Psychedelics as Medicines: An Emerging New Paradigm Nichols, DE; Johnson, MW; Nichols, CD
Clinical pharmacology and therapeutics,
February 2017, 2017-Feb, 2017-02-00, 20170201, Letnik:
101, Številka:
2
Journal Article
Recenzirano
Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5‐HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics ...with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation‐related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.
This paper examines the implications of using the absolute value of discretionary accruals when testing for earnings management. First, we analytically develop the mean and variance of the ...distribution of absolute discretionary accruals, and show that the expected value is an increasing function of the variance in the underlying error term from the first-stage discretionary accrual estimation model. Second, we highlight several firm characteristics that are related to the error variance in discretionary accrual estimation models. Using simulations, we show that correlation between the earns management partitioning variable and these firm characteristics leads to an overrejection of the null hypothesis of no earnings management. Third, we provide research design suggestions to help researchers mitigate the potential bias arising from the use of unsigned measures of earnings management. Using these suggestions, we replicate a recent study, and demonstrate that the inferences change after controlling for operating volatility.
Psilocybin has been shown to be a powerful, long-lasting antidepressant in human clinical trials and in rodent models. Although rodents have commonly been used to model psychiatric disorders, ...Drosophila have neurotransmitter systems similar to mammals and many comparable brain structures involved in similar behaviors. The forced swim test (FST), which has been used extensively to evaluate compounds for antidepressant efficacy, has recently been adapted for Drosophila. The fly FST has potential to be a cost-effective, high-throughput assay for evaluating potential antidepressants. For this study we pharmacologically validated the fly FST using methamphetamine, DL-α-methyltyrosine, and the antidepressant citalopram. While methamphetamine and DL-α-methyltyrosine altered overall locomotor activity in the Drosophila Activity Monitor System (DAMS), they had no significant impact on measures of immobility in the FST. Conversely, chronic citalopram decreased measures of immobility in the FST in both sexes without increasing DAMS activity. We used the validated FST to evaluate the antidepressant-like effects of high (3.5 mM) and low (0.03 mM) doses of psilocybin. Both doses of psilocybin significantly reduced measures of immobility in male flies, but not females. 0.03 mM had an effect size comparable to chronic citalopram, and 3.5 mM had an effect size approximately twice that of chronic citalopram.
We present calculations of the auroral radio powers expected from exoplanets with magnetospheres driven by an Earth-like magnetospheric interaction with the solar wind. Specifically, we compute the ...twin cell-vortical ionospheric flows, currents, and resulting radio powers resulting from a Dungey cycle process driven by dayside and nightside magnetic reconnection, as a function of planetary orbital distance and magnetic field strength. We include saturation of the magnetospheric convection, as observed at the terrestrial magnetosphere, and we present power-law approximations for the convection potentials, radio powers and spectral flux densities. We specifically consider a solar-age system and a young (1 Gyr) system. We show that the radio power increases with magnetic field strength for magnetospheres with saturated convection potential, and broadly decreases with increasing orbital distance. We show that the magnetospheric convection at hot Jupiters will be saturated, and thus unable to dissipate the full available incident Poynting flux, such that the magnetic Radiometric Bode's Law (RBL) presents a substantial overestimation of the radio powers for hot Jupiters. Our radio powers for hot Jupiters are ∼5–1300 TW for hot Jupiters with field strengths of 0.1–10 B
J orbiting a Sun-like star, while we find that competing effects yield essentially identical powers for hot Jupiters orbiting a young Sun-like star. However, in particular, for planets with weaker magnetic fields, our powers are higher at larger orbital distances than given by the RBL, and there are many configurations of planet that are expected to be detectable using SKA.
Tumor necrosis factor alpha (TNF-α) plays a key role in inflammation, and its production and signaling contribute to many inflammatory related diseases. Recently, we discovered that selective ...activation of serotonin 5-HT2A receptors with the agonist (R)-DOI produces a super-potent blockade of proinflammatory markers in primary rat aortic smooth muscle cells. Here, we demonstrate that systemic administration of (R)-DOI can block the systemic effects of TNF-α in whole animal, with potent anti-inflammatory effects in the aortic arch and small intestine. This includes blockade of TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1), cytokine (Il-6, IL-1b), and chemokine (Mcp-1, Cx3cl1) genes, and expression of VCAM-1 protein in the intestine. Further, systemic (R)-DOI also prevents the TNF-α-induced increase of circulating IL-6. Importantly, utilizing receptor selective antagonists, we have demonstrated that the mechanism underlying the systemic anti-inflammatory effects of (R)-DOI is activation of serotonin 5-HT2A receptors. Our results highlight a powerful new role for the serotonin 5-HT2A receptor in inflammatory processes, and indicate that agonism of serotonin receptors may represent an effective and novel approach to develop powerful small molecule therapeutics for inflammatory diseases and conditions such as atherosclerosis and inflammatory bowel disease.
Monitoring for conservation Nichols, James D.; Williams, Byron K.
