The modal logic of forcing

What are the most general principles in set theory relating forceability and truth? As with Solovay's celebrated analysis of provability, both this question and its answer are naturally formulated with modal logic. We aim to do for forceability what Solovay did for provability. A set theoretical assertion psi is forceable or possible, if psi holds in some forcing extension, and necessary, if psi holds in all forcing extensions. In this forcing interpretation of modal logic, we establish that if ZFC is consistent, then the ZFC-provable principles of forcing are exactly those in the modal theory known as S4.2.Comment: 31 page

Learning, conditionals, causation

This dissertation is on conditionals and causation. In particular, we (i) propose a method of how an agent learns conditional information, and (ii) analyse causation in terms of a new type of conditional. Our starting point is Ramsey's (1929/1990) test: accept a conditional when you can infer its consequent upon supposing its antecedent. Inspired by this test, Stalnaker (1968) developed a semantics of conditionals. In Ch. 2, we define and apply our new method of learning conditional information. It says, roughly, that you learn conditional information by updating on the corresponding Stalnaker conditional. By generalising Lewis's (1976) updating rule to Jeffrey imaging, our learning method becomes applicable to both certain and uncertain conditional information. The method generates the correct predictions for all of Douven's (2012) benchmark examples and Van Fraassen's (1981) Judy Benjamin Problem. In Ch. 3, we prefix Ramsey's test by suspending judgment on antecedent and consequent. Unlike the Ramsey Test semantics by Stalnaker (1968) and Gärdenfors (1978), our strengthened semantics requires the antecedent to be inferentially relevant for the consequent. We exploit this asymmetric relation of relevance in a semantic analysis of the natural language conjunction 'because'. In Ch. 4, we devise an analysis of actual causation in terms of production, where production is understood along the lines of our strengthened Ramsey Test. Our analysis solves the problems of overdetermination, conjunctive scenarios, early and late preemption, switches, double prevention, and spurious causation -- a set of problems that still challenges counterfactual accounts of actual causation in the tradition of Lewis (1973c). In Ch. 5, we translate our analysis of actual causation into Halpern and Pearl's (2005) framework of causal models. As a result, our analysis is considerably simplified on the cost of losing its reductiveness. The upshot is twofold: (i) Jeffrey imaging on Stalnaker conditionals emerges as an alternative to Bayesian accounts of learning conditional information; (ii) the analyses of causation in terms of our strengthened Ramsey Test conditional prove to be worthy rivals to contemporary counterfactual accounts of causation

Measuring group switching in the European Parliament: Methodology, data and trends (1979-2009)

Party group switching in the European Parliament (ep), where parliamentarians individually or collectively switch from one party group to the other, is a well-known contributor to the volatility of the ep party system. We present a new dataset that contains party group information on all meps from 1979 to 2009. As a first step to a more comprehensive analysis of the phenomenon of party group switching in the ep we describe characteristics of all switches that have occurred in these six legislatures, with a focus on the trends across time, variety between member states, party groups, and ideological party families

Development of novel orthogonal genetic circuits, based on extracytoplasmic function (ECF) σ factors

The synthetic biology field aims to apply the engineering 'design-build-test-learn' cycle for the implementation of synthetic genetic circuits modifying the behavior of biological systems. In order to reach this goal, synthetic biology projects use a set of fully characterized biological parts that subsequently are assembled into complex synthetic circuits following a rational, model-driven design. However, even though the bottom-up design approach represents an optimal starting point to assay the behavior of the synthetic circuits under defined conditions, the rational design of such circuits is often restricted by the limited number of available DNA building blocks. These usually consist only of a handful of transcriptional regulators that additionally are often borrowed from natural biological systems. This, in turn, can lead to cross-reactions between the synthetic circuit and the host cell and eventually to loss of the original circuit function. Thus, one of the challenges in synthetic biology is to design synthetic circuits that perform the designated functions with minor cross-reactions (orthogonality). To overcome the restrictions of the widely used transcriptional regulators, this project aims to apply extracytoplasmic function (ECF) σ factors in the design novel orthogonal synthetic circuits. ECFs are the smallest and simplest alternative σ factors that recognize highly specific promoters. ECFs represent one of the most important mechanisms of signal transduction in bacteria, indeed, their activity is often controlled by anti-σ factors. Even though it was shown that the overexpression of heterologous anti-σ factors can generate an adverse effect on cell growth, they represent an attractive solution to control ECF activity. Finally, to date, we know thousands of ECF σ factors, widespread among different bacterial phyla, that are identifiable together with the cognate promoters and anti-σ factors, using bioinformatic approaches. All the above-mentioned features make ECF σ factors optimal candidates as core orthogonal regulators for the design of novel synthetic circuits. In this project, in order to establish ECF σ factors as standard building blocks in the synthetic biology field, we first established a high throughput experimental setup. This relies on microplate reader experiments performed using a highly sensitive luminescent reporter system. Luminescent reporters have a superior signal-to-noise ratio when compared to fluorescent reporters since they do not suffer from the high auto-fluorescence background of the bacterial cell. However, they also have a drawback represented by the constant light emission that can generate undesired cross-talk between neighboring wells on a microplate. To overcome this limitation, we developed a computational algorithm that corrects for luminescence bleed-through and estimates the “true” luminescence activity for each well of a microplate. We show that the correcting algorithm preserves low-level signals close to the background and that it is universally applicable to different experimental conditions. In order to simplify the assembly of large ECF-based synthetic circuits, we designed an ECF toolbox in E. coli. The toolbox allows for the combinatorial assembly of circuits into expression vectors, using a library of reusable genetic parts. Moreover, it also offers the possibility of integrating the newly generated synthetic circuits into four different phage attachment (att) sites present in the genome of E. coli. This allows for a flawless transition between plasmid-encoded and chromosomally integrated genetic circuits, expanding the possible genetic configurations of a given synthetic construct. Moreover, our results demonstrate that the four att sites are orthogonal in terms of the gene expression levels of the synthetic circuits. With the purpose of rationally design ECF-based synthetic circuits and taking advantage of the ECF toolbox, we characterized the dynamic behavior of a set of 15 ECF σ factors, their cognate promoters, and relative anti-σs. Overall, we found that ECFs are non-toxic and functional and that they display different binding affinities for the cognate target promoters. Moreover, our results show that it is possible to optimize the output dynamic range of the ECF-based switches by changing the copy number of the ECFs and target promoters, thus, tuning the input/output signal ratio. Next, by combining up to three ECF-switches, we generated a set of “genetic-timer circuits”, the first synthetic circuits harboring more than one ECF. ECF-based timer circuits sequentially activate a series of target genes with increasing time delays, moreover, the behavior of the circuits can be predicted by a set of mathematical models. In order to improve the dynamic response of the ECF-based constructs, we introduced anti-σ factors in our synthetic circuits. By doing so we first confirmed that anti-σ factors can exert an adverse effect on the growth of E. coli, thus we explored possible solutions. Our results demonstrate that anti-σ factors toxicity can be partially alleviated by generating truncated, soluble variants of the anti-σ factors and, eventually, completely abolished via chromosomal integration of the anti-σ factor-based circuits. Finally, after demonstrating that anti-σ factors can be used to generate a tunable time delay among ECF expression and target promoter activation, we designed ECF/AS-suicide circuits. Such circuits allow for the time-delayed cell-death of E. coli and will serve as a prototype for the further development of ECF/AS-based lysis circuits