494 research outputs found

    Upward synaptic scaling is dependent on neurotransmission rather than spiking

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    Homeostatic plasticity encompasses a set of mechanisms that are thought to stabilize firing rates in neural circuits. The most widely studied form of homeostatic plasticity is upward synaptic scaling (upscaling), characterized by a multiplicative increase in the strength of excitatory synaptic inputs to a neuron as a compensatory response to chronic reductions in firing rate. While reduced spiking is thought to trigger upscaling, an alternative possibility is that reduced glutamatergic transmission generates this plasticity directly. However, spiking and neurotransmission are tightly coupled, so it has been difficult to determine their independent roles in the scaling process. Here we combined chronic multielectrode recording, closed-loop optogenetic stimulation, and pharmacology to show that reduced glutamatergic transmission directly triggers cell-wide synaptic upscaling. This work highlights the importance of synaptic activity in initiating signalling cascades that mediate upscaling. Moreover, our findings challenge the prevailing view that upscaling functions to homeostatically stabilize firing rates.National Science Foundation (U.S.). Graduate Research Fellowship (09-603)National Science Foundation (U.S.). Graduate Research Fellowship (08-593)National Science Foundation (U.S.). Integrative Graduate Education and Research Traineeship (Fellowship DGE-0333411)Emory University (NI SPINR Fellowship

    Stimulus-evoked high frequency oscillations are present in neuronal networks on microelectrode arrays

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    Pathological high frequency oscillations (250–600 Hz) are present in the brains of epileptic animals and humans. The etiology of these oscillations and how they contribute to the diseased state remains unclear. This work identifies the presence of microstimulation-evoked high frequency oscillations (250–400 Hz) in dissociated neuronal networks cultured on microelectrode arrays (MEAs). Oscillations are more apparent with higher stimulus voltages. As with in vivo studies, activity is isolated to a single electrode, however, the MEA provides improved spatial resolution with no spread of the oscillation to adjacent electrodes 200 μm away. Oscillations develop across four weeks in vitro. Oscillations still occur in the presence of tetrodotoxin and synaptic blockers, and they cause no apparent disruption in the ability of oscillation-presenting electrodes to elicit directly evoked action potentials (dAPs) or promote the spread of synaptic activity throughout the culture. Chelating calcium with ethylene glycol tetraacetic acid (EGTA) causes a temporal prolongation of the oscillation. Finally, carbenoxolone significantly reduces or eliminates the high frequency oscillations. Gap junctions may play a significant role in maintaining the oscillation given the inhibitory effect of carbenoxolone, the propagating effect of reduced calcium conditions and the isolated nature of the activity as demonstrated in previous studies. This is the first demonstration of stimulus-evoked high frequency oscillations in dissociated cultures. Unlike current models that rely on complex in vivo recording conditions, this work presents a simple controllable model in neuronal cultures on MEAs to further investigate how the oscillations occur at the molecular level and how they may contribute to the pathophysiology of disease

    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

    The flexibility of industrial additive manufacturing systems

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    Purpose Flexibility is a fundamental performance objective for manufacturing operations, allowing them to respond to changing requirements in uncertain and competitive global markets. Additive manufacturing machines are often described as “flexible,” but there is no detailed understanding of such flexibility in an operations management context. The purpose of this paper is to examine flexibility from a manufacturing systems perspective, demonstrating the different competencies that can be achieved and the factors that can inhibit these in commercial practice. Design/methodology/approach This study extends existing flexibility theory in the context of an industrial additive manufacturing system through an investigation of 12 case studies, covering a range of sectors, product volumes, and technologies. Drawing upon multiple sources, this research takes a manufacturing systems perspective that recognizes the multitude of different resources that, together with individual industrial additive manufacturing machines, contribute to the satisfaction of demand. Findings The results show that the manufacturing system can achieve seven distinct internal flexibility competencies. This ability was shown to enable six out of seven external flexibility capabilities identified in the literature. Through a categorical assessment the extent to which each competency can be achieved is identified, supported by a detailed explanation of the enablers and inhibitors of flexibility for industrial additive manufacturing systems. Originality/value Additive manufacturing is widely expected to make an important contribution to future manufacturing, yet relevant management research is scant and the flexibility term is often ambiguously used. This research contributes the first detailed examination of flexibility for industrial additive manufacturing systems

    "I'm a bit concerned" - early actions and psychological constructions in a child protection helpline

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    This article analyzes early actions in 50 calls reporting cases of abuse to a national child protection helpline in the UK (the National Society for the Prevention of Cruelty to Children Helpline, NSPCC). It focuses on the early turns in the caller's reason for call, in particular, a class of constructions in which the caller describes himself or herself as "concerned about x" (or similar). Analysis of the corpus of calls suggests concern constructions are canonical early elements of the reason-for-call sequence. Concern constructions (a) are oriented to a pre-move in the caller's reason for call, (b) project the unpacking of concerns in a way oriented to the NSPCCs institutional role, (c) attend to epistemological asymmetries between caller and call taker and remove the requirement for disaffiliative next actions such as asking for the basis of claims, (d) provide a way for the Child Protection Officer to take abuse claims seriously while not presupposing their truth, and (e) display an appropriate caller stance. These observations are supported by an analysis of deviant cases. The broader implications of this study for the relation between psychology, interaction, and institutions are discussed
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