The Challenge of Unifying Semantic and Syntactic Inference Restrictions

While syntactic inference restrictions don't play an important role for SAT, they are an essential reasoning technique for more expressive logics, such as first-order logic, or fragments thereof. In particular, they can result in short proofs or model representations. On the other hand, semantically guided inference systems enjoy important properties, such as the generation of solely non-redundant clauses. I discuss to what extend the two paradigms may be unifiable

On the Expressivity and Applicability of Model Representation Formalisms

A number of first-order calculi employ an explicit model representation formalism for automated reasoning and for detecting satisfiability. Many of these formalisms can represent infinite Herbrand models. The first-order fragment of monadic, shallow, linear, Horn (MSLH) clauses, is such a formalism used in the approximation refinement calculus. Our first result is a finite model property for MSLH clause sets. Therefore, MSLH clause sets cannot represent models of clause sets with inherently infinite models. Through a translation to tree automata, we further show that this limitation also applies to the linear fragments of implicit generalizations, which is the formalism used in the model-evolution calculus, to atoms with disequality constraints, the formalisms used in the non-redundant clause learning calculus (NRCL), and to atoms with membership constraints, a formalism used for example in decision procedures for algebraic data types. Although these formalisms cannot represent models of clause sets with inherently infinite models, through an additional approximation step they can. This is our second main result. For clause sets including the definition of an equivalence relation with the help of an additional, novel approximation, called reflexive relation splitting, the approximation refinement calculus can automatically show satisfiability through the MSLH clause set formalism

Deciding First-Order Satisfiability when Universal and Existential Variables are Separated

We introduce a new decidable fragment of first-order logic with equality, which strictly generalizes two already well-known ones -- the Bernays-Sch\"onfinkel-Ramsey (BSR) Fragment and the Monadic Fragment. The defining principle is the syntactic separation of universally quantified variables from existentially quantified ones at the level of atoms. Thus, our classification neither rests on restrictions on quantifier prefixes (as in the BSR case) nor on restrictions on the arity of predicate symbols (as in the monadic case). We demonstrate that the new fragment exhibits the finite model property and derive a non-elementary upper bound on the computing time required for deciding satisfiability in the new fragment. For the subfragment of prenex sentences with the quantifier prefix $\exists^* \forall^* \exists^*$ the satisfiability problem is shown to be complete for NEXPTIME. Finally, we discuss how automated reasoning procedures can take advantage of our results.Comment: Extended version of our LICS 2016 conference paper, 23 page

Experiences of services and family therapy with refugees and asylum-seekers

The systemic model has been proposed as particularly relevant for addressing the mental health needs of refugees and asylum-seekers. Clinicians working with families from refugee and asylum-seeking backgrounds who have experienced trauma may wish to encourage family communication to promote resilience, but may find it difficult to know whether to address traumatic memories. This study aims to develop a theoretical understanding of how conversations about trauma emerge in systemic family therapy with families from refugee and asylum-seeking backgrounds. Ten systemic family therapists were interviewed, and data was analysed using grounded theory methodology. Resulting constructs highlight co-constructed conversations about trauma between families and therapists. Therapists attend to several factors in order to create a space where unspoken stories can be voiced, so that families can find new meanings and re-connect. Showcasing current practice in this field, the study emphasises the need for clinicians working with this population to actively engage with the wider context, and highlights the need for research investigating the effectiveness of systemic family therapy interventions for this client group

INVESTIGATION OF THE MECHANISM OF ACTION FOR MITHRAMYCIN AND THE BIOSYNTHESIS OF L-REDNOSE IN SAQUAYAMYCINS

Natural products continue to be a major chemical lead matter for drug discovery due to their diverse chemical structures and bioactivities. Clinically significant natural products include anti-cancer and anti-infective compounds and while many more of these compounds show promising bioactivity, their clinical relevance is often limited by toxicity or poor solubility. Combinatorial biosynthesis can be employed to modify existing chemical scaffolds towards reducing these limitations. To fully take advantage of these biochemical tools, it is important to understand the biosynthesis and mechanism of action of the molecules. Saccharides in glycosylated natural products provide specific interactions with cellular targets and are often crucial for a compound’s bioactivity. Genetic engineering of sugar pathways can modify glycosylation patterns leading to the diversification of natural products. Saquayamycins (SQN) H and I are cytotoxic angucycline antibiotics containing five deoxyhexoses including the rare amino sugar rednose. Elucidating the biosynthetic pathway of rednose could add to the arsenal of combinatorial biosynthesis tools for drug development. Our research goal of investigating the rednose biosynthetic pathway was pursued through two specific aims: the identification of the Streptomyces sp. KY 40-1 gene cluster involved in the biosynthesis of SQN H and I (sqn) (specific aim 1), and the validation of the proposed L-rednose biosynthetic pathway up to the glycosyl transfer through enzymatic synthesis of NDP-3,6-dideoxy-L-idosamine (specific aim 2). The sqn gene cluster revealed deoxysugar biosynthetic genes that could be used to alter glycosylation patterns to generate novel compounds while the enzymatic synthesis afforded novel genetic engineering tools to generate novel TDP-deoxysugars that could be used to diversify compounds such as aminoglycosides to circumvent resistance mechanisms. The first step to generate TDP-glucosamine enzymatically was accomplished, however later steps were unsuccessful. The aureolic acid mithramycin (MTM) was recently tested in clinical trials for Ewing sarcoma following the discovery of MTM as a potent inhibitor of the oncogenic transcription factor EWS-FLI1 present only in Ewing sarcoma cells It is understood that MTM binds the minor groove of G/C rich DNA as an Mg2+-coordinated dimer disrupting transcription of proto-oncogenes; however, the DNA recognition rules were not completely understood, making further interrogation of MTM’s DNA binding preferences necessary. This research goal of further understanding the mechanism of action for MTM was approached through two specific aims: the investigation of the dimerization of MTM (specific aim 3), and the investigation of MTM’s DNA binding preferences (specific aim 4). This work established that MTM and its biosynthetic precursor premithramycin B (PreMTM B), and several MTM analogues with modified 3-side chains: mithramycin SDK (MTM SDK), mithramycin SA tryptophan (MTM SA-Trp), and mithramycin SA alanine (MTM SA-Ala) dimerize even in the absence of DNA under physiologically relevant conditions. The study also demonstrated that modification of the 3-side chain modulates DNA binding affinity of MTM analogues, established a minimum MTM binding site on DNA, and revealed MTM DNA recognition is driven by direct (sequence) and not indirect (conformation) readout laying the foundation for subsequent research based on the interaction between MTM, DNA, and the oncogenic transcription factor EWS-FLI1 in the rational design of new MTM analogues for the treatment of Ewing sarcoma

Unification in sort theories and its applications

In this article I investigate the properties of unification in sort theories. The usual notion of a sort consisting of a sort symbol is extended to a set of sort symbols. In this language sorted unification in elementary sort theories is of unification type finitary. The rules of standard unification with the addition of four sorted rules form the new sorted unification algorithm. The algorithm is proved sound and complete. The rule based form of the algorithm is not suitable for an implementation because there is no control and the used data structures are weak. Therefore we transform the algorithm into a deterministic sorted unification procedure. For the procedure sorted unification in pseudo-linear sort theories is proved decidable. The notions of a sort and a sort theory are developed in a way such that a standard calculus can be turned into a sorted calculus by replacing standard unification with sorted unification. To this end sorts may denote the empty set. Sort theories may contain clauses with more than one declaration and may change dynamically during the deduction process. The applicability of the approach is exemplified for the resolution and the tableau calculus