In vitro metabolism of the synthetic cannabinoid 3,5-AB-CHMFUPPYCA and its 5,3-regioisomer and investigation of their thermal stability.

Recently, the pyrazole-containing synthetic cannabinoid N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (3,5-AB-CHMFUPPYCA) has been identified as a 'research chemical' both in powdered form and as an adulterant present in herbal preparations. Urine is the most common matrix used for abstinence control and the extensive metabolism of synthetic cannabinoids requires implementation of targeted analysis. The present study describes the investigation of the in vitro phase I metabolism of 3,5-AB-CHMFUPPYCA and its regioisomer 5,3-AB-CHMFUPPYCA using pooled human liver microsomes. Metabolic patterns of both AB-CHMFUPPYCA isomers were qualitatively similar and dominated by oxidation of the cyclohexylmethyl side chain. Biotransformation to monohydroxylated metabolites of high abundance confirmed that these species might serve as suitable targets for urine analysis. Furthermore, since synthetic cannabinoids are commonly administered by smoking and because some metabolites can also be formed as thermolytic artefacts, the stability of both isomers was assessed under smoking conditions. Under these conditions, pyrolytic cleavage of the amide bond occurred that led to approximately 3 % conversion to heat-induced degradation products that were also detected during metabolism. These artefactual 'metabolites' could potentially bias in vivo metabolic profiles after smoking and might have to be considered for interpretation of metabolite findings during hair analysis. This might be relevant to the analysis of hair samples where detection of metabolites is generally accepted as a strong indication of drug use rather than a potential external contamination. Copyright © 2016 John Wiley & Sons, Ltd

Mackintosh lecture: Association and cognition: two processes, one system

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this record.There is another ORE record for this item: http://hdl.handle.net/10871/33264This paper argues that the dual-process position can be a useful first approximation when studying human mental life, but it cannot be the whole truth. Instead, we argue that cognition is built on association, in that associative processes provide the fundamental building blocks that enable propositional thought. One consequence of this position is to suggest that humans are able to learn associatively in a similar fashion to a rat or a pigeon, but another is that we must typically suppress the expression of basic associative learning in favour of rule-based computation. This stance conceptualizes us as capable of symbolic computation, but acknowledges that, given certain circumstances, we will learn associatively and, more importantly, be seen to do so. We present three types of evidence that support this position: The first is data on human Pavlovian conditioning that directly supports this view. The second is data taken from task switching experiments that provides convergent evidence for at least two modes of processing, one of which is automatic and carried out “in the background”. And the last suggests that when the output of propositional processes is uncertain, then the influence of associative processes on behaviour can manifest

Transcriptome Analysis in Peripheral Blood of Humans Exposed to Environmental Carcinogens: A Promising New Biomarker in Environmental Health Studies

BACKGROUND: Human carcinogenesis is known to be initiated and/or promoted by exposure to chemicals that occur in the environment. Molecular cancer epidemiology is used to identify human environmental cancer risks by applying a range of effect biomarkers, which tend to be nonspecific and do not generate insights into underlying modes of action. Toxicogenomic technologies may improve on this by providing the opportunity to identify, molecular biomarkers consisting of altered gene expression profiles. OBJECTIVES: The aim of the present study, was to monitor the expression of selected genes in a random sample of adults in Flanders selected from specific regions with (presumably,) different environmental burdens. Furthermore, associations of gene expression with blood and urinary, measures of biomarkers of exposure, early, phenotypic effects, and tumor markers were investigated. RESULTS: Individual gene expression of cytochrome p450 1B1, activating transcription factor 4, mitogen-activated protein kinase K superoxide dismutase 2 (Mn), chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha), diacylglycerol 0 acyltransferase homolog 2 (mouse), tigger transposable element derived 3, and PTEN-induced putative kinasel were measured by means of quantitative polymerase chain reaction in peripheral blood cells of 398 individuals. After correction for the confounding effect of tobacco smoking, inhabitants of the Olen region showed the highest differences in gene expression levels compared with inhabitants from the Gent and fruit cultivation regions. Importantly, we observed multiple significant correlations of particular gene expressions with blood and urinary, measures of various environmental carcinogens. CONCLUSIONS: Considering the observed significant differences between gene expression levels in inhabitants of various regions in Flanders and the associations of gene expression with blood or urinary measures of environmental carcinogens, we conclude that gene expression profiling appears promising as a tool for biological monitoring in relation to environmental exposures in humans

