B Cell Activation Triggered by the Formation of the Small Receptor Cluster: A Computational Study

We proposed a spatially extended model of early events of B cell receptors (BCR) activation, which is based on mutual kinase-receptor interactions that are characteristic for the immune receptors and the Src family kinases. These interactions lead to the positive feedback which, together with two nonlinearities resulting from the double phosphorylation of receptors and Michaelis-Menten dephosphorylation kinetics, are responsible for the system bistability. We demonstrated that B cell can be activated by a formation of a tiny cluster of receptors or displacement of the nucleus. The receptors and Src kinases are activated, first locally, in the locus of the receptor cluster or the region where the cytoplasm is the thinnest. Then the traveling wave of activation propagates until activity spreads over the whole cell membrane. In the models in which we assume that the kinases are free to diffuse in the cytoplasm, we found that the fraction of aggregated receptors, capable to initiate B cell activation decreases with the decreasing thickness of cytoplasm and decreasing kinase diffusion. When kinases are restricted to the cell membrane - which is the case for most of the Src family kinases - even a cluster consisting of a tiny fraction of total receptors becomes activatory. Interestingly, the system remains insensitive to the modest changes of total receptor level. The model provides a plausible mechanism of B cells activation due to the formation of small receptors clusters collocalized by binding of polyvalent antigens or arising during the immune synapse formation

Computation and measurement of cell decision making errors using single cell data

Author summary Cell continuously receives signals from the surrounding environment and is supposed to make correct decisions, i.e., respond properly to various signals and initiate certain cellular functions. Modeling and quantification of decision making processes in a cell have emerged as important areas of research in recent years. Due to signal transduction noise, cells respond differently to similar inputs, which may result in incorrect cell decisions. Here we develop a novel method for characterization of decision making processes in cells, using statistical signal processing and decision theory concepts. To demonstrate the utility of the method, we apply it to an important signaling pathway that regulates molecules which play key roles in cell survival. Our method reveals that cells can make two types of incorrect decisions, namely, false alarm and miss events. We measure the likelihood of these decisions using single cell experimental data, and demonstrate how these incorrect decisions are related to the signal transduction noise or absence of certain molecular functions. Using our method, decision making errors in other molecular systems can be modeled. Such models are useful for understanding and developing treatments for pathological processes such as inflammation, various cancers and autoimmune diseases

Relaxation oscillations and hierarchy of feedbacks in MAPK signaling

We formulated a computational model for a MAPK signaling cascade downstream of the EGF receptor to investigate how interlinked positive and negative feedback loops process EGF signals into ERK pulses of constant amplitude but dose-dependent duration and frequency. A positive feedback loop involving RAS and SOS, which leads to bistability and allows for switch-like responses to inputs, is nested within a negative feedback loop that encompasses RAS and RAF, MEK, and ERK that inhibits SOS via phosphorylation. This negative feedback, operating on a longer time scale, changes switch-like behavior into oscillations having a period of 1 hour or longer. Two auxiliary negative feedback loops, from ERK to MEK and RAF, placed downstream of the positive feedback, shape the temporal ERK activity profile but are dispensable for oscillations. Thus, the positive feedback introduces a hierarchy among negative feedback loops, such that the effect of a negative feedback depends on its position with respect to the positive feedback loop. Furthermore, a combination of the fast positive feedback involving slow-diffusing membrane components with slower negative feedbacks involving faster diffusing cytoplasmic components leads to local excitation/global inhibition dynamics, which allows the MAPK cascade to transmit paracrine EGF signals into spatially non-uniform ERK activity pulses.Peer reviewe

Debundling and Selective Enrichment of SWNTs for Applications in Dye-Sensitized Solar Cells

We present an overview of the recent developments in de-bundling and sorting of Single-Wall Carbon Nanotubes (SWNTs), which are useful for hi-tech applications in dye sensitized solar cells (DSSCs). Applications of SWNTs as transparent and conductive films, catalyst, and scaffold in DSSCs are also reviewed.Peer Reviewe

Journal of Nonlinear Mathematical Physics 2001, V.8, Supplement, 188--194 Proceedings: NEEDS'99 Torsional Travelling Waves in DNA

The simple model of the non-linear DNA dynamics [4] is pursued in order to study the local untwisting of DNA double helix. It is shown how the advancing RNA polymerase may force the motion of the torsional solitary wave along DNA