Modular Verification of Biological Systems

Systems of interest in systems biology (such as metabolic pathways, signalling pathways and gene regulatory networks) often consist of a huge number of components interacting in different ways, thus exhibiting very complex behaviours. In biology, such behaviours are usually explored by means of simulation techniques applied to models defined on the basis of system observation and of hypotheses on its functioning. Model checking has also been recently applied to the analysis of biological systems. This analysis technique typically relies on a state space representation whose size, unfortunately, makes the analysis often intractable for realistic models. A method for trying to avoid the state space explosion problem is to consider a decomposition of the system, and to apply a modular verification technique. In particular, properties to be verified often concern only a small portion of the modelled system rather than the system as a whole. Hence, for each property it would be useful to be able to isolate a minimal fragment of the model that is necessary to verify such a property. In this thesis we introduce a modular verification technique in which the system of interest is described by means of an automata-based formalism, called sync-programs, that supports modular construction. Our modular verification technique is based on results of Grumberg et al.~and on their application to the theory of concurrent systems proposed by Attie and Emerson. In particular, we adapt Attie and Emerson's approach to deal with biological systems by allowing automata to synchronise by performing transitions simultaneously. Modular verification allows qualitative aspects of systems to be analysed with the guarantee that properties proved to hold in a suitable model fragment also hold in the whole model. The correctness of the verification technique is proved. The class of properties preserved is ACTL$^{-}$, the universal fragment of temporal logic CTL. The preservation holds only for positive answers and negative answers are not necessarily preserved. In order to verify properties we use the NuSMV model checker, which is a well-established and efficient instrument. We provide a formal translation of sync-programs to simpler automata, which can be given as input to NuSMV. We prove the correspondence of the verification problems. We show the application of our verification technique in some biological case studies. We compare the time required to verify the property on the whole model with the time needed to verify the same property by only considering those modules which are involved in the behaviour of the system related to the property. In order to handle modelling and verification of more realistic biological scenarios, we propose also a dynamic version of our formalism. It allows entities to be created dynamically, in particular by other already running entities, as it often happens in biological systems. Moreover, multiple copies of the same entities can be present at the same time in a system. We show a correspondence of our model with Petri Nets. This has a consequence that tools developed for Petri Nets could be used also for dynamic sync-programs. Modular verification allows properties expressed as DACTL- formulae (dynamic version of ACTL-) to be verified on a portion of the model. The results of analysis of the case study of the MAP kinase cascade activated by surface and internalised EGF receptors, which consists of 143 species and 80 reactions, suggest applicability and scalability of the approach. The results raise the prospect of rendering tractable problems that are currently intractable in the verification of biological systems. In addition, we expect that the techniques developed in the thesis could be applied with profit not only to models of biological systems, but more generally to models of concurrent systems

Integrating the Agricultural Sector into the New EU Climate Policy Framework for 2030: A Scenario Analysis to Highlight Potential Impacts and Challenges

According to the European Council's recent agreement on domestic climate and energy goals, greenhouse gas emissions from sectors outside the EU's Emission Trading Scheme have to be cut by 30% below 2005 levels by 2030. So far no decision has been taken on agriculture's specific involvement in mitigation obligations or on how mitigation targets would be distributed between Member States. Based on hypothetical assumptions, we employ the CAPRI model to illustrate and highlight some potential impacts and challenges related to an integration of the agricultural sector into the new EU climate policy framework. Results of the hypothetical mitigation policy scenario show important impacts on EU agriculture, in particular the livestock sector, if the distribution key of the current Effort Sharing Decision would be rigidly applied as in our assumptions. The results highlight the importance of a targeted but flexible implementation of mitigation policy instruments in the EU and its Member States, as well as the need for a wider consideration and adoption of technological mitigation options

An economic assessment of GHG mitigation policy options for EU agriculture

The report presents an overview of the historical and projected development of agricultural GHG emissions in the EU. The major objective of the report is to present the improvements made in the CAPRI modelling system with respect to GHG emission accounting and especially regarding the implementation of endogenous technological mitigation options. Furthermore, the CAPRI model was applied to provide a quantitative assessment of illustrative GHG mitigation policy options in the agricultural sector, and their production and economic implications.JRC.J.4-Agriculture and Life Sciences in the Econom

Antibiotic research and development: business as usual?

