Zoltán Neufeld

MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia

The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1α (but not HIF-2α) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxiainducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1α mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1α in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1α mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1α stabilization and activity. Based on these data and a mathematical model of HIF-1α suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1α activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1α-dependent transcription.ABSTRACT The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1α (but not HIF-2α) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxia-inducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1α mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1α in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1α mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1α stabilization and activity. Based on these data and a mathematical model of HIF-1α suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1α activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1α-dependent transcription.

Context-dependent interaction leads to emergent search behavior in social aggregates

Locating the source of an advected chemical signal is a common challenge facing many living organisms. When the advecting medium is characterized by either high Reynolds number or high Peclet number, the task becomes highly nontrivial due to the generation of heterogeneous, dynamically changing filamental concentrations that do not decrease monotonically with distance to the source. Defining search strategies that are effective in these environments has important implications for the understanding of animal behavior and for the design of biologically inspired technology. Here we present a strategy that is able to solve this task without the higher intelligence required to assess spatial gradient direction, measure the diffusive properties of the flow field, or perform complex calculations. Instead, our method is based on the collective behavior of autonomous individuals following simple social interaction rules which are modified according to the local conditions they are experiencing. Through these context-dependent interactions, the group is able to locate the source of a chemical signal and in doing so displays an awareness of the environment not present at the individual level. This behavior illustrates an alternative pathway to the evolution of higher cognitive capacity via the emergent, group-level intelligence that can result from local interactions.

Ocean fertilization experiments may initiate a large scale phytoplankton bloom

Oceanic plankton plays an important role in the marine food chain and through its significant contribution to the global carbon cycle can also influence the climate. Plankton bloom is a sudden rapid increase of the population. It occurs naturally in the North Atlantic as a result of seasonal changes. Ocean fertilization experiments have shown that supply of iron, an important trace element, can trigger a phytoplankton bloom in oceanic regions with low natural phytoplankton density. Here we use a simple mathematical model of the combined effects of stirring by ocean eddies and plankton evolution to consider the impact of a transient local perturbation, e.g. in the form of iron enrichment as in recent ‘ocean fertilization’ experiments. The model not only explains aspects of the bloom observed in such experiments but predicts the unexpected outcome of a large scale bloom that in its extent could be comparable to the spring bloom in the North Atlantic.

Chaotic advection of reacting substances: Plankton dynamics on a meandering jet

We study the spatial patterns formed by interacting populations or reacting chemicals under the influence of chaotic flows. In particular, we have considered a three-component model of plankton dynamics advected by a meandering jet. We report general results, stressing the existence of a smooth-filamental transition in the concentration patterns depending on the relative strength of the stirring by the chaotic flow and the relaxation properties of planktonic dynamical system. Patterns obtained in open and closed flows are compared.

Chemical and biological processes in fluid flows: A dynamical systems approach

Introduction to Fluid Flows Mixing in Fluids Ecological and Chemical Models Reaction-Diffusion Models Decay Type Reactions in Flows Autocatalytic Processes in Flows Oscillatory and Complex Behavior in Flows.

Positional information generated by spatially distributed signaling cascades.

The temporal and stationary behavior of protein modification cascades has been extensively studied, yet little is known about the spatial aspects of signal propagation. We have previously shown that the spatial separation of opposing enzymes, such as a kinase and a phosphatase, creates signaling activity gradients. Here we show under what conditions signals stall in the space or robustly propagate through spatially distributed signaling cascades. Robust signal propagation results in activity gradients with long plateaus, which abruptly decay at successive spatial locations. We derive an approximate analytical solution that relates the maximal amplitude and propagation length of each activation profile with the cascade level, protein diffusivity, and the ratio of the opposing enzyme activities. The control of the spatial signal propagation appears to be very different from the control of transient temporal responses for spatially homogenous cascades. For spatially distributed cascades where activating and deactivating enzymes operate far from saturation, the ratio of the opposing enzyme activities is shown to be a key parameter controlling signal propagation. The signaling gradients characteristic for robust signal propagation exemplify a pattern formation mechanism that generates precise spatial guidance for multiple cellular processes and conveys information about the cell size to the nucleus.

Small-scale structure of nonlinearly interacting species advected by chaotic flows

We study the spatial patterns formed by interacting biological populations or reacting chemicals under the influence of chaotic flows. Multiple species and nonlinear interactions are explicitly considered, as well as cases of smooth and nonsmooth forcing sources. The small-scale structure can be obtained in terms of characteristic Lyapunov exponents of the flow and of the chemical dynamics. Different kinds of morphological transitions are identified. Numerical results from a three-component plankton dynamics model support the theory, and they serve also to illustrate the influence of asymmetric couplings. (c) 2002 American Institute of Physics.

Tactile interactions lead to coherent motion and enhanced chemotaxis of migrating cells

When motile cells come into contact with one another their motion is often considerably altered. In a process termed contact inhibition of locomotion (CIL) cells reshape and redirect their movement as a result of cell-cell contact. Here we describe a mathematical model that demonstrates that CIL alone is sufficient to produce coherent, collective cell migration. Our model illustrates a possible mechanism behind collective cell migration that is observed, for example, in neural crest cells during development, and in metastasizing cancer cells. We analyse the effects of varying cell density and shape on the alignment patterns produced and the transition to coherent motion. Finally, we demonstrate that this process may have important functional consequences by enhancing the accuracy and robustness of the chemotactic response, and factors such as cell shape and cell density are more significant determinants of migration accuracy than the individual capacity to detect environmental gradients.

Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line

We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca2+ handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca2+ levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca2+ levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca2+ influx triggered by L-alanine/Na+ co-transport. Our simulations indicate that both high intracellular ATP and Ca2+ concentrations are required in order to develop full insulin secretory responses. The model confirmed that K+ ATP channel independent mechanisms of stimulation of intracellular Ca2+ levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells.

The vortex dynamics analogue of the restricted three-body problem: advection in the field of three identical point vortices

The passive advection of tracers in the field of three identical point vortices is considered as the hydrodynamical analogue of the restricted three-body problem. The chaotic motion is analysed by means of two-dimensional maps, its parameter dependence, Lyapunov exponents and topological entropies. The latter can be obtained as the growth rate of a dye droplets perimeter in time. Similarities and differences of the vortex and gravitational problem are discussed.