Trends in ecology & evolution (Amsterdam),
12/2006, Letnik:
21, Številka:
12
Journal Article
Recenzirano
Human-mediated environmental changes have resulted in appropriate concern for the conservation of ecological systems and have led to the development of many ecological monitoring programs worldwide. ...Many programs that are identified with the purpose of ‘surveillance’ represent an inefficient use of conservation funds and effort. Here, we revisit the 1964 paper by Platt and argue that his recommendations about the conduct of science are equally relevant to the conduct of ecological monitoring programs. In particular, we argue that monitoring should not be viewed as a stand-alone activity, but instead as a component of a larger process of either conservation-oriented science or management. Corresponding changes in monitoring focus and design would lead to substantial increases in the efficiency and usefulness of monitoring results in conservation.
Inflammasomes are cytosolic multi-protein complexes that detect infection or cellular damage and activate the Caspase-1 (CASP1) protease. The NAIP5/NLRC4 inflammasome detects bacterial flagellin and ...is essential for resistance to the flagellated intracellular bacterium Legionella pneumophila. The effectors required downstream of NAIP5/NLRC4 to restrict bacterial replication remain unclear. Upon NAIP5/NLRC4 activation, CASP1 cleaves and activates the pore-forming protein Gasdermin-D (GSDMD) and the effector caspase-7 (CASP7). However, Casp1-/- (and Casp1/11-/-) mice are only partially susceptible to L. pneumophila and do not phenocopy Nlrc4-/-mice, because NAIP5/NLRC4 also activates CASP8 for restriction of L. pneumophila infection. Here we show that CASP8 promotes the activation of CASP7 and that Casp7/1/11-/- and Casp8/1/11-/- mice recapitulate the full susceptibility of Nlrc4-/- mice. Gsdmd-/- mice exhibit only mild susceptibility to L. pneumophila, but Gsdmd-/-Casp7-/- mice are as susceptible as the Nlrc4-/- mice. These results demonstrate that GSDMD and CASP7 are the key substrates downstream of NAIP5/NLRC4/CASP1/8 required for resistance to L. pneumophila.
We describe an approach for estimating occupancy rate or the proportion of area occupied when heterogeneity in detection probability exists as a result of variation in abundance of the organism under ...study. The key feature of such problems, which we exploit, is that variation in abundance induces variation in detection probability. Thus, heterogeneity in abundance can be modeled as heterogeneity in detection probability. Moreover, this linkage between heterogeneity in abundance and heterogeneity in detection probability allows one to exploit a heterogeneous detection probability model to estimate the underlying distribution of abundances. Therefore, our method allows estimation of abundance from repeated observations of the presence or absence of animals without having to uniquely mark individuals in the population.
Thraustochytrids were first discovered in 1934, and since the 1960's they have been increasingly studied for their beneficial and deleterious effects. This review aims to provide an enhanced ...understanding of these protists with a particular emphasis on their taxonomy, ecology and biotechnology applications. Over the years, thraustochytrid taxonomy has improved with the development of modern molecular techniques and new biochemical markers, resulting in the isolation and description of new strains. In the present work, the taxonomic history of thraustochytrids is reviewed, while providing an up-to-date classification of these organisms. It also describes the various biomarkers that may be taken into consideration to support taxonomic characterization of the thraustochytrids, together with a review of traditional and modern techniques for their isolation and molecular identification. The originality of this review lies in linking taxonomy and ecology of the thraustochytrids and their biotechnological applications as producers of docosahexaenoic acid (DHA), carotenoids, exopolysaccharides and other compounds of interest. The paper provides a summary of these aspects while also highlighting some of the most important recent studies in this field, which include the diversity of polyunsaturated fatty acid metabolism in thraustochytrids, some novel strategies for biomass production and recovery of compounds of interest. Furthermore, a detailed overview is provided of the direct and current applications of thraustochytrid-derived compounds in the food, fuel, cosmetic, pharmaceutical, and aquaculture industries and of some of the commercial products available. This review is intended to be a source of information and references on the thraustochytrids for both experts and those who are new to this field.
Athletic performance data are modeled in an effort to better understand the relationship between both hours spent training and a measurement of “commitment” to that training, and improvements in ...performance. Both increased training time and greater commitment were predicted to produce larger increases in performance improvement, and commitment was predicted to be the more important determinant of improvement. The performance of 108 soccer players (ages 9–18) was quantified over a 10-week training program. Hours spent training ranged from 16 to 90 during the course of the study, while commitment scores ranged from 0.55 to 2.00, based on a scale from 0.00 to 2.40. A model selection approach was used to discriminate among models specifying relationships between training hours and improvement, and commitment and improvement. Despite considerable variability in the data, results provided strong evidence for an increase in performance improvement with both training hours and commitment score. The best models for hours and commitment were directly compared by computing an evidence ratio of 5799, indicating much stronger evidence favoring the model based on commitment. Results of analyses such as these go beyond anecdotal experience in an effort to establish a formal evidentiary basis for athletic training programs.
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