KLM-Style Defeasible Reasoning for Datalog

In many problem domains, particularly those related to mathematics and philosophy, classical logic has enjoyed great success as a model of valid reasoning and discourse. For real-world reasoning tasks, however, an agent typically only has partial knowledge of its domain, and at most a statistical understanding of relationships between properties. In this context, classical inference is considered overly restrictive, and many systems for non-monotonic reasoning have been proposed in the literature to deal with these tasks. A notable example is the Klm framework, which describes an agent's defeasible knowledge qualitatively in terms of conditionals of the form “if A, then typically B”. The goal of this research project is to investigate Klm-style semantics for defeasible reasoning over Datalog knowledge bases. Datalog is a declarative logic programming language, designed for querying large deductive databases. Syntactically, it can be viewed as a computationally feasible fragment of firstorder logic, so this continues a recent line of work in which the Klm framework is lifted to more expressive languages

KLM-Style Defeasibility for Restricted First-Order Logic

We extend the KLM approach to defeasible reasoning to be applicable to a restricted version of first-order logic. We de- scribe defeasibility for this logic using a set of rationality postulates, provide an appropriate semantics for it, and present a representation result that characterises the semantic descrip- tion of defeasibility in terms of the rationality postulates. Based on this theoretical core, we then propose a version of defeasible entailment that is inspired by Rational Closure as it is defined for defeasible propositional logic and defeasible description logics. We show that this form of defeasible entailment is rational in the sense that it adheres to our rationality postulates. The work in this paper is the first step towards our ultimate goal of introducing KLM-style defeasible rea- soning into the family of Datalog+/- ontology languages

BKLM - An expressive logic for defeasible reasoning

Propositional KLM-style defeasible reasoning involves a core propositional logic capable of expressing defeasible (or con- ditional) implications. The semantics for this logic is based on Kripke-like structures known as ranked interpretations. KLM-style defeasible entailment is referred to as rational whenever the defeasible entailment relation under consider- ation generates a set of defeasible implications all satisfying a set of rationality postulates known as the KLM postulates. In a recent paper Booth et al. proposed PTL, a logic that is more expressive than the core KLM logic. They proved an impossibility result, showing that defeasible entailment for PTL fails to satisfy a set of rationality postulates similar in spirit to the KLM postulates. Their interpretation of the im- possibility result is that defeasible entailment for PTL need not be unique. In this paper we continue the line of research in which the expressivity of the core KLM logic is extended. We present the logic Boolean KLM (BKLM) in which we allow for dis- junctions, conjunctions, and negations, but not nesting, of de- feasible implications. Our contribution is twofold. Firstly, we show (perhaps surprisingly) that BKLM is more expressive than PTL. Our proof is based on the fact that BKLM can characterise all single ranked interpretations, whereas PTL cannot. Secondly, given that the PTL impossibility result also applies to BKLM, we adapt the different forms of PTL entail- ment proposed by Booth et al. to apply to BKLM

On pedagogy of a Soil Science Centre for Doctoral Training

Here we describe and evaluate the success of a multi-institutional Centre for Doctoral Training (CDT), which was established to address a UK skills shortage in Soil Science. The government-funded ‘STARS’ (Soils Training And Research Studentships) CDT was established in 2015 across a range of universities and research institutes in the UK. It recruited 41 PhD students equitably split across the institutions under four core research themes identified as being central to the national need, namely, (1) Understanding the soil–root interface, (2) Soils and the delivery of ecosystem services, (3) Resilience and response of functions in soil systems and (4) Modelling the soil ecosystem at different spatial and temporal scales. In addition, the STARS CDT provided a diverse skills programme, including: Holistic training in soils, the promotion of collegiality and joint working, strategies to promote science and generate impact, internships with end users (e.g., policymakers, industry), personal wellbeing, and ways to generate a lasting soils training legacy. Overall, both supervisors and students have reported a positive experience of the CDT in comparison to the conventional doctoral training programmes, which have less discipline focus and little chance for students to scientifically interact with their cohorts or to undertake joint training activities. The STARS CDT also allowed students to freely access research infrastructure across the partner institutions (e.g., long-term field trials, specialised analytical facilities, high-performance computing), breaking down traditional institutional barriers and thus maximising the students' potential to undertake high-quality research. The success and legacy of the STARS CDT can be evidenced in many ways; however, it is exemplified by the large number and diversity of journal papers produced, the lasting collaborations, final career destinations, and creation of a web-based legacy portal including new and reflective video material.STARS CDT, Grant/Award Numbers: NE/V017667/1, NE/R010218/1, NE/M009106/1; UKR

Functional interaction between mouse erbB3 and wild-type rat c-neu in transgenic mouse mammary tumor cells

INTRODUCTION: Co-expression of several receptor tyrosine kinases (RTKs), including erbB2 and erbB3, is frequently identified in breast cancers. A member of the RTK family, the kinase-deficient erbB3 can activate downstream signaling via heterodimer formation with erbB2. We studied the expression of RTK receptors in mammary tumors from the wild-type (wt) rat c-neu transgenic model. We hypothesized that physical and functional interactions between the wt rat neu/ErbB2 transgene and mouse ErbB3-encoded proteins could occur, activating downstream signaling and promoting mammary oncogenesis. METHODS: Immunohistochemical and Western blot analyses were performed to study the expression of rat c-neu/ErbB2 and mouse erbB3 in mammary tumors and tumor-derived cell lines from the wt rat c-neu transgenic mice. Co-immunoprecipitation methods were employed to quantitate heterodimerization between the transgene-encoded protein erbB2 and the endogenous mouse erbB3. Tumor cell growth in response to growth factors, such as Heregulin (HRG), epidermal growth factor (EGF), or insulin-like growth factor-1 (IGF-1), was also studied. Post-HRG stimulation, activation of the RTK downstream signaling was determined by Western blot analyses using antibodies against phosphorylated Akt and mitogen-activated protein kinase (MAPK), respectively. Specific inhibitors were then used with cell proliferation assays to study the phosphoinositide-3 kinase (PI-3K)/Akt and MAPK kinase (MEK)/MAPK pathways as possible mechanisms of HRG-induced tumor cell proliferation. RESULTS: Mammary tumors and tumor-derived cell lines frequently exhibited elevated co-expression of erbB2 and erbB3. The transgene-encoded protein erbB2 formed a stable heterodimer complex with endogenous mouse erbB3. HRG stimulation promoted physical and functional erbB2/erbB3 interactions and tumor cell growth, whereas no response to EGF or IGF-1 was observed. HRG treatment activated both the Akt and MAPK pathways in a dose- and time-dependent manner. Both the PI-3K inhibitor LY 294002 and MEK inhibitor PD 98059 significantly decreased the stimulatory effect of HRG on tumor cell proliferation. CONCLUSION: The co-expression of wt rat neu/ErbB2 transgene and mouse ErbB3, with physical and functional interactions between these two species of RTK receptors, was demonstrated. These data strongly suggest a role for erbB3 in c-neu (ErbB2)-associated mammary tumorigenesis, as has been reported in human breast cancers

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability