510 research outputs found

    Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme

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    Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning

    Crossing the midline: An exploration of reference frame conflict

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    Multiple reference frames are used to interact with our surroundings. When these reference frames are in conflict, processing errors can occur. For tactile stimuli, this conflict is highlighted when the hands are crossed over the midline of the body. In this posture, vibrotactile temporal order judgments (TOJs) presented to the hands are impaired compared to an uncrossed posture. This decrease in temporal processing is known as the crossed-hands deficit. The deficit was explored in depth throughout this thesis. In Chapters 2, 3 and 4 different elements of the crossed-hands deficit were evaluated including its connections to the rod and frame test, individual and sex differences within the TOJ task, as well as the influence of vision and body position. These elements were framed with underlying goal of investigating the root cause of the deficit. The data presented here provided evidence for a conflict model of crossed hands processing. A conflict between the internal and external reference frames produced the deficit in temporal processing when the hands were crossed. The role of the body’s midline in understanding multisensory integration was further considered in Chapter 5 through the rubber hand illusion, which is a visuotactile phenomenon whereby an unseen real hand is mislocalized towards a seen rubber hand. When the real hand, rubber hand, or both were crossed over the midline the illusion did not occur. It was hypothesized that a failure to integrate the tactile information presented to the real hand with the visual rubber hand was responsible for the absence of the illusion. Taken together, the data presented in this thesis contribute to the greater understanding of how reference frame conflicts are resolved, particularly when the conflict occurs across the body’s midline.Doctor of Philosophy (PhD

    GSU Event Portal

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    The GSU Events website will solve a major problem with the current student portal - GSU student boredom. The current GSU Student portal is lacking entertainment, and the GSU Events website will fill that gap. The entertainment piece is currently not available on the GSU Student Portal, and this feature will hopefully be added to the GSU Student Portal in the near future. It will be a way for students to communicate and advertise music, theater, conferences, and entertainment in the surrounding area. It could also be used and advertised for new students to explore the area and get to know their new environment. The GSU Events website will be an excellent addition to the existing GSU Student Portal, and will be used by all GSU students. The GSU Events feature will be ready for release December 4th, 2017

    Traces du passé Images du présent : Anthropologie amérindienne du Moyen-nord québécois

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    Ce fichier contient les textes suivants : Le site DaGt-1 : un établissement Algonquin du sylvicole supérieur en Abitibi-Témiscamingue Par Marc Côté. Le site d’Askwaapsuanuuts et la chasse à l’oie dans la partie orientale de la Baie James au 18e et au début du 19e siècle par David Denton. Les Amérindiens en milieu urbain ; le cas de Val-D’Or par Micheline Laplante et Monique Potvin. On n’a plus le lac qu’on avait! par Norman Clermont. Les dieux de la terres : Histoire des Algonquins de l’Outaouais, 1600-1650 par Roland Viau. L’ostéoarchéologie du cimetière autochtone du Lac-Saint-Patrice (CcGh-1) par Gérard Gagné. La rivière Dumoine, une route commerciale aux confins du Témiscamingue au cours de la préhistoire par Marcel Laltberté. Le militantisme ethno-culturel des métis de Destor par Gabriel Bertrand. Algonquins et Iroquoiens dans l’Outaouais : aculturation et confrontation par Claude Chapdelaine. L’Abitibi et la route du cuivre par Denis Cadieux

    Perceived difficulty and appropriateness of decision making by General Practitioners: a systematic review of scenario studies

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    Background: Health-care quality in primary care depends largely on the appropriateness of General Practitioners’ (GPs; Primary Care or Family Physicians) decisions, which may be influenced by how difficult they perceive decisions to be. Patient scenarios (clinical or case vignettes) are widely used to investigate GPs’ decision making. This review aimed to identify the extent to which perceived decision difficulty, decision appropriateness, and their relationship have been assessed in scenario studies of GPs’ decision making; identify possible determinants of difficulty and appropriateness; and investigate the relationship between difficulty and appropriateness. Methods: MEDLINE, EMBASE, PsycINFO, the Cochrane Library and Web of Science were searched for scenario studies of GPs’ decision making. One author completed article screening. Ten percent of titles and abstracts were checked by an independent volunteer, resulting in 91% agreement. Data on decision difficulty and appropriateness were extracted by one author and descriptively synthesised. Chi-squared tests were used to explore associations between decision appropriateness, decision type and decision appropriateness assessment method. Results: Of 152 included studies, 66 assessed decision appropriateness and five assessed perceived difficulty. While no studies assessed the relationship between perceived difficulty and appropriateness, one study objectively varied the difficulty of the scenarios and assessed the relationship between a measure of objective difficulty and appropriateness. Across 38 studies where calculations were possible, 62% of the decisions were appropriate as defined by the appropriateness standard used. Chi-squared tests identified statistically significant associations between decision appropriateness, decision type and decision appropriateness assessment method. Findings suggested a negative relationship between decision difficulty and appropriateness, while interventions may have the potential to reduce perceived difficulty. Conclusions: Scenario-based research into GPs’ decisions rarely considers the relationship between perceived decision difficulty and decision appropriateness. The links between these decisional components require further investigation

    Spatiotemporal processing of somatosensory stimuli in schizotypy

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    Unusual interaction behaviors and perceptual aberrations, like those occurring in schizotypy and schizophrenia, may in part originate from impaired remapping of environmental stimuli in the body space. Such remapping is contributed by the integration of tactile and proprioceptive information about current body posture with other exteroceptive spatial information. Surprisingly, no study has investigated whether alterations in such remapping occur in psychosis-prone individuals. Four hundred eleven students were screened with respect to schizotypal traits using the Schizotypal Personality Questionnaire. A subgroup of them, classified as low, moderate, and high schizotypes were to perform a temporal order judgment task of tactile stimuli delivered on their hands, with both uncrossed and crossed arms. Results revealed marked differences in touch remapping in the high schizotypes as compared to low and moderate schizotypes. For the first time here we reveal that the remapping of environmental stimuli in the body space, an essential function to demarcate the boundaries between self and external world, is altered in schizotypy. Results are discussed in relation to recent models of 'self-disorders' as due to perceptual incoherence

    Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases

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    Age-associated neurodegenerative disorders such as Alzheimer’s disease are a major public health challenge, due to the demographic increase in the proportion of older individuals in society. However, the relatively few currently approved drugs for these conditions provide only symptomatic relief. A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with ageing. This requires model systems that can recapitulate key features of human neurodegenerative diseases that are also amenable to compound screening approaches. Mammalian models are very powerful, but are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for neuroprotective compound screening. Here we describe how C. elegans has been used to model various human ageing-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential

    Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

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    Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis
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