This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner

The 42nd Symposium Chromatographic Methods of Investigating Organic Compounds : Book of abstracts

The 42nd Symposium Chromatographic Methods of Investigating Organic Compounds : Book of abstracts. June 4-7, 2019, Szczyrk, Polan

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort

A Quantitative Approach for Inexact Enforcement of Security Policies

A run-time enforcement mechanism is a program in charge of ensuring that all the traces of a system satisfy a given security policy. Following Schneider\u27s seminal work, there have been several approaches defining what kind of policies can be automatically enforced, and in particular, non-safety properties cannot be correctly and transparently enforced. In this paper, we first propose to build an enforcement mechanism using an abstract notion of selector. We then propose to quantify the inexact enforcement of a non-safety property by an enforcement mechanism, by considering both the traces leading to a non-secure output by this mechanism and the secure traces not output, thus formalizing an intuitive notion of security/usability tradeoff. Finally, we refine this notion when probabilistic and quantitative information is known about the traces. We illustrate all the different concepts with a running example, representing an abstract policy dealing with emergency situations

Quality scores do not predict discrepant statistical significances among meta-analyses on different targets of glycemic control in type 2 diabetes

Objectives: To examine differences in conclusions, statistical significances, and quality of systematic reviews on preventive effects of different targets of blood glucose lowering on macrovascular events in patients with type 2 diabetes. Study Design and Setting: We searched MEDLINE, the Cochrane Database of Systematic Reviews, and Embase until October 15, 2011. Systematic reviews using meta-analyses to compare macrovascular events in patients with type 2 diabetes randomized to different therapeutic targets of blood glucose were eligible for inclusion in this study. Effect measures were extracted and quality was assessed by Overview Quality Assessment Questionnaire, Assessment of Multiple Systematic Reviews, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses. An additional checklist was used to control for completeness and suitability of included trials, correctness of data extraction, and choice of outcome parameters. Results: The 16 included systematic reviews were partially discrepant in statistical significances of reported outcome parameters. Twelve systematic reviews did not include available relevant trials and included eight systematic reviews that should not have been included according to the systematic review's aim and search strategies. Quality differed considerably among systematic reviews. Conclusion: Physicians, researchers, and policy makers should bear in mind that common quality assessment instruments are necessary but not sufficient to guarantee reliable results and conclusions obtained from meta-analyses. (C) 2013 Elsevier Inc. All rights reserved

Modular Verification of Qualitative Pathway Models with Fairness

Modular verification is a technique used to face the state explosion problem often encountered in the verification of properties of complex systems such as concurrent interactive systems. The modular approach is based on the observation that properties of interest often concern a rather small portion of the system. As a consequence, reduced models can be constructed which approximate the overall system behaviour thus allowing more efficient verification. Biochemical pathways can be seen as complex concurrent interactive systems. Consequently, verification of their properties is often computationally very expensive and could take advantage of the modular approach. In this paper we develop a modular verification framework for biochemical pathways. We view biochemical pathways as concurrent systems of reactions competing for molecular resources. A modular verification technique could be based on reduced models containing only reactions involving molecular resources of interest. For a proper description of the system behaviour we argue that it is essential to consider a suitable notion of fairness, which is a well-established notion in concurrency theory but novel in the field of pathway modelling. The fairness notion we consider forbids starvation of reactions, namely it ensures that a reaction that is enabled infinitely often cannot always occur to the detriment of another infinitely often enabled reaction causing the latter to never occur. We prove the correctness of the approach and demonstrate it on the model of the EGF receptor-induced MAP kinase cascade by Schoeberl et al