Toxicological impact of JWH-018 and its phase I metabolite N-(3-hydroxypentyl) on human cell lines

"The emergence and abuse of synthetic cannabinoids has been increasing as an alternative to cannabis, mainly among youth. As their appearance on the drug market has been recent, the pharmacological and toxicological profiles of these psychoactive substances are poorly understood. Current studies suggest that they have stronger effects compared to their natural alternatives and their metabolites retain affinity towards CB1 receptors in CNS. Since studies on its toxicological properties are scarce, the effects of the drug in human derived cell lines were investigated. The present study was designed to explore the toxicological impact of parent drug versus phase I metabolites of synthetic cannabinoids on human cells with and without CB1 receptor. The human cell line of neuroblastoma SH-SY5Y and human kidney cell line HEK-293T were exposed to JWH-018 and to its N-(3-hydroxypentyl) metabolite. Cell toxicity was evaluated using the MTT and LDH assay. Additionally, a dual staining methodology with fluorescent Annexin V-FITC and propidium iodide was performed to address the question of whether JWH-018 N-(3-hydroxypentyl) metabolite is inducing cell death through apoptosis or necrosis, in HEK293T and SH-SY5Y cell lines. The obtained results show that JWH-018 does not cause a statistically significant decrease in cell viability, in contrast to its N-(3-hydroxypentyl) metabolite, which at ≥25μM causes a significant decrease in cell viability. Both cell lines are affected by JWH-018 metabolite. Our results point to higher toxicity of JWH-018 metabolite when compared to its parent drug, suggesting a non-CB1 receptor mediated toxicological mechanism. Comparing the results from Annexin V/PI with MTT and LDH assays of SH-SY5Y and HEK293T in the presence of the synthetic cannabinoid metabolite, emerges the picture that cellular viability decreases and associated death is occurring through necrosis."

Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice

Rapamycin consistently increases longevity in mice although the mechanism of action of this drug is unknown. In the present investigation we studied the effect of rapamycin on mitochondrial oxidative stress at the same dose that is known to increase longevity in mice (14 mg of rapamycin/kg of diet). Middle aged mice (16 months old) showed significant age-related increases in mitochondrial ROS production at complex I, accumulation of mtDNA fragments inside nuclear DNA, mitochondrial protein lipoxidation, and lipofuscin accumulation compared to young animals (4 months old) in the liver. After 7 weeks of dietary treatment all those increases were totally or partially (lipofuscin) abolished by rapamycin, middle aged rapamycin-treated animals showing similar levels in those parameters to young animals. The decrease in mitochondrial ROS production was due to qualitative instead of quantitative changes in complex I. The decrease in mitochondrial protein lipoxidation was not due to decreases in the amount of highly oxidizable unsaturated fatty acids. Rapamycin also decreased the amount of RAPTOR (of mTOR complex) and increased the amounts of the PGC1-α and ATG13 proteins. The results are consistent with the possibility that rapamycin increases longevity in mice at least in part by lowering mitochondrial ROS production and increasing autophagy, decreasing the derived final forms of damage accumulated with age which are responsible for increased longevity. The decrease in lipofuscin accumulation induced by rapamycin adds to previous information suggesting that the increase in longevity induced by this drug can be due to a decrease in the rate of aging. © 2016 Elsevier Inc.

FY 2014-15 & 2015-16 Evaluation of State-Funded Full-Day 4K, part I

This report documents the expansion of 4K and expenditure of funds in Fiscal Years 2014-15 and 2015-16; provides 2015-16 projections for the number of at-risk four-year-olds in each school district and the number of at-risk four-year-olds served in a publicly funded program using available information; details the results of the CIRCLE assessment, which was administered to children in publicly-funded four-year-old (4K) and five-year-old (5K) kindergarten during the 2014-15 school year; describes the four language and literacy assessments that measure 4K and 5K students’ abilities during the 2015-16 school year; and discusses how 4K quality can be defined and the important role of teacher-child instructional interactions in assessing quality of publicly-funded 4K.

