The meaning of the word owoai (save) in the Gospel of Mark (a semiotic analysis approach)

The verb owoai "save" is used fifteen times in the Gospel of Mark. However no explanation is given of the meaning of the word by the evangelist, Jesus or any person using it. This thesis studies the various instances where the word is used and proposes a definition of the word. The method of investigation that is used throughout this research is the Semiotic Analysis. Of the numerous schools of semioticians, this research has opted for Walter Vogels' method of analysis which provides a more systematic approach to narratives. This study examines five specific episodes of the Gospel of Mark, selected because in each of them the word save is used in an encounter between Jesus and other participants

Assessment of biological role and insight into druggability of the Plasmodium falciparum protease plasmepsin V

Upon infecting a red blood cell (RBC), the malaria parasit

Non-contrast CT markers of intracerebral hematoma expansion : a reliability study

Objectives: We evaluated whether clinicians agree in the detection of non-contrast CT markers of intracerebral hemorrhage (ICH) expansion. Methods: From our local dataset, we randomly sampled 60 patients diagnosed with spontaneous ICH. Fifteen physicians and trainees (Stroke Neurology, Interventional and Diagnostic Neuroradiology) were trained to identify six density (Barras density, black hole, blend, hypodensity, fluid level, swirl) and three shape (Barras shape, island, satellite) expansion markers, using standardized definitions. Thirteen raters performed a second assessment. Inter and intra-rater agreement were measured using Gwet’s AC1, with a coefficient > 0.60 indicating substantial to almost perfect agreement. Results: Almost perfect inter-rater agreement was observed for the swirl (0.85, 95% CI: 0.78-0.90) and fluid level (0.84, 95% CI: 0.76-0.90) markers, while the hypodensity (0.67, 95% CI: 0.56-0.76) and blend (0.62, 95% CI: 0.51-0.71) markers showed substantial agreement. Inter-rater agreement was otherwise moderate, and comparable between density and shape markers. Inter-rater agreement was lower for the three markers that require the rater to identify one specific axial slice (Barras density, Barras shape, island: 0.46, 95% CI: 0.40-0.52 versus others: 0.60, 95% CI: 0.56-0.63). Inter-observer agreement did not differ when stratified for raters’ experience, hematoma location, volume or anticoagulation status. Intrarater agreement was substantial to almost perfect for all but the black hole marker. Conclusion: In a large sample of raters with different backgrounds and expertise levels, only four of nine non-contrast CT markers of ICH expansion showed substantial to almost perfect inter-rater agreement

Prioritization of Molecular Targets for Antimalarial Drug Discovery

There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in Plasmodium species. Given the high attrition rate and high cost of drug discovery, it is important to select the targets most likely to deliver progressible drug candidates. In this paper, we describe the criteria that we consider important for selecting targets for antimalarial drug discovery. We describe the analysis of a number of drug targets in the Malaria Drug Accelerator (MalDA) pipeline, which has allowed us to prioritize targets that are ready to enter the drug discovery process. This selection process has also highlighted where additional data are required to inform target progression or deprioritization of other targets. Finally, we comment on how additional drug targets may be identified

Connectivité spatiale et diversité des espèces: Mise en place d’un réseau de conservation dans le Parc National du Mercantour

La thématique des forêts anciennes et des forêts matures a été au cœur du séminaire physique du GT Forêt-Eau, avec l'organisation le 27 octobre 2015 d'une journée d'échanges et de visite, associant une douzaine de partenaires (INRA, IRSTEA, Purpan, RNF, FPNR, CBNMC...). Au delà, PNF [Parcs Nationaux de France] continuera à suivre les différents projets en cours, menés par des Parcs nationaux ou d'autres partenaires, et à envisager d'autres projets collectifs pour aller plus loin dans la connaissance des forêts anciennes et matures

Tuning the aggregation behavior of pH-responsive micelles by copolymerization

YesAmphiphilic diblock copolymers, poly(2-(diethylamino)ethyl methacrylate-co-2-(dimethylamino)ethyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate), P(DEAEMA-co-DMAEMA)-b-PDMAEMA with various amounts of DEAEMA have been synthesized by RAFT polymerization. Their micellization in water has been investigated by scattering measurements over a wide pH range. It appeared that the polymers self-assembled into pH sensitive star like micelles. For a given composition, when the pH is varied the extent of aggregation can be tuned reversibly by orders of magnitude. By varying the copolymer composition in the hydrophobic block, the onset and extent of aggregation were shifted with respect to pH. This class of diblock copolymer offers the possibility to select the range of stimuli-responsiveness that is useful for a given application, which can rarely be achieved with conventional diblock copolymers consisting of homopolymeric blocks.European Science Foundation (ESF), Engineering and Physical Sciences Research Council (EPSRC), BP (Firm), Birmingham Science City, Advantage West Midlands (AWM), European Regional Development Fund (ERDF

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.</p

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism