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Ca 2+ signalling is pivotal in T cell activation, an essential process in adaptive immune responses. Key to this activation are Ca 2+ microdomains, which are transient increases in cytosolic Ca 2+ concentration occurring within narrow regions between the endoplasmic reticulum (ER) and the plasma membrane (PM), lasting a few tens of milliseconds. Adhesion Dependent Ca 2+ Microdomains (ADCM) rely on store-operated Ca 2+ entry (SOCE) via the ORAI/STIM system. The nanometric scale at which these microdomains form poses challenges for direct experimental observation. Following the previous work of Gil et al. [1], which introduced a three-dimensional model of the ER-PM junction, this study combines a detailed description of the Ca 2+ fluxes at the junction with stochastic dynamics of a cluster of D-myo-inositol 1,4,5 trisphosphate receptors (IP 3 R) located in the ER surrounding the junction. Because the consideration of Ca 2+ release through the IP 3 R calls for the simulation of a portion of the cytoplasm considerably larger than the junction, our study also investigates the spatial distribution of PMCAs, revealing their likely localization outside the ER-PM junction. Simulations indicate that Ca 2+ puffs implying the opening of 2-6 IP 3 Rs create ADCMs by provoking local depletions of ER Ca 2+ stimulating Ca 2+ entry through the ORAI1 channels. Such conditions allow the reproduction of the amplitude, duration and spatial extent of the observed ADCMs. By integrating advanced computational techniques with insights from experimental studies, our approach provides valuable information on the mechanisms governing early Ca 2+ signalling in T cell activation, paving the way for a deeper understanding of immune responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Early mammalian embryo is a paradigm of dynamic, self-organised process. It involves gene expression, cell division and intercellular signalling. How these processes interact to ensure reproducible development is being often investigated by modelling, which allows to dissect the mechanisms controlling cell fate decisions. In this work, we present two models based on ordinary differential equations describing the first and second specification processes in the mouse embryo. Together, they describe the cell fate decisions leading to the first three cell lineages which form the blastocyst 4.5 days after fertilisation: the trophectoderm, the epiblast and the primitive endoderm. Both specifications rely on multistability, and signalling allows the selection of the appropriate steady-state. In addition to the gene regulatory network, the first specification process is indeed controlled by the Hippo pathway, which is itself controlled by cell polarity and cell-to-cell contacts. This leads to a spatially organised arrangement of cells. The second specification process is controlled by Fgf signalling and leads to a salt and pepper distribution of the two cell types. We discuss the respective mechanisms and their physiological implications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent reports have highlighted the pivotal role of Ca 2+ during host cell infection by bacterial pathogens. Here, we review how bacterial pore-forming toxins (PFTs) trigger global Ca 2+ signals to regulate cell adhesion-, inflammatory- or death processes. We comment recent reports describing the role of bacterial effectors injected by a type III secretion system (T3SS) as well as host cell players in the formation of Ca 2+ microdomains during Shigella invasion and Chlamydia extrusion of host cells. We discuss how modeling and comparison between bacterial-induced and physiological Ca 2+ microdomains provides insight into the critical parameters shaping the duration of local Ca 2+ responses., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Alzheimer's disease is a progressive neurodegenerative disorder affecting millions of people. It is characterized by the slow deposition of cerebral amyloid-β peptides in the brain and by dysregulations in neuronal Ca(2+) homeostasis. Numerous experimental studies have revealed the existence of a feed-forward loop wherein amyloids-β disturb neuronal Ca(2+) levels, which in turn affect the production of amyloids. Here, we formalize this positive loop in a minimal, qualitative model and show that it exhibits bistability. Thus, a stable steady state characterized by low levels of Ca(2+) and amyloids, corresponding to a healthy situation, coexists with another 'pathological state' where the levels of both compounds are high. The onset of the disease corresponds to the switch from the lower steady state to the higher one induced by a large-enough perturbation in either the metabolism of amyloids or the homeostasis of intracellular Ca(2+). Numerical simulations of the model reproduce a variety of experimental observations about the disease, as its irreversible character, the threshold-like transition to a severe pathology after the slow accumulation of symptoms, the effect of presenilins, the so-called 'prion-like' autocatalytic behaviour of amyloids and the inherent random character of the apparition of the disease that is well known for the sporadic form. The model thus provides a conceptual framework that could be useful when developing therapeutic protocols to slow down the progression of Alzheimer's disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The rules that govern the activation and autophosphorylation of the multifunctional Ca2+-calmodulin kinase II (CaMKII) by Ca2+ and calmodulin (CaM) are thought to underlie its ability to decode Ca2+ oscillations and to control multiple cellular functions. We propose a simple biophysical model for the activation of CaMKII by Ca2+ and calmodulin. The model describes the transition of the subunits of the kinase between their different possible states (inactive, bound to Ca2+-CaM, phosphorylated at Thr(286), trapped and autonomous). All transitions are described by classical kinetic equations except for the autophosphorylation step, which is modeled in an empirical manner. The model quantitatively reproduces the experimentally demonstrated frequency sensitivity of CaMKII [Science 279 (1998) 227]. We further use the model to investigate the role of several characterized features of the kinase--as well as some that are not easily attainable by experiments--in its frequency-dependent responses. In cellular microdomains, CaMKII is expected to sense very brief Ca2+ spikes; our simulations under such conditions reveal that the enzyme response is tuned to optimal frequencies. This prediction is then confirmed by experimental data. This novel and simple model should help in understanding the rules that govern CaMKII regulation, as well as those involved in decoding intracellular Ca2+ signals.