Developing optimal input design strategies in cancer systems biology with applications to microfluidic device engineering

<p>Abstract</p> <p>Background</p> <p>Mechanistic models are becoming more and more popular in Systems Biology; identification and control of models underlying biochemical pathways of interest in oncology is a primary goal in this field. Unfortunately the scarce availability of data still limits our understanding of the intrinsic characteristics of complex pathologies like cancer: acquiring information for a system understanding of complex reaction networks is time consuming and expensive. Stimulus response experiments (SRE) have been used to gain a deeper insight into the details of biochemical mechanisms underlying cell life and functioning. Optimisation of the input time-profile, however, still remains a major area of research due to the complexity of the problem and its relevance for the task of information retrieval in systems biology-related experiments.</p> <p>Results</p> <p>We have addressed the problem of quantifying the information associated to an experiment using the Fisher Information Matrix and we have proposed an optimal experimental design strategy based on evolutionary algorithm to cope with the problem of information gathering in Systems Biology. On the basis of the theoretical results obtained in the field of control systems theory, we have studied the dynamical properties of the signals to be used in cell stimulation. The results of this study have been used to develop a microfluidic device for the automation of the process of cell stimulation for system identification.</p> <p>Conclusion</p> <p>We have applied the proposed approach to the Epidermal Growth Factor Receptor pathway and we observed that it minimises the amount of parametric uncertainty associated to the identified model. A statistical framework based on Monte-Carlo estimations of the uncertainty ellipsoid confirmed the superiority of optimally designed experiments over canonical inputs. The proposed approach can be easily extended to multiobjective formulations that can also take advantage of identifiability analysis. Moreover, the availability of fully automated microfluidic platforms explicitly developed for the task of biochemical model identification will hopefully reduce the effects of the 'data rich-data poor' paradox in Systems Biology.</p

Dependence on plasma shape and plasma fueling for small edge-localized mode regimes in TCV and ASDEX Upgrade

\u3cp\u3eWithin the EUROfusion MST1 work package, a series of experiments has been conducted on AUG and TCV devices to disentangle the role of plasma fueling and plasma shape for the onset of small ELM regimes. On both devices, small ELM regimes with high confinement are achieved if and only if two conditions are fulfilled at the same time. Firstly, the plasma density at the separatrix must be large enough (n\u3csub\u3ee,sep\u3c/sub\u3e/n\u3csub\u3eG\u3c/sub\u3e ∼ 0.3), leading to a pressure profile flattening at the separatrix, which stabilizes type-I ELMs. Secondly, the magnetic configuration has to be close to a double null (DN), leading to a reduction of the magnetic shear in the extreme vicinity of the separatrix. As a consequence, its stabilizing effect on ballooning modes is weakened.\u3c/p\u3

Role of fast ion pressure in the isotope effect in JET L-mode plasmas

This paper presents results of JET ITER-like wall L-mode experiments in hydrogen and deuterium (D) plasmas, dedicated to the study of the isotope dependence of ion heat transport by determination of the ion critical gradient and stiffness by varying the ion cyclotron resonance heating power deposition. When no strong role of fast ions in the plasma core is expected, the main difference between the two isotope plasmas is determined by the plasma edge and the core behavior is consistent with a gyro-Bohm scaling. When the heating power (and the fast ion pressure) is increased, in addition to the difference in the edge region, also the plasma core shows substantial changes. The stabilization of ion heat transport by fast ions, clearly visible in D plasmas, appears to be weaker in H plasmas, resulting in a higher ion heat flux in H with apparent anti-gyro-Bohm mass scaling. The difference is found to be caused by the different fast ion pressure between H and D plasmas, related to the heating power settings and to the different fast ion slowing down time, and is completely accounted for in non-linear gyrokinetic simulations. The application of the TGLF quasi-linear model to this set of data is also discussed

A new mechanism for increasing density peaking in tokamaks: improvement of the inward particle pinch with edge E x B shearing

Developing successful tokamak operation scenarios, as well as confident extrapolation of present-day knowledge requires a rigorous understanding of plasma turbulence, which largely determines the quality of the confinement. In particular, accurate particle transport predictions are essential due to the strong dependence of fusion power or bootstrap current on the particle density details. Here, gyrokinetic turbulence simulations are performed with physics inputs taken from a JET power scan, for which a relatively weak degradation of energy confinement and a significant density peaking is obtained with increasing input power. This way physics parameters that lead to such increase in the density peaking shall be elucidated. While well-known candidates, such as the collisionality, previously found in other studies are also recovered in this study, it is furthermore found that edge E x B shearing may adopt a crucial role by enhancing the inward pinch. These results may indicate that a plasma with rotational shear could develop a stronger density peaking as compared to a non-rotating one, because its inward convection is increased compared to the outward diffusive particle flux as long as this rotation has a significant on E x B flow shear stabilization. The possibly significant implications for future devices, which will exhibit much less torque compared to present day experiments, are discussed