Roles of the RAF/MEK/ERK Pathway in Cell Growth, Malignant Transformation and Drug Resistance

Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors. Originally published Biochim Biophys Acta, Vol. 1773, No. 8, August 200

Tyrosine Phosphorylation of Rac1: A Role in Regulation of Cell Spreading

Rac1 influences a multiplicity of vital cellular- and tissue-level control functions, making it an important candidate for targeted therapeutics. The activity of the Rho family member Cdc42 has been shown to be modulated by tyrosine phosphorylation at position 64. We therefore investigated consequences of the point mutations Y64F and Y64D in Rac1. Both mutations altered cell spreading from baseline in the settings of wild type, constitutively active, or dominant negative Rac1 expression, and were accompanied by differences in Rac1 targeting to focal adhesions. Rac1-Y64F displayed increased GTP-binding, increased association with βPIX, and reduced binding with RhoGDI as compared with wild type Rac1. Rac1-Y64D had less binding to PAK than Rac1-WT or Rac1-64F. In vitro assays demonstrated that Y64 in Rac1 is a target for FAK and Src. Taken together, these data suggest a mechanism for the regulation of Rac1 activity by non-receptor tyrosine kinases, with consequences for membrane extension

Diagnosis and Prognosis of Scrubber Faults for Underwater Rebreathers based on Stochastic Event Models

©2011 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other users, including reprinting/ republishing this material for advertising or promotional purposes, creating new collective works for resale or redistribution to servers or lists, or reuse of any copyrighted components of this work in other works.Presented at the IEEE International Conference on Prognostics and Health Management (PHM 2011), 20-23 June 2011, Denver, CO.DOI: 10.1109/ICPHM.2011.6024353Imperfect CO₂ removal mechanisms of CO₂ scrubbers often lead to the existence of CO₂ in gas inhaled by a diver from underwater rebreathers. This may cause CO₂ related rebreather faults and subsequently would increase the risk of human injuries. We introduce a stochastic model for three CO₂ related rebreather faults: CO₂ bypass, scrubber exhaustion, and scrubber breakthrough. We establish the concept of CO₂ channeling that describes the cause of the faults and present a CO₂ channeling model based on a stochastic process driven by a Poisson counter. This helps us to investigate how CO₂ flow inside the rebreather is affected by CO₂ related faults. Fault diagnosis/prognosis algorithms are developed based on the stochastic model and are tested in simulation

Cooling‐induced cutaneous vasodilatation is mediated by small‐conductance, calcium‐activated potassium channels in tail arteries from male mice

Abstract Cooling causes cutaneous dilatation to restrain cold‐induced constriction and prevent tissue injury. Cooling increases communication through myoendothelial gap junctions (MEGJs), thereby increasing endothelium‐derived hyperpolarization (EDH)‐type dilatation. EDH is initiated by calcium‐activated potassium channels (KCa) activated by endothelial stimuli or muscle‐derived mediators traversing MEGJs (myoendothelial feedback). The goal of this study was to determine the individual roles of KCa with small (SK3) and intermediate (IK1) conductance in cooling‐induced dilatation. Vasomotor responses of mice isolated cutaneous tail arteries were analyzed by pressure myography at 37°C and 28°C. Cooling increased acetylcholine‐induced EDH‐type dilatation during inhibition of NO and prostacyclin production. IK1 inhibition did not affect dilatations to acetylcholine, whereas SK3 inhibition inhibited dilatation at both temperatures. Cooling uncovered myoendothelial feedback to inhibit constrictions in U46619. IK1 inhibition did not affect U46619 constrictions, whereas SK3 inhibition abolished the inhibitory effect of cooling without affecting U46619 constriction at 37°C. Immunoblots confirmed SK3 expression, which was localized (immunofluorescence) to holes in the internal elastic lamina consistent with myoendothelial projections. Immunoblots and Immunofluorescence did not detect IK1. Studies in non‐cutaneous arteries have highlighted the predominant role of IK1 in EDH‐type dilatation. Cutaneous arteries are distinctly reliant on SK3, which may enable EDH‐type dilation to be amplified by cooling

A Bio-inspired Plume Tracking Algorithm for Mobile Sensing Swarms in Turbulent Flow

©2013 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other users, including reprinting/ republishing this material for advertising or promotional purposes, creating new collective works for resale or redistribution to servers or lists, or reuse of any copyrighted components of this work in other works.Presented at the 2013 IEEE International Conference on Robotics and Automation (ICRA), 6-10 May 2013, Karlsruhe, Germany.DOI: 10.1109/ICRA.2013.6630683We develop a plume tracking algorithm for a swarm of mobile sensing agents in turbulent flow. Inspired by blue crabs, we propose a stochastic model for plume spikes based on the Poisson counting process, which captures the turbulent characteristic of plumes. We then propose an approach to estimate the parameters of the spike model, and transform the turbulent plume field detected by sensing agents into a smoother scalar field that shares the same source with the plume field. This transformation allows us to design path planning algorithms for mobile sensing agents in the smoother field instead of in the turbulent plume field. Inspired by the source seeking behaviors of fish schools, we design a velocity controller for each mobile agent by decomposing the velocities into two perpendicular parts: the forward velocity incorporates feedback from the estimated spike parameters, and the side velocity keeps the swarm together. The combined velocity is then used to plan the path for each agent in the swarm. Theoretical justifications are provided for convergence of the agent group to the plume source. The algorithms are also demonstrated through simulations

Mass Rapid Transit System Passenger Traffic Forecast Using a Re-Sample Recurrent Neural Network

In this study, we developed a model re-sample Recurrent Neural Network (RRNN) to forecast passenger traffic on Mass Rapid Transit Systems (MRT). The Recurrent Neural Network was applied to build a model to perform passenger traffic prediction, where the forecast task was transformed into a classification task. However, in this process, the training dataset usually ended up being imbalanced. To address this dataset imbalance, our research proposes re-sample Recurrent Neural Network. A case study of the California Mass Rapid Transit System revealed that the model introduced in this work could timely and effectively predict passenger traffic of MRT. The measurements of passenger traffic themselves were also studied and showed that the new method provided a good understanding of the level of passenger traffic and was able to achieve prediction accuracy upwards of 90% higher than standard tests. The development of this model adds value to the methodology of traffic applications by employing these Recurrent Neural Networks