation and vascular reactivity in the absence and presence of antioxidants. Both authentic CO and the CO-releasing molecule (CORM)-3 constricted renal arteries and increased O2*- production in a dose-dependent manner. The antioxidants tempol, ebselen, and deferoxamine inhibited CO-induced O2*- production and converted CO from constrictor to dilator. CO-induced O2*- generation was found to involve the activity of multiple oxidases including nitric oxide synthase, NADPH oxidase, xanthine oxidase, and complex IV of the mitochondrial electron chain. Furthermore, inhibition of these enzymes converted CO from constrictor to dilator. Similarly, biliverdin and bilirubin inhibited CO-induced O2*- production and vasoconstriction, allowing for a vasodilatory response to CO to be expressed. CO-induced vasoconstriction was dependent on a non-thromboxane agonist of the thromboxane receptor, whereas vasodilatory mechanisms of CO relied on the activation of soluble guanylate cyclase and calcium-gated potassium channels.ConclusionsCO-induced vasoconstriction involves the generation of reactive oxygen species, which, when negated, allows for the expression of vasodilatory pathways which are masked by the primary oxidative stress response to this gas.

| S-EPMC2771695 | biostudies-literature

Atropine-induced sinus tachycardia protects against exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia.

Project description:AimsCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by exercise-induced ventricular arrhythmias, sudden death, and sinus bradycardia. Elevating supraventricular rates with pacing or atropine protects against catecholaminergic ventricular arrhythmias in a CPVT mouse model. We tested the hypothesis that increasing sinus heart rate (HR) with atropine prevents exercise-induced ventricular arrhythmias in CPVT patients.Methods and resultsWe performed a prospective open-label trial of atropine prior to exercise in CPVT patients (clinicaltrials.gov NCT02927223). Subjects performed a baseline standard Bruce treadmill test on their usual medical regimen. After a 2-h recovery period, subjects performed a second exercise test after parasympathetic block with atropine (0.04 mg/kg intravenous). The primary outcome measure was the total number of ventricular ectopic beats during exercise. All six subjects (5 men, 22-57 years old) completed the study with no adverse events. Atropine increased resting sinus rate from median 52 b.p.m. (range 52-64) to 98 b.p.m. (84-119), P = 0.02. Peak HRs (149 b.p.m., range 136-181 vs. 149 b.p.m., range 127-182, P = 0.46) and exercise duration (612 s, range 544-733 vs. 584 s, range 543-742, P = 0.22) were not statistically different. All subjects had ventricular ectopy during the baseline exercise test. Atropine pre-treatment significantly decreased the median number of ventricular ectopic beats from 46 (6-192) to 0 (0-29), P = 0.026; ventricular ectopy was completely eliminated in 4/6 subjects.ConclusionElevating sinus rates with atropine reduces or eliminates exercise-induced ventricular ectopy in patients with CPVT. Increasing supraventricular rates may represent a novel therapeutic strategy in CPVT.

| S-EPMC7132542 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data