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

Development and evaluation of a remote training strategy for the implementation of mental health evidence-based practices in rural schools: pilot study protocol.

BACKGROUND: An increasing number of schools in rural settings are implementing multi-tier positive behavioral interventions and supports (PBIS) to address school-climate problems. PBIS can be used to provide the framework for the implementation of evidence-based practices (EBPs) to address children\u27s mental health concerns. Given the large service disparities for children in rural areas, offering EBPs through PBIS can improve access and lead to better long-term outcomes. A key challenge is that school personnel need technical assistance in order to implement EBPs with fidelity and clinical effectiveness. Providing ongoing on-site support is not feasible or sustainable in the majority of rural schools, due to their remote physical location. For this reason, remote training technology has been recommended for providing technical assistance to behavioral health staff (BHS) in under-served rural communities. OBJECTIVES: The purpose of this study is to use the user-centered design, guided by an iterative process (rapid prototyping), to develop and evaluate the appropriateness, feasibility, acceptability, usability, and preliminary student outcomes of two online training strategies for the implementation of EBPs at PBIS Tier 2. METHODS: The study will employ a pragmatic design comprised of a mixed-methods approach for the development of the training platform, and a hybrid type 2, pilot randomized controlled trial to examine the implementation and student outcomes of two training strategies: Remote Video vs. Remote Video plus Coaching. DISCUSSION: There is a clear need for well-designed remote training studies focused on training in non-traditional settings. Given the lack of well-trained mental health professionals in rural settings and the stark disparities in access to services, the development and pilot-testing of a remote training strategy for BHS in under-served rural schools could have a significant public health impact. ETHICS AND DISSEMINATION: The project was reviewed and approved by the institutional review board. Results will be submitted to ClinicalTrials.gov and disseminated to community partners and participants, peer-reviewed journals, and academic conferences. TRIAL REGISTRATION: ClinicialTrials.gov, NCT05034198 and NCT05039164

Genetic diversity and population structure of bermudagrass (Cynodon spp.) revealed by genotyping-by-sequencing

Bermudagrass (Cynodon spp.) breeding and cultivar development is hampered by limited information regarding its genetic and phenotypic diversity. To explore diversity in bermudagrass, a total of 206 Cynodon accessions consisting of 193 common bermudagrass (C. dactylon var. dactylon) and 13 African bermudagrass (C. transvaalensis) accessions of worldwide origin were assembled for genetic characterization. Genotyping-by-sequencing (GBS) was employed for genetic marker development. With a minor allele frequency of 0.05 and a minimum call rate of 0.5, a total of 37,496 raw single nucleotide polymorphisms (SNPs) were called de novo and were used in the genetic diversity characterization. Population structure analysis using ADMIXTURE revealed four subpopulations in this germplasm panel, which was consistent with principal component analysis (PCA) and phylogenetic analysis results. The first three principal components explained 15.6%, 10.1%, and 3.8% of the variance in the germplasm panel, respectively. The first subpopulation consisted of C. dactylon accessions from various continents; the second subpopulation was comprised mainly of C. transvaalensis accessions; the third subpopulation contained C. dactylon accessions primarily of African origin; and the fourth subpopulation represented C. dactylon accessions obtained from the Oklahoma State University bermudagrass breeding program. Genetic diversity parameters including Nei’s genetic distance, inbreeding coefficient, and Fst statistic revealed substantial genetic variation in the Cynodon accessions, demonstrating the potential of this germplasm panel for further genetic studies and cultivar development in breeding programs

The Grizzly, February 9, 1990

Students Grapple With Rising Costs • USEAC Plants Seeds for First Ursinus Earth Day • Letter: Cynosure Cynic • Michener Bids Campus Adieu • The Trojans are Coming • Get your Act in Gear • Feb 14: A Woman\u27s Holiday? • UC Aquabears Squash Susquehanna • Susquehanna Drowned • Hoopsters Split Again • Making Tracks • Wismer Looking Gamely • Stop The Sex Wars • Grapplers Rebound With Big Victory • Gymnasts Prepare for Nationals • Athletes of the Week • Countdownhttps://digitalcommons.ursinus.edu/grizzlynews/1251/thumbnail.jp

The Grizzly, January 26, 1990

Campus Additions are Muddling Thru • Dennis Gould Makes His Life in Art With Inner Voice • Letters: GDI Supports Power\u27s Points; Corson Operator Boxing Impersonal; Fashion Focus Offensive • A Civil Voice Inspires • Bookstore Buyback Prices Fair? • UC Hoopsters Have Winning Potential! • Slippery When Wet! • Aquabears: Quality not Quantity • Lady Tumblers Hopeful • Grappling to Victory • Corson Special: Phone in a Box • Student Symposium • Lantern Finally Here • Vacancies Filled • Bears On Their Way! • Athletes of the Week • Changes on Track • Student-Faculty Interactions Beneficial for Both • Kriebel to Lecture at Museum • Workshops Offeredhttps://digitalcommons.ursinus.edu/grizzlynews/1249/thumbnail.jp

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg−1 day−1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR

The myofibroblast matrix: implications for tissue repair and fibrosis

Myofibroblasts, and the extracellular matrix ( ECM ) in which they reside, are critical components of wound healing and fibrosis. The ECM , traditionally viewed as the structural elements within which cells reside, is actually a functional tissue whose components possess not only scaffolding characteristics, but also growth factor, mitogenic, and other bioactive properties. Although it has been suggested that tissue fibrosis simply reflects an ‘exuberant’ wound‐healing response, examination of the ECM and the roles of myofibroblasts during fibrogenesis instead suggest that the organism may be attempting to recapitulate developmental programmes designed to regenerate functional tissue. Evidence of this is provided by the temporospatial re‐emergence of embryonic ECM proteins by fibroblasts and myofibroblasts that induce cellular programmatic responses intended to produce a functional tissue. In the setting of wound healing (or physiological fibrosis), this occurs in a highly regulated and exquisitely choreographed fashion which results in cessation of haemorrhage, restoration of barrier integrity, and re‐establishment of tissue function. However, pathological tissue fibrosis, which oftentimes causes organ dysfunction and significant morbidity or mortality, likely results from dysregulation of normal wound‐healing processes or abnormalities of the process itself. This review will focus on the myofibroblast ECM and its role in both physiological and pathological fibrosis, and will discuss the potential for therapeutically targeting ECM proteins for treatment of fibrotic disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94657/1/path4104.pd

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease