Antony Overstall, James McGree.

Source: Bayesian Analysis, Volume 15, Number 1, 103--131.

Abstract:
A Bayesian design is given by maximising an expected utility over a design space. The utility is chosen to represent the aim of the experiment and its expectation is taken with respect to all unknowns: responses, parameters and/or models. Although straightforward in principle, there are several challenges to finding Bayesian designs in practice. Firstly, the utility and expected utility are rarely available in closed form and require approximation. Secondly, the design space can be of high-dimensionality. In the case of intractable likelihood models, these problems are compounded by the fact that the likelihood function, whose evaluation is required to approximate the expected utility, is not available in closed form. A strategy is proposed to find Bayesian designs for intractable likelihood models. It relies on the development of an automatic, auxiliary modelling approach, using multivariate Gaussian process emulators, to approximate the likelihood function. This is then combined with a copula-based approach to approximate the marginal likelihood (a quantity commonly required to evaluate many utility functions). These approximations are demonstrated on examples of stochastic process models involving experimental aims of both parameter estimation and model comparison.

Haolun Shi, Guosheng Yin.

Source: Bayesian Analysis, Volume 14, Number 2, 399--425.

Abstract:
Bayesian approaches to phase II clinical trial designs are usually based on the posterior distribution of the parameter of interest and calibration of certain threshold for decision making. If the posterior probability is computed and assessed in a sequential manner, the design may involve the problem of multiplicity, which, however, is often a neglected aspect in Bayesian trial designs. To effectively maintain the overall type I error rate, we propose solutions to the problem of multiplicity for Bayesian sequential designs and, in particular, the determination of the cutoff boundaries for the posterior probabilities. We present both theoretical and numerical methods for finding the optimal posterior probability boundaries with $alpha$ -spending functions that mimic those of the frequentist group sequential designs. The theoretical approach is based on the asymptotic properties of the posterior probability, which establishes a connection between the Bayesian trial design and the frequentist group sequential method. The numerical approach uses a sandwich-type searching algorithm, which immensely reduces the computational burden. We apply least-square fitting to find the $alpha$ -spending function closest to the target. We discuss the application of our method to single-arm and double-arm cases with binary and normal endpoints, respectively, and provide a real trial example for each case.

London (33 Stillness Rd, London, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

London (33 Stillness Rd, London, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London (33 Stillness Rd, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London (33 Stillness Rd, London, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London (33 Stillness Rd, London, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair, Smoke-free Environment (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair (33 Stillness Rd, London, SE23 1NG), [1989?]

London : Cleanair (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair (33 Stillness Rd, London, SE23 1NG), [198-?]

London : Cleanair (33 Stillness Rd, London, SE23 1NG), [198-?]

London (33 Stillness Road London SE23 1NG) : Cleanair Campaign for a Smoke-free Environment, [198-?]

London (33 Stillness Road, London SE23 ING) : Cleanair, [198-?]

[London?], [199-?]

[London?], 6th November 1989.

London, 26 January 2003.

London, [29 January 1994]

Erin E. Hecht
Sep 25, 2019; 39:7748-7758
BehavioralSystemsCognitive

In today's evolving business environment, every operational decision is critical -- and that includes best practices for managing the customer journey. The CRM platform is an integral part of the process. In fact, 91 percent of companies with more than 11 employees use a CRM system. Because of the time it saves and the structure CRM delivers, it can seem daunting for businesses to make a switch.

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABA_A receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca²⁺ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABA_ARs synapses through a GABA receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.

SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca²⁺-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABA_A receptor synapses via Ca²⁺/calmodulin-dependent protein kinase II. Although Ca²⁺ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.

SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity at individual dendritic spines on hippocampal CA1 neurons from mice and rats of both sexes, we demonstrate that p38 MAPK is generally required downstream of non-ionotropic NMDAR signaling to drive both spine shrinkage and LTD. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP (nitric oxide synthase 1 adaptor protein) and neuronal nitric oxide synthase (nNOS), nNOS enzymatic activity, activation of MK2 (MAPK-activated protein kinase 2) and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that can drive shrinkage and elimination of dendritic spines during synaptic plasticity.

SIGNIFICANCE STATEMENT Signaling through the NMDA receptor (NMDAR) is vitally important for the synaptic plasticity that underlies learning. Recent studies highlight a novel role for the NMDAR, independent of ion flow, in driving synaptic weakening and dendritic spine shrinkage during synaptic plasticity. Here, we delineate several key components of the molecular pathway that links conformational signaling through the NMDAR to dendritic spine shrinkage during synaptic plasticity.

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