Psychedelics

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network

Boundary changing operators in the O(n) matrix model

We continue the study of boundary operators in the dense O(n) model on the random lattice. The conformal dimension of boundary operators inserted between two JS boundaries of different weight is derived from the matrix model description. Our results are in agreement with the regular lattice findings. A connection is made between the loop equations in the continuum limit and the shift relations of boundary Liouville 3-points functions obtained from Boundary Ground Ring approach.Comment: 31 pages, 4 figures, Introduction and Conclusion improve

Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated

At first glance, it appears there is little difference between the molecular structures of methylenedioxymethamphetamine (MDMA), which has an N-methyl attached to its amino group, and methylenedioxyamphetamine (MDA), a primary amine that is recognized to have hallucinogenic activity. It is known from studies with other hallucinogenic amphetamines that N-methylation of hallucinogenic amphetamines attenuates or abolishes hallucinogenic activity. Nevertheless, MDMA is biologically active and has a potency only slightly less than its MDA parent. Importantly, it is the Ievo-isomer of hallucinogenic phenethylamines that is more biologically active, whereas it is the dextro isomer of MDMA that is more active. This reversal of stereochemistry for the activity of two very closely related molecules is a very powerful clue that their mechanisms of action differ. Finally, extension of the alpha-methyl of hallucinogenic amphetamines to an alpha-ethyl moiety completely abolishes their hallucinogenic activity. Ultimately, we extended the alpha-methyl group of MDMA to an alpha-ethyl to afford a molecule we named (N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) that retained significant MDMA-like psychoactivity. Hence, there are three structural features that distinguish MDMA from the hallucinogenic amphetamines: (1) the N-methyl on the basic nitrogen, (2) the reversal of stereochemistry and, (3) tolerance of an alpha-ethyl moiety as contrasted with the alpha-methyl of hallucinogenic phenethylamines. Clearly, MDMA is distinct from classical hallucinogenic phenethylamines in its structure, and its psychopharmacology is also unique. Thus, in 1986 I proposed the name “Entactogen” for the pharmacological class of drugs that includes 3,4-methylenedioxymethamphetamine (MDMA) and other substances with a similar psychopharmacological effect. The name is derived from roots that indicate that entactogens produce a “touching within.” Rather than having significant psychostimulant, or hallucinogenic effects, MDMA powerfully promotes affiliative social behavior, has acute anxiolytic effects, and can lead to profound states of introspection and personal reflection. Its mechanism of action is now established as involving transport of MDMA by the neuronal serotonin reuptake carrier followed by carrier-mediated release of stored neuronal serotonin

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Herein, we test the present iteration of the vibrational theory of protein activation by comparing predictions obtained from Turin’s vibrational theory for the activation of olfactory receptors measuring affinity and activation at a nonolfactory receptor family of G protein-coupled receptors. This was done at the CNS serotonin receptor family h5-HT2 and with both the 2,5-dimethoxy-4-iodoamphetamine and N,N-dimethyllysergamide agonists. Invalidation was performed through a comparative analysis of agonist behavior between isotopologues

inbreedR: An R package for the analysis of inbreeding based on genetic markers

1. Heterozygosity fitness correlations (HFCs) have been used extensively to explore the impact of inbreeding on individual fitness. Initially, most studies used small panels of microsatellites, but more recently with the advent of next generation sequencing, large SNP datasets are becoming increasingly available and these provide greater power and precision to quantify the impact of inbreeding on fitness. 2. Despite the popularity of HFC studies, effect sizes tend to be rather small. One reason for this may be a low variation in inbreeding level across individuals. Using genetic markers, it is possible to measure variance in inbreeding through the strength of correlation in heterozygosity across marker loci, termed identity disequilibrium (ID). 3. ID can be quantified using the measure g2 which is also a central parameter in HFC theory that can be used within a wider framework to estimate the direct impact of inbreeding on both marker heterozygosity and fitness. However, no software exists to calculate g2 for large SNP datasets nor to implement this framework. 4. inbreedR is an R package that provides functions to calculate g2 based on microsatellite and SNP markers with associated p-values and confidence intervals. Within the framework of HFC theory, inbreedR also estimates the impact of inbreeding on marker heterozygosity and fitness. Moreover, we implemented easy-to-use simulations to explore the precision and magnitude of estimates based on different numbers of genetic markers. We hope this package will facilitate good practice in the analysis of HFCs and help to deepen our understanding of inbreeding effects in natural populations

Fast and powerful heritability inference for family-based neuroimaging studies.

