Pharmacokinetics of delta-9-tetrahydrocannabinol following acute cannabis smoke exposure in mice; effects of sex, age, and strain

Increased use of cannabis and cannabinoids for recreational and medical purposes has led to a growth in research on their effects in animal models. The majority of this work has employed cannabinoid injections; however, smoking remains the most common route of cannabis consumption. To better model real-world cannabis use, we exposed mice to cannabis smoke to establish the pharmacokinetics of Δ9THC and its metabolites in plasma and brain. To determine the time course of Δ9THC and two major metabolites [11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (11-COOH-THC)], male and female C57BL/6J mice were exposed to smoke from sequentially burning 5 cannabis cigarettes. Following smoke exposure, trunk blood and brains were collected at 6 time points (10–240 min). Plasma and brain homogenates were analyzed for Δ9THC and metabolites using a validated ultraperformance liquid chromatography-tandem mass spectrometry method. To assess effects of age, sex, and mouse strain, we exposed mice of four strains (C57BL/6J, FVB, Swiss Webster, and 129S6/SvEv, aged 4–24 months) to cannabis using the same smoke regimen. Samples were collected 10 and 40 min following exposure. Lastly, to assess effects of dose, C57BL/6J mice were exposed to smoke from burning 3 or 5 cannabis cigarettes, with samples collected 40 min following exposure. The pharmacokinetic study revealed that maximum plasma Δ9THC concentrations (Cmax) were achieved at 10 and 40 min for males and females, respectively, while Cmax for brain Δ9THC was observed at 20 and 40 min for males and females, respectively. There were no age or strain differences in plasma Δ9THC concentrations at 10 or 40 min; however, 129S6/SvEv mice had significantly higher brain Δ9THC concentrations than FVB mice. Additionally, 3 cigarettes produced significantly lower plasma 11-COOH-THC concentrations compared to 5 cigarettes, although dose differences were not evident in plasma or brain concentrations of Δ9THC or 11-OH-THC. Across all experiments, females had higher levels of 11-COOH-THC in plasma compared to males. The results reveal robust sex differences in Δ9THC pharmacokinetics, and lay the groundwork for future studies using mice to model the pharmacodynamics of smoked cannabis

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25–44%; P \u3c 3 × 10−14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p \u3c 3 × 10−9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p \u3c6× 10−6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p \u3c 7.1 × 10−10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation

Association of protein function-altering variants with cardiometabolic traits:the strong heart study

Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), similar to 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p= 8 x 10(-9)) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p= 2.1 x 10(-6); TRPM3, rs760461668, p= 5 x10(-8); SPTY2D1, rs756851199, p= 1.6 x 10(-8); and TSPO, rs566547284, p= 2.4 x 10(-6)). PHIL encoded protein is involved in pancreatic beta-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic beta-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories

Einstein-Yang-Mills Theory with a Massive Dilaton and Axion: String-Inspired Regular and Black Hole Solutions

We study the classical theory of a non-Abelian gauge field (gauge group $SU(2)$) coupled to a massive dilaton, massive axion and Einstein gravity. The theory is inspired by the bosonic part of the low-energy heterotic string action for a general Yang-Mills field, which we consider to leading order after compactification to $(3+1)$ dimensions. We impose the condition that spacetime be static and spherically symmetric, and we introduce masses via a dilaton-axion potential associated with supersymmetry (SUSY)-breaking by gaugino condensation in the hidden sector. In the course of describing the possible non-Abelian solutions of the simplified theory, we consider in detail two candidates: a massive dilaton coupled to a purely magnetic Yang-Mills field, and a massive axion field coupled to a non-Abelian dyonic configuration, in which the electric and magnetic fields decay too rapidly to correspond to any global gauge charge. We discuss the feasibility of solutions with and without a nontrivial dilaton for the latter case, and present numerical regular and black hole solutions for the former.Comment: 44 page

ReQON: a Bioconductor package for recalibrating quality scores from next-generation sequencing data

AbstractBackgroundNext-generation sequencing technologies have become important tools for genome-wide studies. However, the quality scores that are assigned to each base have been shown to be inaccurate. If the quality scores are used in downstream analyses, these inaccuracies can have a significant impact on the results.ResultsHere we present ReQON, a tool that recalibrates the base quality scores from an input BAM file of aligned sequencing data using logistic regression. ReQON also generates diagnostic plots showing the effectiveness of the recalibration. We show that ReQON produces quality scores that are both more accurate, in the sense that they more closely correspond to the probability of a sequencing error, and do a better job of discriminating between sequencing errors and non-errors than the original quality scores. We also compare ReQON to other available recalibration tools and show that ReQON is less biased and performs favorably in terms of quality score accuracy.ConclusionReQON is an open source software package, written in R and available through Bioconductor, for recalibrating base quality scores for next-generation sequencing data. ReQON produces a new BAM file with more accurate quality scores, which can improve the results of downstream analysis, and produces several diagnostic plots showing the effectiveness of the recalibration

