Fluoxetine: a case history of its discovery and preclinical development

Introduction: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine. Areas covered: The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment. Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetine’s effects on depressive-like behaviour, anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine. Expert opinion: Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved

How should we incentivize private landowners to "produce" more biodiversity?

Globally, much biodiversity is found on private land. Acting to conserve such biodiversity thus requires the design of policies which influence the decision-making of farmers and foresters. In this paper, we outline the economic characteristics of this problem, before reviewing a number of policy options such as conservation auctions and conservation easements. We then discuss a number of policy design problems, such as need for spatial coordination and the choice between paying for outcomes rather than actions, before summarizing what the evidence and theory developed to date tells us about those aspects of biodiversity policy design which need careful attention from policy makers and environmental regulators

Resourcing Scholar-Activism: Collaboration, Transformation, and the Production of Knowledge

In this article we offer a set of resources for scholar-activists to reflect on and guide their practice. We begin by suggesting that research questions should be triangulated to consider not only their scholarly merit but the intellectual and political projects the findings will advance and the research questions of interest to community and social movement collaborators

In-situ characterization of the Hamamatsu R5912-HQE photomultiplier tubes used in the DEAP-3600 experiment

The Hamamatsu R5912-HQE photomultiplier-tube (PMT) is a novel high-quantum efficiency PMT. It is currently used in the DEAP-3600 dark matter detector and is of significant interest for future dark matter and neutrino experiments where high signal yields are needed. We report on the methods developed for in-situ characterization and monitoring of DEAP's 255 R5912-HQE PMTs. This includes a detailed discussion of typical measured single-photoelectron charge distributions, correlated noise (afterpulsing), dark noise, double, and late pulsing characteristics. The characterization is performed during the detector commissioning phase using laser light injected through a light diffusing sphere and during normal detector operation using LED light injected through optical fibres

Measurement of the scintillation time spectra and pulse-shape discrimination of low-energy beta and nuclear recoils in liquid argon with DEAP-1

The DEAP-1 low-background liquid argon detector was used to measure scintillation pulse shapes of electron and nuclear recoil events and to demonstrate the feasibility of pulse-shape discrimination (PSD) down to an electron-equivalent energy of 20 keV. In the surface dataset using a triple-coincidence tag we found the fraction of beta events that are misidentified as nuclear recoils to be $<1.4\times 10^{-7}$ (90% C.L.) for energies between 43-86 keVee and for a nuclear recoil acceptance of at least 90%, with 4% systematic uncertainty on the absolute energy scale. The discrimination measurement on surface was limited by nuclear recoils induced by cosmic-ray generated neutrons. This was improved by moving the detector to the SNOLAB underground laboratory, where the reduced background rate allowed the same measurement with only a double-coincidence tag. The combined data set contains $1.23\times10^8$ events. One of those, in the underground data set, is in the nuclear-recoil region of interest. Taking into account the expected background of 0.48 events coming from random pileup, the resulting upper limit on the electronic recoil contamination is $<2.7\times10^{-8}$ (90% C.L.) between 44-89 keVee and for a nuclear recoil acceptance of at least 90%, with 6% systematic uncertainty on the absolute energy scale. We developed a general mathematical framework to describe PSD parameter distributions and used it to build an analytical model of the distributions observed in DEAP-1. Using this model, we project a misidentification fraction of approx. $10^{-10}$ for an electron-equivalent energy threshold of 15 keV for a detector with 8 PE/keVee light yield. This reduction enables a search for spin-independent scattering of WIMPs from 1000 kg of liquid argon with a WIMP-nucleon cross-section sensitivity of $10^{-46}$ cm$^2$, assuming negligible contribution from nuclear recoil backgrounds.Comment: Accepted for publication in Astroparticle Physic

A habituation account of change detection in same/different judgments

We investigated the basis of change detection in a short-term priming task. In two experiments, participants were asked to indicate whether or not a target word was the same as a previously presented cue. Data from an experiment measuring magnetoencephalography failed to find different patterns for “same” and “different” responses, consistent with the claim that both arise from a common neural source, with response magnitude defining the difference between immediate novelty versus familiarity. In a behavioral experiment, we tested and confirmed the predictions of a habituation account of these judgments by comparing conditions in which the target, the cue, or neither was primed by its presentation in the previous trial. As predicted, cue-primed trials had faster response times, and target-primed trials had slower response times relative to the neither-primed baseline. These results were obtained irrespective of response repetition and stimulus–response contingencies. The behavioral and brain activity data support the view that detection of change drives performance in these tasks and that the underlying mechanism is neuronal habituation

Development and testing scenarios for implementing land use and land cover changes during the Holocene in Earth system model experiments

Anthropogenic changes in land use and land cover (LULC) during the pre-industrial Holocene could have affected regional and global climate. Current LULC scenarios are based on relatively simple assumptions and highly uncertain estimates of population changes through time. Archaeological and palaeoenvironmental reconstructions have the potential to refine these assumptions and estimates. The Past Global Changes (PAGES) LandCover6k initiative is working towards improved reconstructions of LULC globally. In this paper, we document the types of archaeological data that are being collated and how they will be used to improve LULC reconstructions. Given the large methodological uncertainties involved, we propose methods to evaluate the revised scenarios by using independent pollen-based reconstructions of land cover and of climate. A further test involves carbon-cycle simulations to determine whether the LULC reconstructions are consistent with constraints provided by ice-core records of CO2 evolution and modern-day LULC. Finally, we outline a protocol for using the improved LULC reconstructions in palaeoclimate simulations within the framework of the Palaeoclimate Modelling Intercomparison Project in order to quantify the magnitude of anthropogenic impacts on climate through time and ultimately to improve the realism of Holocene climate simulations