Parameter-adaption for a vehicle dynamics model for the evaluation of powertrain concept designs

The powertrain design of multi-motor electric vehicles directly affects not only costs, consumption and acceleration, but also the handling of a vehicle. Therefore, a holistic powertrain design optimization needs to include a vehicle dynamics model in its objective function. While the parameters for the powertrain model result from the design variables that describe the powertrain, the parameters for the vehicle dynamics model must be adapted in a feasible way to ensure comparable results. Therefore, the authors present a method on how to adaptively parametrize a double-track vehicle dynamics model for the use in powertrain design optimization. Automated design calculations for all main chassis and suspension parts are used to determine the parameters for the model. A parameter variation proves the plausibility of the approach. The results show that an adaption of the suspension and chassis parameters due to changes in the powertrain make results more comparable but do not compensate for the effects on the vehicle handling. In particular, the steady state longitudinal load distribution still has major influences on the vehicle handling

Biologic Monitoring of Exposure to Environmental Chemicals throughout the Life Stages: Requirements and Issues for Consideration for the National Children’s Study

Biomonitoring of exposure is a useful tool for assessing environmental exposures. The matrices available for analyses include blood, urine, breast milk, adipose tissue, and saliva, among others. The sampling can be staged to represent the particular time period of concern: preconceptionally from both parents, from a pregnant woman during each of the three trimesters, during and immediately after childbirth, from the mother postnatally, and from the child as it develops to 21 years of age. The appropriate sample for biomonitoring will depend upon matrix availability, the time period of concern for a particular exposure or health effect, and the different classes of environmental chemicals to be monitored. This article describes the matrices available for biomonitoring during the life stages being evaluated in the National Children’s Study; the best biologic matrices for exposure assessment for each individual chemical class, including consideration of alternative matrices; the analytical methods used for analysis, including quality control procedures and less costly alternatives; the costs of analysis; optimal storage conditions; and chemical and matrix stability during long-term storage

Fast Photon Detection for Particle Identification with COMPASS RICH-1

Particle identification at high rates is an important challenge for many current and future high-energy physics experiments. The upgrade of the COMPASS RICH-1 detector requires a new technique for Cherenkov photon detection at count rates of several $10^6$ per channel in the central detector region, and a read-out system allowing for trigger rates of up to 100 kHz. To cope with these requirements, the photon detectors in the central region have been replaced with the detection system described in this paper. In the peripheral regions, the existing multi-wire proportional chambers with CsI photocathode are now read out via a new system employing APV pre-amplifiers and flash ADC chips. The new detection system consists of multi-anode photomultiplier tubes (MAPMT) and fast read-out electronics based on the MAD4 discriminator and the F1-TDC chip. The RICH-1 is in operation in its upgraded version for the 2006 CERN SPS run. We present the photon detection design, constructive aspects and the first Cherenkov light in the detector.Comment: Proceedings of the Imaging 2006 conference, Stockholm, Sweden, 27-30 June 2006, 5 pages, 6 figures, to appear in NIM A; corrected typo in caption of Fig.

Fast photon detection for the COMPASS RICH detector

The COMPASS experiment at the SPS accelerator at CERN uses a large scale Ring Imaging CHerenkov detector (RICH) to identify pions, kaons and protons in a wide momentum range. For the data taking in 2006, the COMPASS RICH has been upgraded in the central photon detection area (25% of the surface) with a new technology to detect Cherenkov photons at very high count rates of several 10^6 per second and channel and a new dead-time free read-out system, which allows trigger rates up to 100 kHz. The Cherenkov photons are detected by an array of 576 visible and ultra-violet sensitive multi-anode photomultipliers with 16 channels each. The upgraded detector showed an excellent performance during the 2006 data taking.Comment: Proceeding of the IPRD06 conference (Siena, Okt. 06

The PANDA GEM-based TPC Prototype

We report on the development of a GEM-based TPC prototype for the PANDA experiment. The design and requirements of this device will be illustrated, with particular emphasis on the properties of the recently tested GEM-detector, the characterization of the read-out electronics and the development of the tracking software that allows to evaluate the GEM-TPC data.Comment: submitted to NIMA 4 pages, 6 picture