46,068 research outputs found

    Actions of Agonists, Fipronil and Ivermectin on the Predominant In Vivo Splice and Edit Variant (RDLbd, I/V) of the Drosophila GABA Receptor Expressed in Xenopus laevis Oocytes

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    Ionotropic GABA receptors are the targets for several classes of insecticides. One of the most widely-studied insect GABA receptors is RDL (resistance to dieldrin), originally isolated from Drosophila melanogaster. RDL undergoes alternative splicing and RNA editing, which influence the potency of GABA. Most work has focussed on minority isoforms. Here, we report the first characterisation of the predominant native splice variant and RNA edit, combining functional characterisation with molecular modelling of the agonist-binding region. The relative order of agonist potency is GABA> muscimol> TACA> β-alanine. The I/V edit does not alter the potency of GABA compared to RDLbd. Docking calculations suggest that these agonists bind and activate RDLbdI/V through a similar binding mode. TACA and β-alanine are predicted to bind with lower affinity than GABA, potentially explaining their lower potency, whereas the lower potency of muscimol and isoguvacine cannot be explained structurally from the docking calculations. The A301S (resistance to dieldrin) mutation reduced the potency of antagonists picrotoxin, fipronil and pyrafluprole but the I/V edit had no measurable effect. Ivermectin suppressed responses to GABA of RDLbdI/V, RDLbd and RDLbdI/VA301S. The dieldrin resistant variant also showed reduced sensitivity to Ivermectin. This study of a highly abundant insect GABA receptor isoform will help the design of new insecticides

    Degradation of a quantum directional reference frame as a random walk

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    We investigate if the degradation of a quantum directional reference frame through repeated use can be modeled as a classical direction undergoing a random walk on a sphere. We demonstrate that the behaviour of the fidelity for a degrading quantum directional reference frame, defined as the average probability of correctly determining the orientation of a test system, can be fit precisely using such a model. Physically, the mechanism for the random walk is the uncontrollable back-action on the reference frame due to its use in a measurement of the direction of another system. However, we find that the magnitude of the step size of this random walk is not given by our classical model and must be determined from the full quantum description.Comment: 5 pages, no figures. Comments are welcome. v2: several changes to clarify the key results. v3: journal reference added, acknowledgements and references update

    Comments on black holes I: The possibility of complementarity

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    We comment on a recent paper of Almheiri, Marolf, Polchinski and Sully who argue against black hole complementarity based on the claim that an infalling observer 'burns' as he approaches the horizon. We show that in fact measurements made by an infalling observer outside the horizon are statistically identical for the cases of vacuum at the horizon and radiation emerging from a stretched horizon. This forces us to follow the dynamics all the way to the horizon, where we need to know the details of Planck scale physics. We note that in string theory the fuzzball structure of microstates does not give any place to 'continue through' this Planck regime. AMPS argue that interactions near the horizon preclude traditional complementarity. But the conjecture of 'fuzzball complementarity' works in the opposite way: the infalling quantum is absorbed by the fuzzball surface, and it is the resulting dynamics that is conjectured to admit a complementary description.Comment: 34 pages, 6 figures, v3: clarifications & references adde

    Timescale analysis of a mathematical model of acetaminophen metabolism andtoxicity

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    Acetaminophen is a widespread and commonly used painkiller all over the world. However, it can cause liver damage when taken in large doses or at repeated chronic doses. Current models of acetaminophen metabolism are complex, and limited to numerical investigation though provide results that represent clinical investigation well. We derive a mathematical model based on mass action laws aimed at capturing the main dynamics of acetaminophen metabolism, in particular the contrast between normal and overdose cases, whilst remaining simple enough for detailed mathematical analysis that can identify key parameters and quantify their role in liver toxicity. We use singular perturbation analysis to separate the di fferent timescales describing the sequence of events in acetaminophen metabolism, systematically identifying which parameters dominate during each of the successive stages. Using this approach we determined, in terms of the model parameters, the critical dose between safe and overdose cases, timescales for exhaustion and regeneration of important cofactors for acetaminophen metabolism and total toxin accumulation as a fraction of initial dose

    Preserving Liveness Guarantees from Synchronous Communication to Asynchronous Unstructured Low-Level Languages

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    In the implementation of abstract synchronous communication in asynchronous unstructured low-level languages, e.g. using shared variables, the preservation of safety and especially liveness properties is a hitherto open problem due to inherently different abstraction levels. Our approach to overcome this problem is threefold: First, we present our notion of handshake refinement with which we formally prove the correctness of the implementation relation of a handshake protocol. Second, we verify the soundness of our handshake refinement, i.e., all safety and liveness properties are preserved to the lower level. Third, we apply our handshake refinement to show the correctness of all implementations that realize the abstract synchronous communication with the handshake protocol. To this end, we employ an exemplary language with asynchronous shared variable communication. Our approach is scalable and closes the verification gap between different abstraction levels of communication

    Jet Trimming

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    Initial state radiation, multiple interactions, and event pileup can contaminate jets and degrade event reconstruction. Here we introduce a procedure, jet trimming, designed to mitigate these sources of contamination in jets initiated by light partons. This procedure is complimentary to existing methods developed for boosted heavy particles. We find that jet trimming can achieve significant improvements in event reconstruction, especially at high energy/luminosity hadron colliders like the LHC.Comment: 20 pages, 11 figures, 3 tables - Minor changes to text/figure
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