Interdefinability of defeasible logic and logic programming under the well-founded semantics

We provide a method of translating theories of Nute's defeasible logic into logic programs, and a corresponding translation in the opposite direction. Under certain natural restrictions, the conclusions of defeasible theories under the ambiguity propagating defeasible logic ADL correspond to those of the well-founded semantics for normal logic programs, and so it turns out that the two formalisms are closely related. Using the same translation of logic programs into defeasible theories, the semantics for the ambiguity blocking defeasible logic NDL can be seen as indirectly providing an ambiguity blocking semantics for logic programs. We also provide antimonotone operators for both ADL and NDL, each based on the Gelfond-Lifschitz (GL) operator for logic programs. For defeasible theories without defeaters or priorities on rules, the operator for ADL corresponds to the GL operator and so can be seen as partially capturing the consequences according to ADL. Similarly, the operator for NDL captures the consequences according to NDL, though in this case no restrictions on theories apply. Both operators can be used to define stable model semantics for defeasible theories.Comment: 36 pages; To appear in Theory and Practice of Logic Programming (TPLP

Reconciling OWL and non-monotonic rules for the semantic web

We propose a description logic extending SROIQ (the description logic underlying OWL 2 DL) and at the same time encompassing some of the most prominent monotonic and nonmonotonic rule languages, in particular Datalog extended with the answer set semantics. Our proposal could be considered a substantial contribution towards fulfilling the quest for a unifying logic for the Semantic Web. As a case in point, two non-monotonic extensions of description logics considered to be of distinct expressiveness until now are covered in our proposal. In contrast to earlier such proposals, our language has the "look and feel" of a description logic and avoids hybrid or first-order syntaxes

OWL and Rules

The relationship between the Web Ontology Language OWL and rule-based formalisms has been the subject of many discussions and research investigations, some of them controversial. From the many attempts to reconcile the two paradigms, we present some of the newest developments. More precisely, we show which kind of rules can be modeled in the current version of OWL, and we show how OWL can be extended to incorporate rules. We finally give references to a large body of work on rules and OWL

Insights into the Interaction of Heart Failure with Preserved Ejection Fraction and Sleep-Disordered Breathing

Heart failure with preserved ejection fraction (HFpEF) is emerging as a widespread disease with global socioeconomic impact. Patients with HFpEF show a dramatically increased morbidity and mortality, and, unfortunately, specific treatment options are limited. This is due to the various etiologies that promote HFpEF development. Indeed, cluster analyses with common HFpEF comorbidities revealed the existence of several HFpEF phenotypes. One especially frequent, yet underappreciated, comorbidity is sleep-disordered breathing (SDB), which is closely intertwined with the development and progression of the “obese HFpEF phenotype”. The following review article aims to provide an overview of the common HFpEF etiologies and phenotypes, especially in the context of SDB. As general HFpEF therapies are often not successful, patient- and phenotype-individualized therapeutic strategies are warranted. Therefore, for the “obese HFpEF phenotype”, a better understanding of the mechanistic parallels between both HFpEF and SDB is required, which may help to identify potential phenotype-individualized therapeutic strategies. Novel technologies like single-cell transcriptomics or CRISPR-Cas9 gene editing further broaden the groundwork for deeper insights into pathomechanisms and precision medicin

Demographic patterns and outcomes of patients in level I trauma centers in three international trauma systems

Introduction: Trauma systems were developed to improve the care for the injured. The designation and elements comprising these systems vary across countries. In this study, we have compared the demographic patterns and patient outcomes of Level I trauma centers in three international trauma systems. Methods: International multicenter prospective trauma registry-based study, performed in the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands, John Hunter Hospital (JHH), Newcastle, Australia, and Harborview Medical Center (HMC), Seattle, the United States. Inclusion: patients =18 years, admitted in 2012, registered in the institutional trauma registry. Results: In UMCU, JHH, and HMC, respectively, 955, 1146, and 4049 patients met the inclusion criteria of which 300, 412, and 1375 patients with Injury Severity Score (ISS) > 15. Mean ISS was higher in JHH (13.5; p < 0.001) and HMC (13.4; p < 0.001) compared to UMCU (11.7). Unadjusted mortality: UMCU = 6.5 %, JHH = 3.6 %, and HMC = 4.8 %. Adjusted odds of death: JHH = 0.498 [95 % confidence interval (CI) 0.303-0.818] and HMC = 0.473 (95 % CI 0.325-0.690) compared to UMCU. HMC compared to JHH was 1.002 (95 % CI 0.664-1.514). Odds of death patients ISS > 15: JHH = 0.507 (95 % CI 0.300-0.857) and HMC = 0.451 (95 % CI 0.297-0.683) compared to UMCU. HMC = 0.931 (95 % CI 0.608-1.425) compared to JHH. TRISS analysis: UMCU: Ws = 0.787, Z = 1.31, M = 0.87; JHH, Ws = 3.583, Z = 6.7, M = 0.89; HMC, Ws = 3.902, Z = 14.6, M = 0.84. Conclusion: This study demonstrated substantial differences across centers in patient characteristics and mortality, mainly of neurological cause. Future research must investigate whether the outcome differences remain with nonfatal and long-term outcomes. Furthermore, we must focus on the development of a more valid method to compare systems

Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor β Superfamily Type 1 Receptors.

