Browsing by Subject "Computer Simulation"

Now showing 1 - 3 of 3
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    Open Access
    Functional microdomains in G-protein-coupled receptors: the conserved arginine-cage motif in the gonadotropin-releasing hormone receptor
    (1998) Ballesteros, Juan; Kitanovic, Smiljka; Guarnieri, Frank; Davies, Peter; Fromme, Bernard J; Konvicka, Karel; Chi, Ling; Millar, Robert P; Davidson, James S; Weinstein, Harel; Sealfon, Stuart C
    An Arg present in the third transmembrane domain of all rhodopsin-like G-protein-coupled receptors is required for efficient signal transduction. Mutation of this Arg in the gonadotropin-releasing hormone receptor to Gln, His, or Lys abolished or severely impaired agonist-stimulated inositol phosphate generation, consistent with Arg having a role in receptor activation. To investigate the contribution of the surrounding structural domain in the actions of the conserved Arg, an integrated microdomain modeling and mutagenesis approach has been utilized. Two conserved residues that constrain the Arg side chain to a limited number of conformations have been identified. In the inactive wild-type receptor, the Arg side chain is proposed to form an ionic interaction with Asp3.49(138). Experimental results for the Asp3. 49(138) --> Asn mutant receptor show a modestly enhanced receptor efficiency, consistent with the hypothesis that weakening the Asp3. 49(138)-Arg3.50(139) interaction by protonation of the Asp or by the mutation to Asn favors activation. With activation, the Asp3. 49(138)-Arg3.50(139) ionic bond would break, and the unrestrained Arg would be prevented from orienting itself toward the water phase by a steric clash with Ile3.54(143). The mutation Ile3.54(143) --> Ala, which eliminates this clash in simulations, causes a marked reduction in measured receptor signaling efficiency, implying that solvation of Arg3.50(139) prevents it from functioning in the activation of the receptor. These data are consistent with residues Asp3.49(138) and Ile3.54(143) forming a structural motif, which helps position Arg in its appropriate inactive and active receptor conformations.
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    Open Access
    Meeting national response time targets for priority 1 incidents in an urban emergency medical services system in South Africa: More ambulances won’t help
    (2015) Stein, Christopher; Wallis, Lee; Adetunji, Olufemi
    BACKGROUND: Response time is viewed as a key performance indicator in most emergency medical services (EMS) systems. OBJECTIVE: To determine the effect of increased emergency vehicle numbers on response time performance for priority 1 incidents in an urban EMS system in Cape Town, South Africa, using discrete-event computer simulation. METHOD: A simulation model was created, based on input data from part of the EMS operations. Two different versions of the model were used, one with primary response vehicles and ambulances and one with only ambulances. In both cases the models were run in seven different scenarios. The first scenario used the actual number of emergency vehicles in the real system, and in each subsequent scenario vehicle numbers were increased by adding the baseline number to the cumulative total. RESULTS: The model using only ambulances had shorter response times and a greater number of responses meeting national response time targets than models using primary response vehicles and ambulances. In both cases an improvement in response times and the number of responses meeting national response time targets was observed with the first incremental addition of vehicles. After this the improvements rapidly diminished and eventually became negligible with each successive increase in vehicle numbers. The national response time target for urban areas was never met, even with a seven-fold increase in vehicle numbers. CONCLUSION: The addition of emergency vehicles to an urban EMS system improves response times in priority 1 incidents, but alone is not capable of the magnitude of response time improvement needed to meet the national response time targets.
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    Open Access
    Purely competitive evolutionary dynamics for games
    (2012) Veller, Carl; Rajpaul, Vinesh
    We introduce and analyze a purely competitive dynamics for the evolution of an infinite population subject to a 3-strategy game. We argue that this dynamics represents a characterization of how certain systems, both natural and artificial, are governed. In each period, the population is randomly sorted into pairs, which engage in a once-off play of the game; the probability that a member propagates its type to its offspring is proportional only to its payoff within the pair. We show that if a type is dominant (obtains higher payoffs in games with both other types), its 'pure' population state, comprising only members of that type, is globally attracting. If there is no dominant type, there is an unstable 'mixed' fixed point; the population state eventually oscillates between the three near-pure states. We then allow for mutations, where offspring have a non-zero probability of randomly changing their type. In this case, the existence of a dominant type renders a point near its pure state globally attracting. If no dominant type exists, a supercritical Hopf bifurcation occurs at the unique mixed fixed point, and above a critical (typically low) mutation rate, this fixed point becomes globally attracting: the implication is that even very low mutation rates can stabilize a system that would, in the absence of mutations, be unstable.