Psychedelics and the Human Receptorome

We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT2A (and possibly 5-HT2C) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference work on the receptor affinity pharmacology of psychedelic drugs. New data is presented on the affinity of twenty-five psychedelic drugs at fifty-one receptors, transporters, and ion channels, assayed by the National Institute of Mental Health – Psychoactive Drug Screening Program (NIMH-PDSP). In addition, comparable data gathered from the literature on ten additional drugs is also presented (mostly assayed by the NIMH-PDSP). A new method is introduced for normalizing affinity (Ki) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted. The method is then used to compare the thirty-five drugs in graphical and tabular form. It is shown that psychedelic drugs, especially phenylalkylamines, are not as selective as generally believed, interacting with forty-two of forty-nine broadly assayed sites. The thirty-five drugs of the study have very diverse patterns of interaction with different classes of receptors, emphasizing eighteen different receptors. This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind

Dark Matter Annihilation Signatures from Electroweak Bremsstrahlung

We examine observational signatures of dark matter annihilation in the Milky Way arising from electroweak bremsstrahlung contributions to the annihilation cross section. It has been known for some time that photon bremsstrahlung may significantly boost DM annihilation yields. Recently, we have shown that electroweak bremsstrahlung of W and Z gauge bosons can be the dominant annihilation channel in some popular models with helicity-suppressed 2 --> 2 annihilation. W/Z-bremsstrahlung is particularly interesting because the gauge bosons produced via annihilation subsequently decay to produce large correlated fluxes of electrons, positrons, neutrinos, hadrons (including antiprotons) and gamma rays, which are all of importance in indirect dark matter searches. Here we calculate the spectra of stable annihilation products produced via gamma/W/Z-bremsstrahlung. After modifying the fluxes to account for the propagation through the Galaxy, we set upper bounds on the annihilation cross section via a comparison with observational data. We show that stringent cosmic ray antiproton limits preclude a sizable dark matter contribution to observed cosmic ray positron fluxes in the class of models for which the bremsstrahlung processes dominate.Comment: 11 pages, 6 figures. Updated to match PRD versio

Sensitivity of the Cherenkov Telescope Array to the detection of a dark matter signal in comparison to direct detection and collider experiments

Imaging atmospheric Cherenkov telescopes (IACTs) that are sensitive to potential $\gamma$-ray signals from dark matter (DM) annihilation above $\sim50$ GeV will soon be superseded by the Cherenkov Telescope Array (CTA). CTA will have a point source sensitivity an order of magnitude better than currently operating IACTs and will cover a broad energy range between 20 GeV and 300 TeV. Using effective field theory and simplified models to calculate $\gamma$-ray spectra resulting from DM annihilation, we compare the prospects to constrain such models with CTA observations of the Galactic center with current and near-future measurements at the Large Hadron Collider (LHC) and direct detection experiments. For DM annihilations via vector or pseudoscalar couplings, CTA observations will be able to probe DM models out of reach of the LHC, and, if DM is coupled to standard fermions by a pseudoscalar particle, beyond the limits of current direct detection experiments.Comment: Accepted for publication in PRD. 20 pages, 11 figure

Cauchy, infinitesimals and ghosts of departed quantifiers

Procedures relying on infinitesimals in Leibniz, Euler and Cauchy have been interpreted in both a Weierstrassian and Robinson's frameworks. The latter provides closer proxies for the procedures of the classical masters. Thus, Leibniz's distinction between assignable and inassignable numbers finds a proxy in the distinction between standard and nonstandard numbers in Robinson's framework, while Leibniz's law of homogeneity with the implied notion of equality up to negligible terms finds a mathematical formalisation in terms of standard part. It is hard to provide parallel formalisations in a Weierstrassian framework but scholars since Ishiguro have engaged in a quest for ghosts of departed quantifiers to provide a Weierstrassian account for Leibniz's infinitesimals. Euler similarly had notions of equality up to negligible terms, of which he distinguished two types: geometric and arithmetic. Euler routinely used product decompositions into a specific infinite number of factors, and used the binomial formula with an infinite exponent. Such procedures have immediate hyperfinite analogues in Robinson's framework, while in a Weierstrassian framework they can only be reinterpreted by means of paraphrases departing significantly from Euler's own presentation. Cauchy gives lucid definitions of continuity in terms of infinitesimals that find ready formalisations in Robinson's framework but scholars working in a Weierstrassian framework bend over backwards either to claim that Cauchy was vague or to engage in a quest for ghosts of departed quantifiers in his work. Cauchy's procedures in the context of his 1853 sum theorem (for series of continuous functions) are more readily understood from the viewpoint of Robinson's framework, where one can exploit tools such as the pointwise definition of the concept of uniform convergence. Keywords: historiography; infinitesimal; Latin model; butterfly modelComment: 45 pages, published in Mat. Stu

Two trans-acting eQTLs modulate the penetrance of PRPF31 mutations

Dominant mutations in the gene encoding the ubiquitously-expressed splicing factor PRPF31 cause retinitis pigmentosa, a form of hereditary retinal degeneration, with reduced penetrance. We and others have previously shown that penetrance is tightly correlated with PRPF31 expression, as lymphoblastoid cell lines (LCLs) from affected patients produce less abundant PRPF31 transcripts than LCLs from their unaffected relatives carrying the same mutation. We have investigated the genetic elements determining the variable expression of PRPF31, and therefore possibly influencing the penetrance of its mutations, by quantifying PRPF31 mRNA levels in LCLs derived from 15 CEPH families (200 individuals), representative of the general population. We found that PRPF31 transcript abundance was a highly variable and highly heritable character. Moreover, by linkage analysis we showed that PRPF31 expression was significantly associated with at least one expression quantitative trait locus (eQTL), spanning a 8.2-Mb region on chromosome 14q21-23. We also investigated a previously mapped penetrance factor located near PRPF31 itself in LCLs from individuals belonging to selected families segregating PRPF31 mutations that displayed reduced penetrance. Our results indicate that, despite its constant association with the non-mutant allele, this factor was able to modulate the expression of both PRPF31 alleles. Furthermore, we showed that LCLs from affected patients have less PRPF31 RNA than those of asymptomatic patients, even at the pre-splicing stage. Altogether, these data demonstrate that PRPF31 mRNA expression and consequently the penetrance of PRPF31 mutations is managed by diffusible compounds encoded by at least two modifiers, acting in a co-regulatory system on both PRPF31 alleles during transcriptio

Ultrasound Biosafety Considerations for the Practicing Sonographer and Sonologist

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135175/1/jum2009282139.pd

Adiposity, Cardiometabolic Risk, and Vitamin D Status: The Framingham Heart Study

OBJECTIVE: Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear. RESEARCH DESIGN AND METHODS: We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT). RESULTS: In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (−1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (−2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m2). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001). CONCLUSIONS: Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.National Institutes of Health's National Heart, Lung, and Blood Institute (N01-HC-25195, R01-DK-80739): American Heart Associatio

Methodology for studying strain inhomogeneities in polycrystalline thin films during in situ thermal loading using coherent x-ray diffraction

International audienceCoherent x-ray diffraction is used to investigate the mechanical properties of a single grain within a polycrystalline thin film in situ during a thermal cycle. Both the experimental approach and finite element simulation are described. Coherent diffraction from a single grain has been monitored in situ at different temperatures. This experiment offers unique perspectives for the study of the mechanical properties of nano-objects