Heritability estimation has become an important tool for imaging genetics studies. The large number of voxel- and vertex-wise measurements in imaging genetics studies presents a challenge both in terms of computational intensity and the need to account for elevated false positive risk because of the multiple testing problem. There is a gap in existing tools, as standard neuroimaging software cannot estimate heritability, and yet standard quantitative genetics tools cannot provide essential neuroimaging inferences, like family-wise error corrected voxel-wise or cluster-wise P-values. Moreover, available heritability tools rely on P-values that can be inaccurate with usual parametric inference methods. In this work we develop fast estimation and inference procedures for voxel-wise heritability, drawing on recent methodological results that simplify heritability likelihood computations (Blangero et al., 2013). We review the family of score and Wald tests and propose novel inference methods based on explained sum of squares of an auxiliary linear model. To address problems with inaccuracies with the standard results used to find P-values, we propose four different permutation schemes to allow semi-parametric inference (parametric likelihood-based estimation, non-parametric sampling distribution). In total, we evaluate 5 different significance tests for heritability, with either asymptotic parametric or permutation-based P-value computations. We identify a number of tests that are both computationally efficient and powerful, making them ideal candidates for heritability studies in the massive data setting. We illustrate our method on fractional anisotropy measures in 859 subjects from the Genetics of Brain Structure study

Prediction of Critical Power and W′ in Hypoxia: Application to Work-Balance Modelling

Purpose: Develop a prediction equation for critical power (CP) and work above CP (W′) in hypoxia for use in the work-balance ([Formula: see text]) model. Methods: Nine trained male cyclists completed cycling time trials (TT; 12, 7, and 3 min) to determine CP and W′ at five altitudes (250, 1,250, 2,250, 3,250, and 4,250 m). Least squares regression was used to predict CP and W′ at altitude. A high-intensity intermittent test (HIIT) was performed at 250 and 2,250 m. Actual and predicted CP and W′ were used to compute W′ during HIIT using differential ([Formula: see text]) and integral ([Formula: see text]) forms of the [Formula: see text] model. Results: CP decreased at altitude (P < 0.001) as described by 3rd order polynomial function (R(2) = 0.99). W′ decreased at 4,250 m only (P < 0.001). A double-linear function characterized the effect of altitude on W′ (R(2) = 0.99). There was no significant effect of parameter input (actual vs. predicted CP and W′) on modelled [Formula: see text] at 2,250 m (P = 0.24). [Formula: see text] returned higher values than [Formula: see text] throughout HIIT (P < 0.001). During HIIT, [Formula: see text] was not different to 0 kJ at completion, at 250 m (0.7 ± 2.0 kJ; P = 0.33) and 2,250 m (−1.3 ± 3.5 kJ; P = 0.30). However, [Formula: see text] was lower than 0 kJ at 250 m (−0.9 ± 1.3 kJ; P = 0.058) and 2,250 m (−2.8 ± 2.8 kJ; P = 0.02). Conclusion: The altitude prediction equations for CP and W′ developed in this study are suitable for use with the [Formula: see text] model in acute hypoxia. This enables the application of [Formula: see text] modelling to training prescription and competition analysis at altitude

Structure of the PII signal transduction protein of Neisseria meningitidis at 1.85 Å resolution

The structure of the PII signal transduction protein of N. meningitidis at 1.85 Å resolution is described

Genetic Introgression and the Survival of Florida Panther Kittens

Estimates of survival for the young of a species are critical for population models. These models can often be improved by determining the effects of management actions and population abundance on this demographic parameter. We used multiple sources of data collected during 1982–2008 and a live-recapture dead-recovery modeling framework to estimate and model survival of Florida panther (Puma concolor coryi) kittens (age 0–1 year). Overall, annual survival of Florida panther kittens was 0.323 ± 0.071 (SE), which was lower than estimates used in previous population models. In 1995, female pumas from Texas (P. c. stanleyana) were released into occupied panther range as part of an intentional introgression program to restore genetic variability. We found that kitten survival generally increased with degree of admixture: F1 admixed and backcrossed to Texas kittens survived better than canonical Florida panther and backcrossed to canonical kittens. Average heterozygosity positively influenced kitten and older panther survival, whereas index of panther abundance negatively influenced kitten survival. Our results provide strong evidence for the positive population-level impact of genetic introgression on Florida panthers. Our approach to integrate data from multiple sources was effective at improving robustness as well as precision of estimates of Florida panther kitten survival, and can be useful in estimating vital rates for other elusive species with sparse data