A principled approach to the implementation of argumentation models

Argumentation theory combines philosophical concepts and computational models to deliver a practical approach to reasoning that handles uncertain information and possibly conflicting viewpoints. This paper focuses on the structured approach to argumentation that incorporates domain specific knowledge and argumentation schemes. There is a lack of implementations and implementation methods for most structured models. This paper shows how taking a principled approach, using the programming language Haskell, helps addressing this problem. We construct a framework for developing structured argumentation models and translations between models (given intertranslatability of models). We furthermore provide a methodology to quickly test and formally prove desirable properties of such implementations using a theorem prover. We demonstrate our approach on the Carneades argumentation model and Dung's abstract argumentation frameworks, implementing both the models and a translation from Carneades into AFs. We then provide implementations of correspondence properties and an initial formalisation of Dung's AFs into a theorem prover. The final result is a verified pipeline from the structured model Carneades into existing efficient SAT-based implementations of Dung's AFs

A framework for relating, implementing and verifying argumentation models and their translations

Computational argumentation theory deals with the formalisation of argument structure, conflict between arguments and domain-specific constructs, such as proof standards, epistemic probabilities or argument schemes. However, despite these practical components, there is a lack of implementations and implementation methods available for most structured models of argumentation and translations between them. This thesis addresses this problem, by constructing a general framework for relating, implementing and formally verifying argumentation models and translations between them, drawing from dependent type theory and the Curry-Howard correspondence. The framework provides mathematical tools and programming methodologies to implement argumentation models, allowing programmers and argumentation theorists to construct implementations that are closely related to the mathematical definitions. It furthermore provides tools that, without much effort on the programmer's side, can automatically construct counter-examples to desired properties, while finally providing methodologies that can prove formal correctness of the implementation in a theorem prover. The thesis consists of various use cases that demonstrate the general approach of the framework. The Carneades argumentation model, Dung's abstract argumentation frameworks and a translation between them, are implemented in the functional programming language Haskell. Implementations of formal properties of the translation are provided together with a formalisation of AFs in the theorem prover, Agda. The result is a verified pipeline, from the structured model Carneades into existing efficient SAT-based implementations of Dung's AFs. Finally, the ASPIC+ model for argumentation is generalised to incorporate content orderings, weight propagation and argument accrual. The framework is applied to provide a translation from this new model into Dung's AFs, together with a complete implementation

A framework for relating, implementing and verifying argumentation models and their translations

Computational argumentation theory deals with the formalisation of argument structure, conflict between arguments and domain-specific constructs, such as proof standards, epistemic probabilities or argument schemes. However, despite these practical components, there is a lack of implementations and implementation methods available for most structured models of argumentation and translations between them. This thesis addresses this problem, by constructing a general framework for relating, implementing and formally verifying argumentation models and translations between them, drawing from dependent type theory and the Curry-Howard correspondence. The framework provides mathematical tools and programming methodologies to implement argumentation models, allowing programmers and argumentation theorists to construct implementations that are closely related to the mathematical definitions. It furthermore provides tools that, without much effort on the programmer's side, can automatically construct counter-examples to desired properties, while finally providing methodologies that can prove formal correctness of the implementation in a theorem prover. The thesis consists of various use cases that demonstrate the general approach of the framework. The Carneades argumentation model, Dung's abstract argumentation frameworks and a translation between them, are implemented in the functional programming language Haskell. Implementations of formal properties of the translation are provided together with a formalisation of AFs in the theorem prover, Agda. The result is a verified pipeline, from the structured model Carneades into existing efficient SAT-based implementations of Dung's AFs. Finally, the ASPIC+ model for argumentation is generalised to incorporate content orderings, weight propagation and argument accrual. The framework is applied to provide a translation from this new model into Dung's AFs, together with a complete implementation

Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation

Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. Conclusion: Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes.UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. beta-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFN gamma and 114 secretion).Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue.Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes

Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation

Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. Conclusion: Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes.UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. beta-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFN gamma and 114 secretion).Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue.Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes

Quantifying resilience of humans and other animals

All life requires the capacity to recover from challenges that are as inevitable as they are unpredictable. Understanding this resilience is essential for managing the health of humans and their livestock. It has long been difficult to quantify resilience directly, forcing practitioners to rely on indirect static indicators of health. However, measurements from wearable electronics and other sources now allow us to analyze the dynamics of physiology and behavior with unsurpassed resolution. The resulting flood of data coincides with the emergence of novel analytical tools for estimating resilience from the pattern of micro-recoveries observed in natural time series. Such dynamic indicators of resilience (DIORs) may be used to monitor the risk of systemic failure across systems ranging from organs to entire organisms. These tools invite a fundamental rethink of our approach to the adaptive management of health and resilience

