BackgroundParameter estimation from experimental data is critical for mathematical modeling of protein regulatory networks. For realistic networks with dozens of species and reactions, parameter estimation is an especially challenging task. In this study, we present an approach for parameter estimation that is effective in fitting a model of the budding yeast cell cycle (comprising 26 nonlinear ordinary differential equations containing 126 rate constants) to the experimentally observed phenotypes (viable or inviable) of 119 genetic strains carrying mutations of cell cycle genes.ResultsStarting from an initial guess of the parameter values, which correctly captures the phenotypes of only 72 genetic strains, our parameter estimation algorithm quickly improves the success rate of the model to 105–111 of the 119 strains. This success rate is comparable to the best values achieved by a skilled modeler manually choosing parameters over many weeks. The algorithm combines two search and optimization strategies. First, we use Latin hypercube sampling to explore a region surrounding the initial guess. From these samples, we choose ∼20 different sets of parameter values that correctly capture wild type viability. These sets form the starting generation of differential evolution that selects new parameter values that perform better in terms of their success rate in capturing phenotypes. In addition to producing highly successful combinations of parameter values, we analyze the results to determine the parameters that are most critical for matching experimental outcomes and the most competitive strains whose correct outcome with a given parameter vector forces numerous other strains to have incorrect outcomes. These “most critical parameters” and “most competitive strains” provide biological insights into the model. Conversely, the “least critical parameters” and “least competitive strains” suggest ways to reduce the computational complexity of the optimization.ConclusionsOur approach proves to be a useful tool to help systems biologists fit complex dynamical models to large experimental datasets. In the process of fitting the model to the data, the tool identifies suggestive correlations among aspects of the model and the data.
Most studies of adaptive immunity to SARS-CoV-2 infection focus on peripheral blood, which may not fully reflect immune responses at the site of infection. Using samples from 110 children undergoing tonsillectomy and adenoidectomy during the COVID-19 pandemic, we identified 24 samples with evidence of previous SARS-CoV-2 infection, including neutralizing antibodies in serum and SARS-CoV-2-specific germinal center and memory B cells in the tonsils and adenoids. Single-cell B cell receptor (BCR) sequencing indicated virus-specific BCRs were class-switched and somatically hypermutated, with overlapping clones in the two tissues. Expanded T cell clonotypes were found in tonsils, adenoids and blood post-COVID-19, some with CDR3 sequences identical to previously reported SARS-CoV-2-reactive T cell receptors (TCRs). Pharyngeal tissues from COVID-19-convalescent children showed persistent expansion of germinal center and antiviral lymphocyte populations associated with interferon (IFN)-γ-type responses, particularly in the adenoids, and viral RNA in both tissues. Our results provide evidence for persistent tissue-specific immunity to SARS-CoV-2 in the upper respiratory tract of children after infection.
This article applies kinetic Monte Carlo simulations to interpret experimental measurements in
the polymerization of hyperbranched poly(ether esters)s in a melt condensation of A2 oligomers and B3 monomers.
Building on the analytical modeling of Flory and Stockmayer, additional effects of cycle formation, unequal
reactivities, and end-capping reagents are added into the simulations to describe A2 + B3 polymerization in the
absence of a solvent. The experimental data have been published separately, and here it is compared to the
model predictions in order to quantitatively assess whether the data are consistent with these models. On the
basis of the modeling, we conclude that cycle formation is negligible, suppression of the third B group is
insignificant, and the mobility of the free B3 monomer leads to enhancement of its reaction rate. The addition of
the monofunctional end-capping reagents does not necessarily lead to suppression of branching in the A2 + B3
system and depends sensitively on the stoichiometry of the reactants.
At least four distinct lineages of CD4+ T cells play diverse roles in the immune system. Both in vivo and in vitro, naïve CD4+ T cells often differentiate into a variety of cellular phenotypes. Previously, we developed a mathematical framework to study heterogeneous differentiation of two lineages governed by a mutual-inhibition motif. To understand heterogeneous differentiation of CD4+ T cells involving more than two lineages, we present here a mathematical framework for the analysis of multiple stable steady states in dynamical systems with multiple state variables interacting through multiple mutual-inhibition loops. A mathematical model for CD4+ T cells based on this framework can reproduce known properties of heterogeneous differentiation involving multiple lineages of this cell differentiation system, such as heterogeneous differentiation of TH1–TH2, TH1–TH17 and iTReg–TH17 under single or mixed types of differentiation stimuli. The model shows that high concentrations of differentiation stimuli favor the formation of phenotypes with co-expression of lineage-specific master regulators.
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