ReQON: a Bioconductor package for recalibrating quality scores from next-generation sequencing data

Background Next-generation sequencing technologies have become important tools for genome-wide studies. However, the quality scores that are assigned to each base have been shown to be inaccurate. If the quality scores are used in downstream analyses, these inaccuracies can have a significant impact on the results. Results Here we present ReQON, a tool that recalibrates the base quality scores from an input BAM file of aligned sequencing data using logistic regression. ReQON also generates diagnostic plots showing the effectiveness of the recalibration. We show that ReQON produces quality scores that are both more accurate, in the sense that they more closely correspond to the probability of a sequencing error, and do a better job of discriminating between sequencing errors and non-errors than the original quality scores. We also compare ReQON to other available recalibration tools and show that ReQON is less biased and performs favorably in terms of quality score accuracy. Conclusion ReQON is an open source software package, written in R and available through Bioconductor, for recalibrating base quality scores for next-generation sequencing data. ReQON produces a new BAM file with more accurate quality scores, which can improve the results of downstream analysis, and produces several diagnostic plots showing the effectiveness of the recalibration

Low-Cost Access to the Deep, High-Cadence Sky: the Argus Optical Array

New mass-produced, wide-field, small-aperture telescopes have the potential to revolutionize ground-based astronomy by greatly reducing the cost of collecting area. In this paper, we introduce a new class of large telescope based on these advances: an all-sky, arcsecond-resolution, 1000-telescope array which builds a simultaneously high-cadence and deep survey by observing the entire sky all night. As a concrete example, we describe the Argus Array, a 5m-class telescope with an all-sky field of view and the ability to reach extremely high cadences using low-noise CMOS detectors. Each 55 GPix Argus exposure covers 20% of the entire sky to g=19.6 each minute and g=21.9 each hour; a high-speed mode will allow sub-second survey cadences for short times. Deep coadds will reach g=23.6 every five nights over 47% of the sky; a larger-aperture array telescope, with an \'etendue close to the Rubin Observatory, could reach g=24.3 in five nights. These arrays can build two-color, million-epoch movies of the sky, enabling sensitive and rapid searches for high-speed transients, fast-radio-burst counterparts, gravitational-wave counterparts, exoplanet microlensing events, occultations by distant solar system bodies, and myriad other phenomena. An array of O(1,000) telescopes, however, would be one of the most complex astronomical instruments yet built. Standard arrays with hundreds of tracking mounts entail thousands of moving parts and exposed optics, and maintenance costs would rapidly outpace the mass-produced-hardware cost savings compared to a monolithic large telescope. We discuss how to greatly reduce operations costs by placing all optics in a thermally controlled, sealed dome with a single moving part. Coupled with careful software scope control and use of existing pipelines, we show that the Argus Array could become the deepest and fastest Northern sky survey, with total costs below $20M.Comment: 17 pages, 5 figures, 2 table

Germline Analysis from Tumor–Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings

To evaluate germline variants in hereditary cancer susceptibility genes among unselected cancer patients undergoing tumor-germline sequencing

Gravitational collapse and thermalization in the hard wall model

We study a simple example of holographic thermalization in a confining field theory: the homogeneous injection of energy in the hard wall model. Working in an amplitude expansion, we find black brane formation for sufficiently fast energy injection and a scattering wave solution for sufficiently slow injection. We comment on our expectations for more sophisticated holographic QCD models.Comment: 33 pages, 5 figure

A Simple Standard for Sharing Ontological Mappings (SSSOM).

Despite progress in the development of standards for describing and exchanging scientific information, the lack of easy-to-use standards for mapping between different representations of the same or similar objects in different databases poses a major impediment to data integration and interoperability. Mappings often lack the metadata needed to be correctly interpreted and applied. For example, are two terms equivalent or merely related? Are they narrow or broad matches? Or are they associated in some other way? Such relationships between the mapped terms are often not documented, which leads to incorrect assumptions and makes them hard to use in scenarios that require a high degree of precision (such as diagnostics or risk prediction). Furthermore, the lack of descriptions of how mappings were done makes it hard to combine and reconcile mappings, particularly curated and automated ones. We have developed the Simple Standard for Sharing Ontological Mappings (SSSOM) which addresses these problems by: (i) Introducing a machine-readable and extensible vocabulary to describe metadata that makes imprecision, inaccuracy and incompleteness in mappings explicit. (ii) Defining an easy-to-use simple table-based format that can be integrated into existing data science pipelines without the need to parse or query ontologies, and that integrates seamlessly with Linked Data principles. (iii) Implementing open and community-driven collaborative workflows that are designed to evolve the standard continuously to address changing requirements and mapping practices. (iv) Providing reference tools and software libraries for working with the standard. In this paper, we present the SSSOM standard, describe several use cases in detail and survey some of the existing work on standardizing the exchange of mappings, with the goal of making mappings Findable, Accessible, Interoperable and Reusable (FAIR). The SSSOM specification can be found at http://w3id.org/sssom/spec. Database URL: http://w3id.org/sssom/spec