The influence of smoking and HIV infection on pulmonary function

Background: Prevalence of HIV, smoking, and pulmonary infections in South Africa are high.Objectives: We investigated the role of smoking and HIV status on lung function.Methods: This is a secondary analysis of a cross-sectional study conducted in South Africa. Data included demographics, pulmonary risk factors and a spirometry test to obtain the forced expiratory volume in one second (FEV1) and the ratio of FEV1/forced vital capacity (FVC). In the initial multivariable regression analysis, the effect of smoking on pulmonary function in HIV-positive adults was assessed. The analysis was repeated, assessing the influence of HIV status on lung function in both HIV-negative and HIV-positive smokers. The models were adjusted for age, sex, body mass index (BMI), time since HIV diagnosis, antiretroviral treatment (ART) use, occupational hazards, history of tuberculosis or pneumonia, indoor smoking and the presence of an indoor fireplace during childhood.Results: This study included 524 people living with HIV (PLWH, 66.7% female, mean age 40.9 years [s.d.; 9.4]) and 79 HIV-negative smokers (77.2% male, mean age 34.4 years [s.d.: 12.1]). Of the PLWH, 118 (22.5%) were past or current smokers and 406 (77.5%) were non-smokers. Smoking was not associated with changes in the FEV1 or FEV1/FVC ratio in multivariable regression analysis. In the second analysis, HIV status was also not associated with reduced pulmonary function following adjustment for confounders.Conclusion: Neither smoking nor being HIV-positive was associated with decreased pulmonary function in this relatively young population. These findings should be confirmed in a longitudinal study, including an older population

Outcome from balloon induced coronary artery dissection after intracoronary beta radiation

OBJECTIVE: To evaluate the healing of balloon induced coronary artery dissection in individuals who have received beta radiation treatment and to propose a new intravascular ultrasound (IVUS) dissection score to facilitate the comparison of dissection through time. DESIGN: Retrospective study. SETTING: Tertiary referral centre. PATIENTS: 31 patients with stable angina pectoris, enrolled in the beta energy restenosis trial (BERT-1.5), were included. After excluding those who underwent stent implantation, the evaluable population was 22 patients. INTERVENTIONS: Balloon angioplasty and intracoronary radiation followed by quantitative coronary angiography (QCA) and IVUS. Repeat QCA and IVUS were performed at six month follow up. MAIN OUTCOME MEASURES: QCA and IVUS evidence of healing of dissection. Dissection classification for angiography was by the National Heart Lung Blood Institute scale. IVUS proven dissection was defined as partial or complete. The following IVUS defined characteristics of dissection were described in the affected coronary segments: length, depth, arc circumference, presence of flap, and dissection score. Dissection was defined as healed when all features of dissection had resolved. The calculated dose of radiation received by the dissected area in those with healed versus non-healed dissection was also compared. RESULTS: Angiography (type A = 5, B = 7, C = 4) and IVUS proven (partial = 12, complete = 4) dissections were seen in 16 patients following intervention. At six month follow up, six and eight unhealed dissections were seen by angiography (A = 2, B = 4) and IVUS (partial = 7, complete = 1), respectively. The mean IVUS dissection score was 5.2 (range 3-8) following the procedure, and 4.6 (range 3-7) at follow up. No correlation was found between the dose prescribed in the treated area and the presence of unhealed disse

A method for single pair mating in an obligate parasitic nematode

Parasitic nematode species have extremely high levels of genetic diversity, presenting a number of experimental challenges for genomic and genetic work. Consequently, there is a need to develop inbred laboratory strains with reduced levels of polymorphism. The most efficient approach to inbred line development is single pair mating, but this is challenging for obligate parasites where the adult sexual reproductive stages are inside the host, and thus difficult to experimentally manipulate. This paper describes a successful approach to single pair mating of a parasitic nematode, Haemonchus contortus. The method allows for polyandrous mating behaviour and involves the surgical transplantation of a single adult male worm with multiple immature adult females directly into the sheep abomasum. We used a panel of microsatellite markers to monitor and validate the single pair mating crosses and to ensure that the genotypes of progeny and subsequent filial generations were consistent with those expected from a mating between a single female parent of known genotype and a single male parent of unknown genotype. We have established two inbred lines that both show a significant overall reduction in genetic diversity based on microsatellite genotyping and genome-wide single nucleotide polymorphism. There was an approximately 50% reduction in heterozygous SNP sites across the genome in the MHco3.N1 line compared with the MoHco3(ISE) parental strain. The MHco3.N1 inbred line has subsequently been used to provide DNA template for whole genome sequencing of H. contortus. This work provides proof of concept and methodologies for forward genetic analysis of obligate parasitic nematodes