Modelling biochemical pathways through enhanced π-calculus

AbstractWe use the π-calculus to model the evolution of biochemical systems, taking advantage of their similarities with global computation applications. First, we present a reduction semantics for the π-calculus from which causality and concurrency can be mechanically derived. We prove that our semantics agrees with the causal definitions presented in the literature. We also extend our semantics to model biological compartments. Then, we show the applicability of our proposal on a couple of biological examples

Causal P-Calculus for Biochemical Modelling

An increasing number of researchers is trying to define models of biochemical pathways via theoretical and technological tools, allowing biologists to simulate reactions before doing them in vitro. The advantages are obvious: a computation normally requires less time then a real experiment, simulation of reactions is cheaper than doing them ectively, and so on

Systemic-onset juvenile idiopathic arthritis complicated by early onset amyloidosis in a patient carrying a mutation in the MEFV gene

Systemic juvenile idiopathic arthritis (SJIA) is a disorder characterized by arthritis in children starting before 16 years of age associated with daily high fever, persisting for more than 2 weeks, and at least one of the following clinical features: evanescent cutaneous rash, lymphadenopathy, serositis or hepatosplenomegaly. SJIA patients carry a significantly higher frequency of MEFV mutations, the gene responsible for familial Mediterranean fever, and may be characterized by a more aggressive disease. In this line, we describe a 9-year-old girl affected with SJIA who carried a heterozygous G196W mutation in MEFV. Our patient was characterized by an aggressive disease course, resistance to conventional immunosuppressive agents and developed renal amyloidosis just 2 years after the disease onset

Conditional up-regulation of IL-2 production by p38 MAPK inactivation is mediated by increased Erk1/2 activity

The p38 mitogen-activated protein kinase regulates many cellular processes in almost all eukaryotic cell types. In T cells, p38 was shown to regulate thymic development and cytokine production. Here, the role of p38 on interleukin-2 (IL-2) production by human peripheral blood CD4+ T cells was examined. When T cells were stimulated under weak stimulation conditions, pharmaceutical and molecular p38 inhibitors induced a dramatic increase of IL-2 production. In contrast, IL-2 levels were not affected significantly when strong stimulation was provided to T cells. The increase in IL-2 production, following p38 inhibition, was associated with a strong up-regulation of extracellular signal-regulated kinase (Erk)1/2 activity. Furthermore the Erk inhibitor U0126 was able to counteract the effect of p38 inhibition on IL-2 production, supporting the conclusion that p38 mediates its effect through Erk. These results suggest that the p38 kinase, through its ability to control Erk activation levels, acts as a gatekeeper, which prevents inappropriate IL-2 production. Also, the finding that p38 acts in a strength-of-stimulation-dependent way provides an explanation for previously reported, contradictory results regarding the role of this kinase in IL-2 expression. © Society for Leukocyte Biology

p66Shc is a negative regulator of Fc{varepsilon}RI-Dependent signaling in mast cells

Aggregation of Fc\u3b5RI on mast cells activates signaling pathways, resulting in degranulation and cytokine release. Release of mast cell-derived inflammatory mediators is tightly regulated by the interplay of positive and negative signals largely orchestrated by adapter proteins. Among these, the Shc family adapter p52Shc, which couples immunoreceptors to Ras activation, positively regulates Fc\u3b5RI-dependent signaling. Conversely, p66Shc was shown to uncouple the TCR for the Ras-MAPK pathway and prime T cells to undergo apoptotic death. Loss of p66Shc in mice results in breaking of immunologic tolerance and development of lupus-like autoimmune disease, which includes alopecia among its pathological manifestations. The presence of numerous activated mast cells in alopecic skin areas suggests a role for this adapter in mast cells. In this study, we addressed the involvement of p66Shc in Fc\u3b5RI-dependent mast cell activation. We showed that p66Shc is expressed in mast cells and that mast cells from p66Shc(-/-) mice exhibit enhanced responses following Ag stimulation of Fc\u3b5RI. Furthermore, using RBL-2H3 cell transfectants, we showed that aggregation of Fc\u3b5RI resulted in the recruitment of a p66Shc-SHIP1 complex to linker for activation of T cells. Collectively, our data identified p66Shc as a negative regulator of mast cell activatio