Englishhaaning8760

Rodents can successfully learn multiple, novel stimulus-response associations after only a few repetitions when the contingencies predict reward. The circuits modified during such reinforcement learning to support decision making are not known, but the olfactory tubercle (OT) and posterior piriform cortex (pPC) are candidates for decoding reward category from olfactory sensory input and relaying this information to cognitive and motor areas. Through single-cell recordings in behaving male and female C57BL/6 mice, we show here that an explicit representation for reward category emerges in the OT within minutes of learning a novel odor-reward association, whereas the pPC lacks an explicit representation even after weeks of overtraining. The explicit reward category representation in OT is visible in the first sniff (50-100ms) of an odor on each trial, and precedes the motor action. Together, these results suggest that coding of stimulus information required for reward prediction does not occur within olfactory cortex, but rather in circuits involving the olfactory striatum.Significance StatementRodents are olfactory specialists and can use odors to learn contingencies quickly and well. We have found that mice can readily learn to place multiple odors into rewarded and unrewarded categories. Once they have learned the rule, they can do such categorization in a matter of minutes (less than 10 trials). We found that neural activity in olfactory cortex largely reflects sensory coding, with very little explicit information about categories. By contrast, neural activity in a brain region in the ventral striatum is rapidly modified in a matter of minutes to reflect reward category. Our experiments set up a paradigm for studying rapid sensorimotor reinforcement in a circuit that is right at the interface of sensory input and reward areas. Copyright © 2020 Millman and Murthy.The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, α2δ-1 or Cava2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The α2δ-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that α2δ-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDA-sensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to α2δ-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. SIGNIFICANCE STATEMENT It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the α2δ-1 protein. However, recent findings show that the α2δ-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects. The American Society for Pharmacology and Experimental Therapeutics.BACKGROUND Valuable information for planning future end-of-life care (EOLC) services and care facilities can be gained by studying trends in place of death (POD). Scarce data exist on the POD in small developing countries. This study aims to examine shifts in the POD of all persons dying between 1999 and 2010 in Trinidad and Tobago, to draw conclusions about changes in the distribution of POD over time and the possible implications for EOLC practice and policy. METHODS A population-level analysis of routinely collected death certificate data of the most recent available fully coded years at the time of the study-1999 to 2010. Observed proportions for the POD of all deaths were standardised according to the age, sex and cause of death distribution in 1999. Mavoglurant Trends for a subgroup of persons who died from causes indicative of a palliative care (PC) need were also examined. RESULTS The proportion of deaths in government hospitals increased from 48.9% to 55.4% and decreased from 38.7% to 29.7% at private homes. There was little variation between observed and standardised rates. The decrease in home deaths was stronger when the PC subcategory was considered, most notably from cancer. CONCLUSION Internationally, the proportion of deaths at institutions is increasing. A national strategy on palliative and EOLC is needed to facilitate the increasing number of people who seek EOLC at government hospitals in Trinidad and Tobago, including an investigation into the reasons for the trend. Alternatives to accommodate out-of-hospital deaths can be considered. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Label-Free Quantitative mass spectrometry based workflows for differential expression (DE) analysis of proteins impose important challenges on the data analysis due to peptide-specific effects and context dependent missingness of peptide intensities. Peptide-based workflows, like MSqRob, test for DE directly from peptide intensities and outperform summarization methods which first aggregate MS1 peptide intensities to protein intensities before DE analysis. However, these methods are computationally expensive, often hard to understand for the non-specialised end-user, and do not provide protein summaries, which are important for visualisation or downstream processing. In this work, we therefore evaluate state-of-the-art summarization strategies using a benchmark spike-in dataset and discuss why and when these fail compared to the state-of-the-art peptide based model, MSqRob. Based on this evaluation, we propose a novel summarization strategy, MSqRobSum, which estimates MSqRob's model parameters in a two-stage procedure circumventing the drawbacks of peptide-based workflows.