Modelling the MAPK signalling pathway using a two-stage identification algorithm

Signal transduction pathways describe the dynamics of cellular response to input signalling molecules at receptors on the cell membrane. The Mitogen-Activated Protein Kinase (MAPK) cascade is one of such pathways that are involved in many important cellular processes including cell growth and proliferation. This paper describes a black-box model of this pathway created using an advanced two-stage identification algorithm. Identification allows us to capture the unique features and dynamics of the pathway and also opens up the possibility of regulatory control design. In the approach described, an optimal model is obtained by performing model subset selection in two stages, where the terms are first determined by a forward selection method and then modified using a backward selection model refinement. The simulation results demonstrate that the model selected using the two-stage algorithm performs better than with the forward selection method alone.

'Murder or Mercy?' an innovative module helping UK medical students to articulate their own ethical standpoints regarding end-of-life decisions

Objectives This student selected component (SSC) was designed to equip United Kingdom (UK) medical students to respond ethically and with sensitivity to requests they might receive as qualified doctors in regard to euthanasia and assisted dying. The aim was to expose students to relevant opinions and experiences and to provide opportunities to explore and justify their own views and rehearse ethical decision making in a safe learning environment. Method The module is delivered by specialists from a number of disciplines including law, theology, medicine and nursing, each providing students with a working knowledge allowing them to actively discuss cases, articulate their own views and practise ethical reasoning through group and individual study. Visits to local intensive care units, palliative care wards and hospices are integrated effectively with theory. Student assessment comprises a dissertation, student-led debate and reflective commentary. Module impact was evaluated by analysis of student coursework and a questionnaire. Results Students found the content stimulating and relevant to their future career and agreed that the module was well-structured and that learning outcomes were achieved. They greatly appreciated the clinical context provided by the visits and opportunities to apply ethical reasoning to real cases and to debate ethical issues with peers. Students reported an increased discernment of the ethical and legal position and practical considerations and a greater awareness of the range of professional and lay viewpoints held. Student perceptions were confirmed on analysis of their submitted coursework. Many participants were less strongly in favour of euthanasia and assisted dying on module completion than at the outset but all felt better equipped to justify their own viewpoint and to respond appropriately to patient requests. Conclusions The multi-disciplinary nature of this course is helpful in preparing students to deal effectively and sensitively with ethical dilemmas they will encounter in their medical career. Use of an integrated, learner-centred approach equips students to actively engage with their peers in discussion of such issues and to formulate and defend their own position.

Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA(2) receptor

The Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-AKT pathways are two downstream effectors of the small GTPase Ras. Although both pathways are positively regulated by Ras, the Raf-MAPK and PI3K-AKT pathways have been shown to control opposing functions within the cell, suggesting a need for cross-talk regulation. The PI3K -AKT pathway can inhibit the Raf-MAPK pathway directly during processes such as muscle differentiation. Here we describe the ability of the Raf-MAPK pathway to negatively regulate the PI3K-AKT pathway during cellular arrest. Constitutive activation of Raf or methyl ethyl ketone 1 (MEK1) leads to inhibition of AKT and cellular arrest. Furthermore, we show that activation of Raf-MEK1 signaling causes negative feedback inhibition of Ras through the ephrin receptor EphA(2). EphA(2)-mediated negative feedback inhibition is required for Raf-induced AKT inhibition and cell cycle arrest, therefore establishing the inhibition of the Ras-PI3K-AKT pathway as a necessary event for the Raf-MEK1-regulated cellular arrest.