An integrated strategy for prediction uncertainty analysis

Motivation: To further our understanding of the mechanisms underlying biochemical pathways mathematical modelling is used. Since many parameter values are unknown they need to be estimated using experimental observations. The complexity of models necessary to describe biological pathways in combination with the limited amount of quantitative data results in large parameter uncertainty which propagates into model predictions. Therefore prediction uncertainty analysis is an important topic that needs to be addressed in Systems Biology modelling

A Bayesian approach to targeted experiment design

Motivation: Systems biology employs mathematical modelling to further our understanding of biochemical pathways. Since the amount of experimental data on which the models are parameterized is often limited, these models exhibit large uncertainty in both parameters and predictions. Statistical methods can be used to select experiments that will reduce such uncertainty in an optimal manner. However, existing methods for optimal experiment design (OED) rely on assumptions that are inappropriate when data are scarce considering model complexity

A rule-based model of insulin signalling pathway

\u3cp\u3eBackground: The insulin signalling pathway (ISP) is an important biochemical pathway, which regulates some fundamental biological functions such as glucose and lipid metabolism, protein synthesis, cell proliferation, cell differentiation and apoptosis. In the last years, different mathematical models based on ordinary differential equations have been proposed in the literature to describe specific features of the ISP, thus providing a description of the behaviour of the system and its emerging properties. However, protein-protein interactions potentially generate a multiplicity of distinct chemical species, an issue referred to as combinatorial complexity , which results in defining a high number of state variables equal to the number of possible protein modifications. This often leads to complex, error prone and difficult to handle model definitions. Results: In this work, we present a comprehensive model of the ISP, which integrates three models previously available in the literature by using the rule-based modelling (RBM) approach. RBM allows for a simple description of a number of signalling pathway characteristics, such as the phosphorylation of signalling proteins at multiple sites with different effects, the simultaneous interaction of many molecules of the signalling pathways with several binding partners, and the information about subcellular localization where reactions take place. Thanks to its modularity, it also allows an easy integration of different pathways. After RBM specification, we simulated the dynamic behaviour of the ISP model and validated it using experimental data. We the examined the predicted profiles of all the active species and clustered them in four clusters according to their dynamic behaviour. Finally, we used parametric sensitivity analysis to show the role of negative feedback loops in controlling the robustness of the system. Conclusions: The presented ISP model is a powerful tool for data simulation and can be used in combination with experimental approaches to guide the experimental design. The model is available at http://sysbiobig.dei.unipd.it/was submitted to Biomodels Database ( https://www.ebi.ac.uk/biomodels-main/ # MODEL 1604100005).\u3c/p\u3

Modelling the molecular mechanisms of ageing

This document is the Accepted Manuscript version of a published work that appeared in final form in Bioscience reports. To access the final edited and published work see http://www.bioscirep.org/content/37/1/BSR20160177.The ageing process is driven at the cellular level by random molecular damage which slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the ageing process. The complexity of the ageing process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards, and discusses many specific examples of models which have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field

Unruhe und Ungewissheit – Stem Cells and Risks

“Die Unruhe und Ungewissheit sind unser Theil”, writes Goethe in a letter to the German novelist Sophie von la Roche in 1774. But is it the incalculable and indeterminate that cause disquiet, or is it our bustling pursuit of knowledge that makes us uncertain? Contemporary psychologists have taught us a great deal about the way we perceive risks and about the way affects and emotions influence our behaviour. Their research has shown that, as decision makers, as risk-assessors, and as risk-controllers, we are short-sighted, one-eyed and prone to serious errors of refraction. Who would have guessed that? We generate too few, and too narrow, hypotheses. We gather information, or evidence, in favour of our guesses that is too narrow, readily available, and skewed in favour of preferred beliefs. Once we have a pet hypothesis, we look for confirmatory evidence, neglecting countervailing evidence. We are simply not rational—not in the way our theories of rationality (logic, probability and decision-making) assume, at any rate. This is an alarming fact, considering the serious risk assessment and risk management tasks that lie ahead of us. This fact of irrationality (the phrase “fact of irrationality” seems fair, since the claim is supported by a vast amount of empirical evidence) should not just bring about unrest; it should make us think—think at least twice about our state of knowledge, in particular when the task is to make a serious risk-assessment in a convoluted situation [1]. We must not go gentle into that uncertainty. In this paper we will focus on a particular type of risk: the risk of unknown and uncertain long-term effects. The problem here is one of not knowing what will happen, and when we know it will, when; and of not being acquainted with the consequences, and therefore being unable to value the unfamiliar. Doing this our centre of attention will be human embryonic stem cells and induced pluripotent stem cells. Adult stem cells are not as interesting – they do not bear the same type of risks and moral difficulties. The paper urges risk analysts to take a Socratic approach to their discipline

