title: Modular model of TNFalpha cytotoxicity.
abstract: BACKGROUND
  Tumour Necrosis Factor alpha (TNF) initiates a complex series of biochemical events in the cell upon binding to its type R1 receptor (TNF-R1). Recent experimental work has unravelled the molecular regulation of the signalling complexes that lead either to cell survival or death. Survival signals are activated by direct binding of TNF to TNF-R1 at the cell membrane whereas apoptotic signals by endocytosed TNF/TNF-R1 complexes. Here we describe a reduced, effective model with few free parameters, where we group some intricate mechanisms into effective modules, that successfully describes this complex set of actions. We study the parameter space to show that the model is structurally stable and robust over a broad range of parameter values.
  
  
  RESULTS
  We use state-of-the-art Bayesian methods (a Sequential Monte Carlo sampler) to perform inference of plausible values of the model parameters from experimental data. As a result, we obtain a robust model that can provide a solid basis for further modelling of TNF signalling. The model is also suitable for inclusion in multi-scale simulation programs that are presently under development to study the behaviour of large tumour cell populations.
  
  
  BACKGROUND
  We provide supplementary material that includes all mathematical details and all algorithms (Matlab code) and models (SBML descriptions).
  
  
  BACKGROUND
  edoardo.milotti@ts.infn.it
authors.affiliation: Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15-CV1, I-37134 Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chignola
authors.forename: Vladislav
authors.initials: V
authors.lastname: Vyshemirsky
authors.forename: Marcello
authors.initials: M
authors.lastname: Farina
authors.forename: Alessio
authors.initials: A
authors.lastname: Del Fabbro
authors.forename: Edoardo
authors.initials: E
authors.lastname: Milotti
mesh_terms: D001499:Bayes Theorem; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha