Lincoln, Yvonna, and Egon Guba, "Postpositivism and the Naturalist Paradigm," pp. 14-46 in Yvonna Lincoln and Egon Guba, Naturalistic Inquiry . Beverly Hills, CA: Sage, 1985.*

Our growing dependence on increasingly complex computer and software systems necessitates the development of formalisms, techniques, and tools for assessing functional properties of these systems. One such technique that has emerged in the last twenty years is model checking, which systematically (and automatically) checks whether a model of a given system satisfies a desired property such as deadlock freedom, invariants, and request-response properties. This automated technique for verification and debugging has developed into a mature and widely used approach with many applications. Principles of Model Checking offers a comprehensive introduction to model checking that is not only a text suitable for classroom use but also a valuable reference for researchers and practitioners in the field. The book begins with the basic principles for modeling concurrent and communicating systems, introduces different classes of properties (including safety and liveness), presents the notion of fairness, and provides automata-based algorithms for these properties. It introduces the temporal logics LTL and CTL, compares them, and covers algorithms for verifying these logics, discussing real-time systems as well as systems subject to random phenomena. Separate chapters treat such efficiency-improving techniques as abstraction and symbolic manipulation. The book includes an extensive set of examples (most of which run through several chapters) and a complete set of basic results accompanied by detailed proofs. Each chapter concludes with a summary, bibliographic notes, and an extensive list of exercises of both practical and theoretical nature.

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Principles of Model Checking

N G van Kampen 1981 Amsterdam: North-Holland xiv + 419 pp price Dfl 180 This is a book which, at a lower price, could be expected to become an essential part of the library of every physical scientist concerned with problems involving fluctuations and stochastic processes, as well as those who just enjoy a beautifully written book. It provides an extensive graduate-level introduction which is clear, cautious, interesting and readable.

https://iopscience.iop.org/article/10.1088/0031-9112/34/4/040/pdf

Stochastic Processes in Physics and Chemistry

The talk with present the key results of the IPCC Working Group III 5th assessment report. Concluding four years of intense scientific collaboration by hundreds of authors from around the world, the report responds to the request of the world's governments for a comprehensive, objective and policy neutral assessment of the current scientific knowledge on mitigating climate change. The report has been extensively reviewed by experts and governments to ensure quality and comprehensiveness.

Climate change 2014 - Mitigation of climate change

DNA methylation is among the best studied epigenetic modifications and is essential to mammalian development. Although the methylation status of most CpG dinucleotides in the genome is stably propagated through mitosis, improvements to methods for measuring methylation have identified numerous regions in which it is dynamically regulated. In this Review, we discuss key concepts in the function of DNA methylation in mammals, stemming from more than two decades of research, including many recent studies that have elucidated when and where DNA methylation has a regulatory role in the genome. We include insights from early development, embryonic stem cells and adult lineages, particularly haematopoiesis, to highlight the general features of this modification as it participates in both global and localized epigenetic regulation.

DNA methylation: roles in mammalian development

The enzymatic control of the setting and maintenance of symmetric and non-symmetric DNA methylation patterns in a particular genome context is not well understood. Here, we describe a comprehensive analysis of DNA methylation patterns generated by high resolution sequencing of hairpin-bisulfite amplicons of selected single copy genes and repetitive elements (LINE1, B1, IAP-LTR-retrotransposons, and major satellites). The analysis unambiguously identifies a substantial amount of regional incomplete methylation maintenance, i.e. hemimethylated CpG positions, with variant degrees among cell types. Moreover, non-CpG cytosine methylation is confined to ESCs and exclusively catalysed by Dnmt3a and Dnmt3b. This sequence position-, cell type-, and region-dependent non-CpG methylation is strongly linked to neighboring CpG methylation and requires the presence of Dnmt3L. The generation of a comprehensive data set of 146,000 CpG dyads was used to apply and develop parameter estimated hidden Markov models (HMM) to calculate the relative contribution of DNA methyltransferases (Dnmts) for de novo and maintenance DNA methylation. The comparative modelling included wild-type ESCs and mutant ESCs deficient for Dnmt1, Dnmt3a, Dnmt3b, or Dnmt3a/3b, respectively. The HMM analysis identifies a considerable de novo methylation activity for Dnmt1 at certain repetitive elements and single copy sequences. Dnmt3a and Dnmt3b contribute de novo function. However, both enzymes are also essential to maintain symmetrical CpG methylation at distinct repetitive and single copy sequences in ESCs.

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In vivo Control of CpG and Non-CpG DNA Methylation by DNA Methyltransferases

This paper presents various semantics in the branching-time spectrum of discrete-time and continuous-time Markov chains (DTMCs and CTMCs). Strong and weak bisimulation equivalence and simulation preorders are covered and are logically characterized in terms of the temporal logics Probabilistic Computation Tree Logic (PCTL) and Continuous Stochastic Logic (CSL). Apart from presenting various existing branching-time relations in a uniform manner, this paper presents the following new results: (i) strong simulation for CTMCs, (ii) weak simulation for CTMCs and DTMCs, (iii) logical characterizations thereof (including weak bisimulation for DTMCs), (iv) a relation between weak bisimulation and weak simulation equivalence, and (v) various connections between equivalences and pre-orders in the continuous-and discrete-time setting. The results are summarized in a branching-time spectrum for DTMCs and CTMCs elucidating their semantics as well as their relationship.

/pdf/comparative-branching-time-semantics-for-markov-chains-1c8ch7arnr.pdf

Comparative branching-time semantics for Markov chains

The time-evolution of continuous-time discrete-state biochemical processes is governed by the Chemical Master Equation (CME), which describes the probability of the molecular counts of each chemical species. As the corresponding number of discrete states is, for most processes, large, a direct numerical simulation of the CME is in general infeasible. In this paper we introduce the method of conditional moments (MCM), a novel approximation method for the solution of the CME. The MCM employs a discrete stochastic description for low-copy number species and a moment-based description for medium/high-copy number species. The moments of the medium/high-copy number species are conditioned on the state of the low abundance species, which allows us to capture complex correlation structures arising, e.g., for multi-attractor and oscillatory systems. We prove that the MCM provides a generalization of previous approximations of the CME based on hybrid modeling and moment-based methods. Furthermore, it improves upon these existing methods, as we illustrate using a model for the dynamics of stochastic single-gene expression. This application example shows that due to the more general structure, the MCM allows for the approximation of multi-modal distributions.

Method of conditional moments (MCM) for the Chemical Master Equation

This paper proposes a novel abstraction technique for continuous-time Markov chains (CTMCs). Our technique fits within the realm of three-valued abstraction methods that have been used successfully for traditional model checking. The key idea is to apply abstraction on uniform CTMCs that are readily obtained from general CTMCs, and to abstract transition probabilities by intervals. It is shown that this provides a conservative abstraction for both true and false for a three-valued semantics of the branching-time logic CSL (Continuous Stochastic Logic). Experiments on an infinite-state CTMC indicate the feasibility of our abstraction technique.

/pdf/three-valued-abstraction-for-continuous-time-markov-chains-hv6ikdt2go.pdf

Three-valued abstraction for continuous-time Markov chains

We present an on-the-fly abstraction technique for infinite-state continuous -time Markov chains. We consider Markov chains that are specified by a finite set of transition classes. Such models naturally represent biochemical reactions and therefore play an important role in the stochastic modeling of biological systems. We approximate the transient probability distributions at various time instances by solving a sequence of dynamically constructed abstract models, each depending on the previous one. Each abstract model is a finite Markov chain that represents the behavior of the original, infinite chain during a specific time interval. Our approach provides complete information about probability distributions, not just about individual parameters like the mean. The error of each abstraction can be computed, and the precision of the abstraction refined when desired. We implemented the algorithm and demonstrate its usefulness and efficiency on several case studies from systems biology.

/pdf/sliding-window-abstraction-for-infinite-markov-chains-3ds74v92jp.pdf

Verena Wolf

Papers

In vivo Control of CpG and Non-CpG DNA Methylation by DNA Methyltransferases

Comparative branching-time semantics for Markov chains

Method of conditional moments (MCM) for the Chemical Master Equation

Three-valued abstraction for continuous-time Markov chains

Sliding Window Abstraction for Infinite Markov Chains