Biology subjects

Sontag, E.

Publications and source records attributed to Sontag, E..

6 recordsLinked to original sources

bioRxiv2018

Immunobiochemical reconstruction of influenza lung infection - Melanoma skin cancer interactions

Our recent experimental results that combine a mouse model of influenza A virus (IAV) infection (A/H1N1/PR8) and a highly aggressive model of infection-unrelated cancer, B16-F10 skin melanoma, showed that acute influenza infection of the lung promotes distal melanoma growth in the dermis of the flank and leads to decreased host survival. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates the T cell receptor signaling pathway, various transcription factors, and a gene regulatory network (GRN). A core component of our model is a biochemical motif, which we call a Triple Incoherent Feed-Forward Loop (TIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the TIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Specifically, both the TIFFL reconstruction and quantitative estimates obtained from the model allowed us to formulate a hypothesis that it is the loss of the fundamental TIFFL-induced adaptation of the expression of PD-1 receptors on anti-melanoma CD8+ T cells that constitutes the essence of the previously unrecognized immunologic factor that promotes the experimentally observed distal tumor growth in the presence of acute non-ocogenic infection. We therefore hope that this work can further highlight the importance of adaptive mechanisms by which immune functions contribute to the balance between self and non-self immune tolerance, adaptive resistance, and the strength of TCR-induced activation, thus contributing to the understanding of a broader complexity of fundamental interactions between pathogens and tumors.

immunology↗

bioRxiv2017

Subharmonics And Chaos In Simple Periodically-Forced Biomolecular Models

This paper uncovers a remarkable behavior in two biochemical systems that commonly appear as components of signal transduction pathways in systems biology. These systems have globally attracting steady states when unforced, so they might have been considered \"uninteresting\" from a dynamical standpoint. However, when subject to a periodic excitation, strange attractors arise via a period-doubling cascade. Quantitative analyses of the corresponding discrete chaotic trajectories are conducted numerically by computing largest Lyapunov exponents, power spectra, and autocorrelation functions. To gain insight into the geometry of the strange attractors, the phase portraits of the corresponding iterated maps are interpreted as scatter plots for which marginal distributions are additionally evaluated. The lack of entrainment to external oscillations, in even the simplest biochemical networks, represents a level of additional complexity in molecular biology, which has previously been insufficiently recognized but is plausibly biologically important.

systems biology↗

bioRxiv2017

Translation Inhibition And Resource Balance In The Cell-Free Gene Expression System

Quantifying the effect of vital resources on transcription and translation helps to understand the degree to which the concentration of each resource must be regulated for achieving homeostasis. Utilizing the synthetic transcription-translation (TX-TL) system, we study the impact of nucleotide triphosphates (NTPs) and magnesium (Mg2+), on gene expression. Recent observations of the counterintuitive phenomenon of suppression of gene expression at high NTP concentrations have led to the speculation that such suppression is due to the consumption of resources by transcription, hence leaving fewer resources for translation. In this work, we investigate an alternative hypothesis: direct suppression of the translation rate via stoichiometric mismatch in necessary reagents. We observe NTP-dependent suppression even in the early phase of gene expression, contradicting the resource limitation argument. To further decouple the contributions of transcription and translation, we performed gene expression experiments with purified mRNA. Simultaneously monitoring mRNA and protein abundances allowed us to extract a time-dependent translation rate. Measuring translation rates for different Mg2+ and NTP concentrations, we observe a complex resource dependence. We demonstrate that translation is the rate-limiting process that is directly inhibited by high NTP concentrations. Additional Mg2+ can partially reverse this inhibition. In several experiments, we observe two maxima of the translation rate viewed as a function of both Mg2+ and NTP concentration, which can be explained in terms of an NTP-independent effect on the ribosome complex and an NTP-Mg2+ titration effect. The non-trivial compensatory effects of abundance of different vital resources signals the presence of complex regulatory mechanisms to achieve optimal gene expression.

synthetic biology↗

bioRxiv2017

A Note On Dynamical Compensation And Its Relation To Parameter Identifiability

We recently identified a motif for dynamical compensation (DC) - a property where a system maintains the dynamics and steady-state of a regulated variable robust in the face of fluctuations in key parameters. Such parameters are therefore unidentifiable from measurements of the regulated variable at steady-state. On the other hand, since the models showing dynamical compensation are typically non-redundant, their parameters are identifiable from experimental data. We clarify this apparent discrepancy by requiring that the parameters of DC circuits be identifiable both away from steady-state and when measuring other system variables. We use this observation to provide a definition for DC in terms of parameter identifiability and discuss its relevance for the examples provided in Karin et al.

systems biology↗

bioRxiv2016

Dynamic compensation, parameter identifiability, and equivariances

A recent paper by Karin, Swisa, Glaser, Dor, and Alon introduced the mathematical notion of dynamical compensation (DC) in biological circuits, arguing that DC helps explain important features of glucose homeostasis as well as other key physiological regulatory mechanisms. The present paper establishes a connection between DC and two well-known notions in systems biology: system equivalence and parameter (un)identifiability. This recasting leads to effective tests for verifying DC in mathematical models.

systems biology↗

bioRxiv2016

Two-zone tumor tolerance can arise from a simple immunological feedforward motif that estimates tumor growth rates

Since the early 1990s, many authors have independently suggested that self/nonself recognition by the immune system might be modulated by the rates of change of antigen challenges. This paper introduces an extremely simple and purely conceptual mathematical model that allows dynamic discrimination of immune challenges. The main component of the model is a motif which is ubiquitous in systems biology, the incoherent feedforward loop, which endows the system with the capability to estimate exponential growth exponents, a prediction which is consistent with experimental work showing that exponentially increasing antigen stimulation is a determinant of immune reactivity. Combined with a bistable system and a simple feedback repression mechanism, an interesting phenomenon emerges as a tumor growth rate increases: elimination, tolerance (tumor growth), again elimination, and finally a second zone of tolerance (tumor escape). This prediction from our model is analogous to the \"two-zone tumor tolerance\" phenomenon experimentally validated since the mid 1970s. Moreover, we provide a plausible biological instantiation of our circuit using combinations of regulatory and effector T cells.

immunology↗