Goodness, Values, Reasons

Contemporary value theory has been characterized by a renewed interest in the analysis of concepts like "good" or "valuable", the most prominent pattern of analysis in recent years being the socalled buck-passing or fitting-attitude analysis which reduces goodness to a matter of having properties that provide reasons for pro-attitudes. Here I argue that such analyses are best understood as metaphysical rather than linguistic and that while the buck-passing analysis has some virtues, it still fails to provide a suitably wide-ranging pattern of analysis for conceptualizing evaluative properties. Instead, a better alternative can be found in a metaphysical version of the Geachean view that goodness is always attributive and never predicative, namely that goodness is always a matter of relative placement in certain kinds of comparison classes. It is then suggested that the good and the valuable need to be separated from each other and that the latter is a species of the former

On for Someone’s Sake Attitudes

In “Analysing Personal Value” (Jour of Ethics, Volume 11, Number 4, 2007) I explored the possibility of expanding standard value taxonomies with a new kind of values, so called personal values, i.e., values that we ascribe to things with an eye to some particular person. By fine-tuning a classic fitting-attitude analysis, it was argued that the following pattern might work, (FAP) An object O’s positive value for a person x (i.e., x’s personal value), consists in the existence of normative reasons for favouring O for x’s sake One drawback with FAP has to do with the fact that there is no well-known or swift and easy way to characterize the type of “favouring O for x’s sake”- attitude referred to in FAP (so called PS-attitudes). This work attempts to remedy this deficiency. In doing so, it sets out from the idea that we should not confuse what causes us to have an attitude with that which is the intentional object of the attitude. This paper then probes to what extent it is possible to situate the defining characteristic of PS- attitudes in their intentional content. What considerably complicates this approach is the idea that attitudes are in general discerning, i.e., they are directed to objects on account of some particular property or properties of the objects to which they are directed. By considering two quite different discerning attitudes, love and admiration, it is argued that properties that figure in the intentional content of love do so (at least in typical cases) differently from the role they play in admiration. Introducing the distinction between justifiers and identifiers, which corresponds to the two roles which properties may play in the intentional content of an attitude, it is argued that when it comes to admiration properties play the role of justifiers rather than identifiers, but that in the case of love, properties are identifiers. It is next argued that the PS attitudes bear more resemblance to those attitudes that display identifiers rather than justifiers in their content

Quelles évolutions du Lean après son implantation en entreprise ? Une analyse longitudinale dans 2 entreprises françaises multinationales

International audienceLean production implementation may lead to intensive work systems and work- ers health issues. Since Lean work situations evolve over time, what factors are likely to turn them later towards more sustainable work systems? This paper is a preliminary attempt to address Lean change from a longitudinal perspective. It combines ergonomics methods with processual analyses of change in order to understand: (a) the overall trajectory of the Lean change over a period of a few years; and (b) its impact on work activity and worker health. Elements are drawn from prior ergonomics case studies and supplemented a few years later. It enables a comparison of 2 Lean trajectories, respectively at a Vehicle Equipment Manu- facturer (VEM) and at an Aeronautical Manufacturer (AM). Data analysis reveals : (1) first a rigid Lean change, decided by multinational group and driven by ex- ternal experts, then (2) 12 to 18 months later, a redirection (characterized by dif- ferent characters at VEM and AM), and (3) a Lean approach managed and adapted by the enterprise, more flexible (both toward method and objectives). These two illustrative case studies call for replications in different settings, in order to better understand the processes implemented during organizational in- novations, to identify the ways to develop workers, collectives and organizations and consolidate ergonomics diachronical method of analysis