Learning to reflect in the first year of legal education : the key to surviving legal education and legal practice

Lawyers and law students suffer significant rates of depression and substance abuse. This paper suggests that Law Schools have an obligation to assist students to develop the emotional intelligence necessary in order to cope with the stressful nature of legal practice. We draw on Schön’s discussion of the indeterminate zone of professional practice to suggest that reflective practice is the means by which students can become sufficiently emotionally intelligent to become balanced and happy lawyers. We suggest that incorporating reflective practice in intentional curriculum design in the first year of law is an effective first step in assisting students to develop the emotional intelligence necessary to survive the study and practice of law.

Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

Tissue damage resulting from the extracellular production of HOCl (hypochlorous acid) by the MPO (myeloperoxidase)-hydrogen peroxide-chloride system of activated phagocytes is implicated as a key event in the progression of a number of human inflammatory diseases. Consequently, there is considerable interest in the development of therapeutically useful MPO inhibitors. Nitroxides are well established antioxidant compounds of low toxicity that can attenuate oxidative damage in animal models of inflammatory disease. They are believed to exert protective effects principally by acting as superoxide dismutase mimetics or radical scavengers. However, we show here that nitroxides can also potently inhibit MPO-mediated HOCl production, with the nitroxide 4-aminoTEMPO inhibiting HOCl production by MPO and by neutrophils with IC50 values of approx. 1 and 6 μM respectively. Structure–activity relationships were determined for a range of aliphatic and aromatic nitroxides, and inhibition of oxidative damage to two biologically-important protein targets (albumin and perlecan) are demonstrated. Inhibition was shown to involve one-electron oxidation of the nitroxides by the compound I form of MPO and accumulation of compound II. Haem destruction was also observed with some nitroxides. Inhibition of neutrophil HOCl production by nitroxides was antagonized by neutrophil-derived superoxide, with this attributed to superoxide-mediated reduction of compound II. This effect was marginal with 4-aminoTEMPO, probably due to the efficient superoxide dismutase-mimetic activity of this nitroxide. Overall, these data indicate that nitroxides have considerable promise as therapeutic agents for the inhibition of MPO-mediated damage in inflammatory diseases.

Restrung New Chamber Festival : Bridging the Gap Between High Art Music and Popular Sensibilities

The Restrung New Chamber Festival was a practice-led research project which explored the intricacies of musical relationships. Specifically, it investigated the relationships between new music ensembles and pop-oriented bands inspired by the new music genre. The festival, held at the Brisbane Powerhouse (28 February-2 March 2009) comprised 17 diverse groups including the Brodsky Quartet, Topology, Wood, Fourplay and CODA. Restrung used a new and distinctive model which presented new music and syncretic musical genres within an immersive environment. Restrung brought together approaches used in both contemporary classical and popular music festivals, using musical, visual and spatial aspects to engage audiences. Interactivity was encouraged through video and sound installations, workshops and forums. This paper will investigate some of the issues surrounding the conception and design of the Restrung model, within the context of an overview of European new music trends. It includes a discussion of curating such an event in a musically sensitive and effective way, and approaches to identifying new and receptive audiences. As a guide to programming Restrung, I formulated a working definition of new music, further developed by interviews with specialists in Australia and Europe, and this will be outlined below.

Radiological aspects of petroleum exploration and production in the sultanate of Oman

This thesis is a study of naturally occurring radioactive materials (NORM) activity concentration, gamma dose rate and radon (222Rn) exhalation from the waste streams of large-scale onshore petroleum operations. Types of activities covered included; sludge recovery from separation tanks, sludge farming, NORM storage, scaling in oil tubulars, scaling in gas production and sedimentation in produced water evaporation ponds. Field work was conducted in the arid desert terrain of an operational oil exploration and production region in the Sultanate of Oman. The main radionuclides found were 226Ra and 210Pb (238U - series), 228Ra and 228Th (232Th - series), and 227Ac (235U - series), along with 40K. All activity concentrations were higher than the ambient soil level and varied over several orders of magnitude. The range of gamma dose rates at a 1 m height above ground for the farm treated sludge had a range of 0.06 0.43 µSv h 1, and an average close to the ambient soil mean of 0.086 ± 0.014 µSv h 1, whereas the untreated sludge gamma dose rates had a range of 0.07 1.78 µSv h 1, and a mean of 0.456 ± 0.303 µSv h 1. The geometric mean of ambient soil 222Rn exhalation rate for area surrounding the sludge was mBq m 2 s 1. Radon exhalation rates reported in oil waste products were all higher than the ambient soil value and varied over three orders of magnitude. This study resulted in some unique findings including: (i) detection of radiotoxic 227Ac in the oil scales and sludge, (ii) need of a new empirical relation between petroleum sludge activity concentrations and gamma dose rates, and (iii) assessment of exhalation of 222Rn from oil sludge. Additionally the study investigated a method to determine oil scale and sludge age by the use of inherent behaviour of radionuclides as 228Ra:226Ra and 228Th:228Ra activity ratios.