The transforming growth factor β (TGFβ) superfamily includes TGFβ, activins, inhibins, and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by coordinately regulating cell proliferation, differentiation, and migration. Aberrant signaling of superfamily members, however, is associated with fibrosis as well as tumorigenesis, cancer progression, metastasis, and drug-resistance mechanisms in a variety of cancer subtypes. Given their involvement in human disease, the identification of novel selective inhibitors of TGFβ superfamily receptors is an attractive therapeutic approach. Seven mammalian type 1 receptors have been identified that have context-specific roles depending on the ligand and the complex formation with the type 2 receptor. Here, we characterize the biologic effects of two transforming growth factor β receptor 1 (TGFBR1) kinase inhibitors designed to target TGFβ signaling. AZ12601011 [2-(2-pyridinyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine]; structure previously undisclosed] and AZ12799734 [4-({4-[(2,6-dimethyl-3-pyridinyl)oxy]-2-pyridinyl}amino)benzenesulfonamide] (IC50 = 18 and 47 nM, respectively) were more effective inhibitors of TGFβ-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC50 = 84 nM) and LY2157299 [4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide monohydrate]] (galunisertib) (IC50 = 380 nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors activin A receptor type 1B (ALK4), TGFBR1, and activin A receptor type 1C (ALK7). AZ12799734, however, is a pan TGF/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by activin A receptor type 1L, bone morphogenetic protein receptor type 1A, and bone morphogenetic protein receptor type 1B and phosphorylation of SMAD2 by ALK4, TGFBR1, and ALK7. AZ12601011 was highly effective at inhibiting basal and TGFβ-induced migration of HaCaT keratinocytes and, furthermore, inhibited tumor growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumor model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFβ- and BMP-regulated signaling pathways to disease states

A site assessment tool for inpatient controlled human infection models for enteric disease pathogens

The use of the controlled human infection model to facilitate product development and to advance understanding of host-pathogen interactions is of increasing interest. While administering a virulent (or infective) organism to a susceptible host necessitates an ongoing evaluation of safety and ethical considerations, a central theme in conducting these studies in a safe and ethical manner that yields actionable data is their conduct in facilities well-suited to address their unique attributes. To that end, we have developed a framework for evaluating potential sites in which to conduct inpatient enteric controlled human infection model to ensure consistency and increase the likelihood of success.publishedVersio

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

Large-scale clinical outcome studies demonstrated the efficacy of SGLT2 inhibitors in patients with type II diabetes. Besides their therapeutic efficacy in diabetes, significant renoprotection was observed in non-diabetic patients with chronic kidney disease (CKD), suggesting the existence of glucose-independent beneficial effects of SGLT2 inhibitors. However, the relevant mechanisms by which SGLT2 inhibition delays the progression of renal injury are still largely unknown and speculative. Previous studies showed that SGLT2 inhibitors reduce diabetic hyperfiltration, which is likely a key element in renoprotection. In line with this hypothesis, this study aimed to investigate the nephroprotective effects of the SGLT2 inhibitor empagliflozin (EMPA) in different mouse models with non-diabetic hyperfiltration and progressing CKD to identify the underlying diabetes-independent cellular mechanisms. Non-diabetic hyperfiltration was induced by unilateral nephrectomy (UNx). Since UNx alone does not result in renal damage, renal disease models with varying degrees of glomerular damage and albuminuria were generated by combining UNx with high NaCl diets ± deoxycorticosterone acetate (DOCA) in different mouse strains with and without genetic predisposition for glomerular injury. Renal parameters (GFR, albuminuria, urine volume) were monitored for 4–6 weeks. Application of EMPA via the drinking water resulted in sufficient EMPA plasma concentration and caused glucosuria, diuresis and in some models renal hypertrophy. EMPA had no effect on GFR in untreated wildtype animals, but significantly reduced hyperfiltration after UNx by 36%. In contrast, EMPA did not reduce UNx induced hyperfiltration in any of our kidney disease models, regardless of their degree of glomerular damage caused by DOCA/salt treatment. Consistent with the lack of reduction in glomerular hyperfiltration, EMPA-treated animals developed albuminuria and renal fibrosis to a similar extent as H2O control animals. Taken together, the data clearly indicate that blockade of SGLT2 has the potential to reduce non-diabetic hyperfiltration in otherwise untreated mice. However, no effects on hyperfiltration or progression of renal injury were observed in hypervolemic kidney disease models, suggesting that high salt intake and extracellular volume might attenuate the protective effects of SGLT2 blockers