Biomedical subjects

Jonathan Rubin

Publications and source records attributed to Jonathan Rubin.

7 recordsLinked to original sources

PubMed2006

A reduced mathematical model of the acute inflammatory response II. Capturing scenarios of repeated endotoxin administration.

Bacterial lipopolysaccharide (LPS; endotoxin) is a potent immunostimulant that can induce an acute inflammatory response comparable to a bacterial infection. Experimental observations demonstrate that this biological response can be either blunted (tolerance) or augmented (potentiation) with repeated administration of endotoxin. Both phenomena are of clinical relevance. We show that a four-dimensional differential equation model of this response reproduces many scenarios involving repeated endotoxin administration. In particular, the model can display both tolerance and potentiation from a single parameter set, under different administration scenarios. The key determinants of the outcome of our simulations are the relative time-scales of model components. These findings support the hypothesis that endotoxin tolerance and other related phenomena can be considered as dynamic manifestations of a unified acute inflammatory response, and offer specific predictions related to the dynamics of this response to endotoxin.

Acute Disease↗

PubMed2006

A reduced mathematical model of the acute inflammatory response: I. Derivation of model and analysis of anti-inflammation.

The acute inflammatory response, triggered by a variety of biological or physical stresses on an organism, is a delicate system of checks and balances that, although aimed at promoting healing and restoring homeostasis, can result in undesired and occasionally lethal physiological responses. In this work, we derive a reduced conceptual model for the acute inflammatory response to infection, built up from consideration of direct interactions of fundamental effectors. We harness this model to explore the importance of dynamic anti-inflammation in promoting resolution of infection and homeostasis. Further, we offer a clinical correlation between model predictions and potential therapeutic interventions based on modulation of immunity by anti-inflammatory agents.

Acute Disease↗

PubMed2006

In silico models of acute inflammation in animals.

Trauma and hemorrhagic shock elicit an acute inflammatory response, predisposing patients to sepsis, organ dysfunction, and death. Few approved therapies exist for these acute inflammatory states, mainly due to the complex interplay of interacting inflammatory and physiological elements working at multiple levels. Various animal models have been used to simulate these phenomena, but these models often do not replicate the clinical setting of multiple overlapping insults. Mathematical modeling of complex systems is an approach for understanding the interplay among biological interactions. We constructed a mathematical model using ordinary differential equations that encompass the dynamics of cells and cytokines of the acute inflammatory response, as well as global tissue dysfunction. The model was calibrated in C57Bl/6 mice subjected to (1) various doses of lipopolysaccharide (LPS) alone, (2) surgical trauma, and (3) surgery + hemorrhagic shock. We tested the model's predictive ability in scenarios on which it had not been trained, namely, (1) surgery +/- hemorrhagic shock + LPS given at times after the beginning of surgical instrumentation, and (2) surgery + hemorrhagic shock + bilateral femoral fracture. Software was created that facilitated fitting of the mathematical model to experimental data, as well as for simulation of experiments with various inflammatory challenges and associated variations (gene knockouts, inhibition of specific cytokines, etc.). Using this software, the C57Bl/6-specific model was recalibrated for inflammatory analyte data in CD14-/- mice and was used to elucidate altered features of inflammation in these animals. In other experiments, rats were subjected to surgical trauma +/- LPS or to bacterial infection via fibrin clots impregnated with various inocula of Escherichia coli. Mathematical modeling may provide insights into the complex dynamics of acute inflammation in a manner that can be tested in vivo using many fewer animals than has been possible previously.

Animals↗

PubMed2005

Timing in synaptic plasticity: from detection to integration.

Timing of cellular and subcellular events contributes to spiking-induced modification of synapses in a variety of ways. Initially, the timing of presynaptic and postsynaptic action potentials must be translated into signals that can initiate intracellular processes. Recent experimental and computational findings suggest that the spatiotemporal details of such signals, in particular the time courses and locations of postsynaptic Ca(2+) transients, might themselves be crucial for driving potentiation and depression modules that interact in a time-dependent way to determine plasticity outcomes. On longer timescales, the effects of multiple spikes are integrated in a nonlinear manner, yielding non-intuitive plasticity results that are likely to be sensitive to local conditions and, finally, additional elements must be called into action to stabilize changes in synaptic strengths. This review is part of the TINS Synaptic Connectivity series.

Action Potentials↗

PubMed2004

Localized activity patterns in excitatory neuronal networks.

The existence of localized activity patterns, or bumps, has been investigated in a variety of spatially distributed neuronal network models that contain both excitatory and inhibitory coupling between cells. Here we show that a neuronal network with purely excitatory synaptic coupling can exhibit localized activity. Bump formation ensues from an initial transient synchrony of a localized group of cells, followed by the emergence of desynchronized activity within the group. Transient synchrony is shown to promote recruitment of cells into the bump, while desynchrony is shown to be good for curtailing recruitment and sustaining oscillations of those cells already within the bump. These arguments are based on the geometric structure of the phase space in which solutions of the model equations evolve. We explain why bump formation and bump size are very sensitive to initial conditions and changes in parameters in this type of purely excitatory network, and we examine how short-term synaptic depression influences the characteristics of bump formation.

Computer Simulation↗

PubMed2003

Multiple-spike waves in a one-dimensional integrate-and-fire neural network.

This paper builds on the past study of single-spike waves in one-dimensional integrate-and-fire networks to provide a framework for the study of waves with arbitrary (finite or countably infinite) collections of spike times. Based on this framework, we prove an existence theorem for single-spike traveling waves, and we combine analysis and numerics to study two-spike traveling waves, periodic traveling waves, and general infinite spike trains. For a fixed wave speed, finite-spike waves, periodic waves, and other infinite-spike waves may all occur, and we discuss the relationships among them. We also relate the waves considered analytically to waves generated in numerical simulations by the transient application of localized excitation.

Action Potentials↗

PubMedDate not supplied

In silico and in vivo approach to elucidate the inflammatory complexity of CD14-deficient mice.

The inflammatory phenotype of genetically modified mice is complex, and the role of Gram-negative lipopolysaccharide (LPS) in acute inflammation induced by surgical cannulation trauma, alone or in combination with hemorrhage and resuscitation ("hemorrhagic shock"), is both complex and controversial. We sought to determine if a mathematical model of acute inflammation could elucidate both the phenotype of CD14-deficient (CD14(-/-)) mice--following LPS, cannulation, or hemorrhagic shock--and the role of LPS in trauma/hemorrhage-induced inflammation. A mathematical model of inflammation initially calibrated in wild-type (C57Bl/6) mice subjected to LPS, cannulation, and hemorrhagic shock was recalibrated in CD14(-/-) mice subjected to the same insults, yielding an ensemble of models that suggested specific differences at the cellular and molecular levels (for example, 43-fold lower activation of leukocytes by LPS). The CD14(-/-)-specific model ensemble could account for complex changes in inflammatory analytes in these mice following LPS treatment. Model prediction of similar organ damage in CD14(-/-) and wild-type mice subjected to cannulation alone or with hemorrhagic shock was verified in vivo (similar ALT levels). These studies suggest that LPS-CD14 responses do not cause inflammation in surgical trauma/hemorrhagic shock and demonstrate a novel use of combined in silico and in vivo methods to elucidate the complex inflammatory phenotype of genetically modified animals.

Acute-Phase Reaction↗