The impact of organisational culture on ERP systems implementation : lessons from Jordan

Jordan is adopting Enterprise Resource Planning (ERP) systems in both its public and private sectors. Jordan's emerging private sector has historically close ties to the public sector; though a global market orientation requires a shift in its organisational culture. ERPs however embed business processes which do not necessarily fit with traditional cultural practices, and implementation success is not assured. This study looks at the perceptions of both public and private sector ERP implementations in Jordan and assesses these on various measures of success. There were few differences between public and private sectors, but the benefits actually realised in Jordanian ERPs fell short of claims made for the technology in other cultures.

Impacts of vessel capacity reduction programs on the efficiency in fisheries. The case of Australia's multispecies in northern prawn fishery

Capacity reduction programs in the form of buybacks or decommissioning programs have had relatively widespread application in fisheries in the US, Europe and Australia. A common criticism of such programs is that they remove the least efficient vessels first, resulting in an increase in average efficiency of the remaining fleet. The effective fishing power of the fleet, therefore, does not decrease in proportion to the number of vessels removed. Further, reduced crowding may increase efficiency of the remaining vessels. In this paper, the effects of a buyback program on average technical efficiency in Australia’s Northern Prawn Fishery are examined using a multi-output distance function approach with an explicit inefficiency model. The results indicate that average efficiency of the remaining vessels was greater than that of the removed vessels, and that average efficiency of remaining vessels also increased as a result of reduced crowding.

One approach to finding evidence for the effectiveness of scientific visualisations in high school physics and chemistry education

Enormous amounts of money and energy are being devoted to the development, use and organisation of computer-based scientific visualisations (e.g. animations and simulations) in science education. It seems plausible that visualisations that enable students to gain visual access to scientific phenomena that are too large, too small or occur too quickly or too slowly to be seen by the naked eye, or to scientific concepts and models, would yield enhanced conceptual learning. When the literature is searched, however, it quickly becomes apparent that there is a dearth of quantitative evidence for the effectiveness of scientific visualisations in enhancing students’ learning of science concepts. This paper outlines an Australian project that is using innovative research methodology to gather evidence on this question in physics and chemistry classrooms.

Association of immunoproteasomes with the endoplasmic reticulum

Proteasomes are complex multisubunit proteases which play a critical role in intracellular proteolysis. Immunoproteasomes, which contain three c-interferon-inducible subunits, are a subset of proteasomes which have a specialized function in antigen processing for presentation by the MHC class I pathway. Two of the c-interferon inducible subunits, LMP2 and LMP7, are encoded within the MHC class II region adjacent to the two TAP (transporter associated with antigen presentation) genes. We have investigated the localization of immunoproteasomes using monoclonal antibodies to LMP2 and LMP7. Immunoproteasomes were strongly enriched around the endoplasmic reticulum as judged by double-immuno¯uorescence experiments with anticalreticulin antibodies, but were also present in the nucleus and throughout the cytosol. In contrast, proteasome subunit C2, which is present in all proteasomes, was found to be evenly distributed throughout the cytoplasm and in the nucleus, as was the delta subunit, which is replaced by LMP2 in immunoproteasomes. c-Interferon increased the level of immunoproteasomes, but had no effect on their distribution. Our results provide the ®rst direct evidence that immunoproteasomes are strongly enriched at the endoplasmic reticulum, where they may be located close to the TAP transporter to provide efficient transport of peptides into the lumen of the endoplasmic recticulum for association with MHC class I molecules.