Search results for "model."

Bioelectrical Coupling of Single-Cell States in Multicellular Systems.

2020

The spatiotemporal distributions of signaling ions and molecules that modulate biochemical pathways in nonexcitable cells are influenced by multicellular electric potentials. These potentials act as distributed controllers encoding instructive spatial patterns in development and regeneration. We review experimental facts and discuss recent bioelectrical models that provide new physical insights and complement biochemical approaches. Single-cell states are modulated at the multicellular level because of the coupling between neighboring cells, thus allowing memories and multicellular patterns. The model is based on (i) two generic voltage-gated ion channels that promote the polarized and depo…

Bioelectrical coupling in multicellular domains regulated by gap junctions: A conceptual approach.

2018

We review the basic concepts involved in bioelectrically-coupled multicellular domains, focusing on the role of membrane potentials (Vmem). In the first model, single-cell Vmem is modulated by two generic polarizing and depolarizing ion channels, while intercellular coupling is implemented via voltage-gated gap junctions. Biochemical and bioelectrical signals are integrated via a feedback loop between Vmem and the transcription and translation of a protein forming an ion channel. The effective rate constants depend on the single-cell Vmem because these potentials modulate the local concentrations of signaling molecules and ions. This electrochemically-based idealization of the complex bioph…

MicroRNA Intercellular Transfer and Bioelectrical Regulation of Model Multicellular Ensembles by the Gap Junction Connectivity.

2017

We have studied theoretically the microRNA (miRNA) intercellular transfer through voltage-gated gap junctions in terms of a biophysically grounded system of coupled differential equations. Instead of modeling a specific system, we use a general approach describing the interplay between the genetic mechanisms and the single-cell electric potentials. The dynamics of the multicellular ensemble are simulated under different conditions including spatially inhomogeneous transcription rates and local intercellular transfer of miRNAs. These processes result in spatiotemporal changes of miRNA, mRNA, and ion channel protein concentrations that eventually modify the bioelectrical states of small multi…

A Thermodynamic Model of Monovalent Cation Homeostasis in the Yeast Saccharomyces cerevisiae

2016

Cationic and heavy metal toxicity is involved in a substantial number of diseases in mammals and crop plants. Therefore, the understanding of tightly regulated transporter activities, as well as conceiving the interplay of regulatory mechanisms, is of substantial interest. A generalized thermodynamic description is developed for the complex interplay of the plasma membrane ion transporters, membrane potential and the consumption of energy for maintaining and restoring specific intracellular cation concentrations. This concept is applied to the homeostasis of cation concentrations in the yeast cells of S. cerevisiae. The thermodynamic approach allows to model passive ion fluxes driven by the…

The role of spatial structure in the evolution of viral innate immunity evasion: A diffusion-reaction cellular automaton model

2020

Most viruses have evolved strategies for preventing interferon (IFN) secretion and evading innate immunity. Recent work has shown that viral shutdown of IFN secretion can be viewed as a social trait, since the ability of a given virus to evade IFN-mediated immunity depends on the phenotype of neighbor viruses. Following this idea, we investigate the role of spatial structure in the evolution of innate immunity evasion. For this, we model IFN signaling and viral spread using a spatially explicit approximation that combines a diffusion-reaction model and cellular automaton. Our results indicate that the benefits of preventing IFN secretion for a virus are strongly determined by spatial struct…

A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expressio…

2019

Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better …

2017

Whether the central nervous system is capable to switch between contexts critically depends on experimental details. Motor control studies regularly adopt robotic devices to perturb the dynamics of a certain task. Other approaches investigate motor control by altering the gravitoinertial context itself as in parabolic flights and human centrifuges. In contrast to conventional robotic experiments, where only the hand is perturbed, these gravitoinertial or immersive settings coherently plunge participants into new environments. However radically different they are, perfect adaptation of motor responses are commonly reported. In object manipulation tasks, this translates into a good matching o…

The Role of Sirtuin1 in Regulating Endothelial Function, Arterial Remodeling and Vascular Aging

2019

Sirtuin1 (SIRT1), which belongs to a highly conserved family of protein deacetylase, is one of the best-studied sirtuins. SIRT1 is involved in a variety of biological processes, including energy metabolism, cell proliferation and survival, chromatin dynamics, and DNA repair. In the vasculature, SIRT1 is ubiquitously expressed in endothelial cells, smooth muscle cells, and perivascular adipose tissues (PVAT). Endothelial SIRT1 plays a unique role in vasoprotection by regulating a large variety of proteins, including endothelial nitric oxide synthase (eNOS). In endothelial cells, SIRT1 and eNOS regulate each other synergistically through positive feedback mechanisms for the maintenance of end…

Developmental programming of somatic growth, behavior and endocannabinoid metabolism by variation of early postnatal nutrition in a cross-fostering m…

2017

Background Nutrient deprivation during early development has been associated with the predisposition to metabolic disorders in adulthood. Considering its interaction with metabolism, appetite and behavior, the endocannabinoid (eCB) system represents a promising target of developmental programming. Methods By cross-fostering and variation of litter size, early postnatal nutrition of CB6F1-hybrid mice was controlled during the lactation period (3, 6, or 10 pups/mother). After weaning and redistribution at P21, all pups received standard chow ad libitum. Gene expression analyses (liver, visceral fat, hypothalamus) were performed at P50, eCB concentrations were determined in liver and visceral …

Metal homeostasis regulators suppress FRDA phenotypes in a drosophila model of the disease

2016

Friedreich's ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin def…