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Discourse Semantics for the Analysis of Change in Language

This paper purports to elaborate and address several issues which lie at the intersection of computational linguistics and psychology. The first issue addressed is that of the interaction between discourse and semantics by virtue of empirical linguistic and psychotherapeutic evidence. This paper then gives a formal account of the knowledge representation and reasoning processes involved in the construction of an XML knowledge base for use in the sematic analysis of psychotherapeutic transcripts. Computational methods for the automatic mark-up and inference of the psychotherapeutic phenomena under investigation are detailed in order to further develop intuitions behind a particular pragmatic theory of language known as the Metamodel. The work presented here ultimately aims to produce a sustainable system for the evaluation of the effectiveness of any given psychotherapeutic technique. The possibility exists for such a system to recognise successful therapeutic mechanisms and further still, to infer new ones, or suggest improvements, or offer novel explanations as to the success or failure of the therapy itself. The work discussed here stems from research in computational linguistics, psychotherapy, and philosophy. The corpus used is a culmination of client transcripts taken before, during, and after therapy. The particular therapeutic technique used here is known as the Metamodel (Bandler and Grinder, 1975). The Metamodel was originally proffered as a method of language analysis suitable for use by practitioners of any psychotherapeutic technique. It theorises that speech utterances are related to a clients deep structure through three primary mechanisms, namely generalisation, deletion, and distortion. Previous hand tagging of our data has proven support for such claims. It is our aim to automate the identification and reasoning process. The issues and processes involved in the automation of such tagging are discussed here. Architectural and philosophical issues relating syntax (or grammar), semantics (Larson and Segal, 1995), and pragmatics (Grice, 1989; Searle, 1969) are raised. Discourse Representation Theory (Kamp, 1981; Asher and Lascarides, 1995) is discussed and used here in order to infer discourse relations.Hosted by the Scholarly Text and Imaging Service (SETIS), the University of Sydney Library, and the Research Institute for Humanities and Social Sciences (RIHSS), the University of Sydney

Roles of ATP binding cassette transporters in drug sensitivity and physiology of Plasmodium parasites

Contains fulltext : 157751.pdf (publisher's version ) (Open Access)RU Radboud Universiteit, 6 juni 2016Promotores : Russel, F.G.M., Sauerwein, R.W. Co-promotor : Koenderink, J.B

PfMDR2 and PfMDR5 are dispensable for Plasmodium falciparum asexual parasite multiplication but change in vitro susceptibility to anti-malarial drugs

Contains fulltext : 153635.pdf (publisher's version ) (Open Access)BACKGROUND: Membrane-associated ATP binding cassette (ABC) transport proteins hydrolyze ATP in order to translocate a broad spectrum of substrates, from single ions to macromolecules across membranes. In humans, members from this transport family have been linked to drug resistance phenotypes, e.g., tumour resistance by enhanced export of chemotherapeutic agents from cancer cells due to gene amplifications or polymorphisms in multidrug resistance (MDR) protein 1. Similar mechanisms have linked the Plasmodium falciparum PfMDR1 transporter to anti-malarial drug resistance acquisition. In this study, the possible involvement of two related MDR proteins, PfMDR2 and PfMDR5, to emerging drug resistance is investigated by a reverse genetics approach. METHODS: A homologous double crossover strategy was used to generate P. falciparum parasites lacking the Pfmdr2 (PfDeltamdr2) or Pfmdr5 (PfDeltamdr5) gene. Plasmodium lactate dehydrogenase activity was used as read-out for sensitivity to artemisinin (ART), atovaquone (ATO), dihydroartemisinin (DHA), chloroquine (CQ), lumefantrine (LUM), mefloquine (MQ), and quinine (QN). Differences in half maximal inhibitory concentration (IC(5)(0)) values between wild type and each mutant line were determined using a paired t-test. RESULTS: Both PfDeltamdr2 and PfDeltamdr5 clones were capable of asexual multiplication. Upon drug exposure, PfDeltamdr2 showed a marginally decreased sensitivity to ATO (IC(5)(0) of 1.2 nM to 1.8 nM), MQ (124 nM to 185 nM) and QN (40 nM to 70 nM), as compared to wild type (NF54) parasites. On the other hand, PfDeltamdr5 showed slightly increased sensitivity to ART (IC(5)(0) of 26 nM to 19 nM). CONCLUSION: Both Pfmdr2 and Pfmdr5 are dispensable for blood stage development while the deletion lines show altered sensitivity profiles to commonly used anti-malarial drugs. The findings show for the first time that next to PfMDR2, the PfMDR5 transport protein could play a role in emerging drug resistance

The ABCs of multidrug resistance in malaria.

Contains fulltext : 89009.pdf (publisher's version ) (Closed access)Expanding drug resistance could become a major problem in malaria treatment, as only a limited number of effective antimalarials are available. Drug resistance has been associated with single nucleotide polymorphisms and an increased copy number of multidrug resistance protein 1 (MDR1), an ATP-binding cassette (ABC) protein family member. Many ABC transport proteins are membrane transporters that actively translocate a wide range of structurally and functionally diverse amphipathic compounds. The Plasmodium falciparum ABC family consists of 16 members and current knowledge of their physiological function and contribution to antimalarial drug resistance is limited. Here, we give an overview of the Plasmodium ABC family members with reference to their possible role in multidrug resistance.1 september 201

Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

Contains fulltext : 136792.pdf (publisher's version ) (Open Access)BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins. METHODS: The interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1-4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins. RESULTS: A strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC50) of 0.23 muM (95% CI 0.17-0.29 muM) and inhibition of P-gp-mediated transport by quinine with an IC50 of 6.8 muM (95% CI 5.9-7.8 muM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine. CONCLUSIONS: Atovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials with drugs that are BCRP or P-gp substrates may potentially lead to drug-drug interactions

The bias between different albumin assays may affect clinical decision-making

Item does not contain fulltextDifferences between laboratory assays can have important clinical implications. For creatinine assays this became apparent soon after the introduction of the Modification of Diet in Renal Disease formula and resulted in international efforts towards standardization. Albumin in blood is measured by different assays, either chromogenic using Bromocresol green (BCG) or Bromocresol purple (BCP), or by an immunoassay. Since differences between these assays have received limited attention we evaluated bias and imprecision of BCG and BCP assays in comparison to the immunoassay using blood samples from patients with membranous nephropathy and nephrotic syndrome. For the BCG assay, the mean bias was high (6.2 g/l, with a standard deviation of 2.4 g/l) compared to a bias of 0.3 g/l (standard deviation 1.5 g/l) for the BCP assay. Importantly, we questioned clinical relevance by evaluating the accuracy of the decision toward the use of prophylactic anticoagulant therapy. Notably, nephrologists may reach inappropriate treatment decisions using the BGC assay in up to 59% of patients. Thus, our study should stimulate efforts towards standardization of the albumin assays