215 results on '"Mark, Connor"'
Search Results
2. Amplifying Limitations, Harms and Risks of Large Language Models.
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Michael O'Neill 0001 and Mark Connor
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- 2023
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3. Context is key: normalization as a novel approach to sport specific preprocessing of KPI’s for match analysis in soccer
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Ashwin A. Phatak, Saumya Mehta, Franz-Georg Wieland, Mikael Jamil, Mark Connor, Manuel Bassek, and Daniel Memmert
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Medicine ,Science - Abstract
Abstract Key Performance Indicators (KPIs) have been investigated, validated and applied in multitude of sports for recruiting, coaching, opponent, self-analysis etc. Although a wide variety of in game performance indicators have been used as KPIs, they lack sports specific context. With the introduction of artificial intelligence and machine learning (AI/ML) in sports, the need for building intrinsic context into the independent variables is even greater as AI/ML models seem to perform better in terms of predictability but lack interpretability. The study proposes domain specific feature preprocessing method (normalization) that can be utilized across a wide range of sports and demonstrates its value through a specific data transformation by using team possession as a normalizing factor while analyzing defensive performance in soccer. The study performed two linear regressions and three gradient boosting machine models to demonstrate the value of normalization while predicting defensive performance. The results demonstrate that the direction of correlation of the relevant variables changes post normalization while predicting defensive performance of teams for the whole season. Both raw and normalized KPIs showing significant correlation with defensive performance (p
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- 2022
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4. Using multiple machine learning algorithms to classify elite and sub-elite goalkeepers in professional men’s football
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Mikael Jamil, Ashwin Phatak, Saumya Mehta, Marco Beato, Daniel Memmert, and Mark Connor
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Medicine ,Science - Abstract
Abstract This study applied multiple machine learning algorithms to classify the performance levels of professional goalkeepers (GK). Technical performances of GK’s competing in the elite divisions of England, Spain, Germany, and France were analysed in order to determine which factors distinguish elite GK’s from sub-elite GK’s. A total of (n = 14,671) player-match observations were analysed via multiple machine learning algorithms (MLA); Logistic Regressions (LR), Gradient Boosting Classifiers (GBC) and Random Forest Classifiers (RFC). The results revealed 15 common features across the three MLA’s pertaining to the actions of passing and distribution, distinguished goalkeepers performing at the elite level from those that do not. Specifically, short distribution, passing the ball successfully, receiving passes successfully, and keeping clean sheets were all revealed to be common traits of GK’s performing at the elite level. Moderate to high accuracy was reported across all the MLA’s for the training data, LR (0.7), RFC (0.82) and GBC (0.71) and testing data, LR (0.67), RFC (0.66) and GBC (0.66). Ultimately, the results discovered in this study suggest that a GK’s ability with their feet and not necessarily their hands are what distinguishes the elite GK’s from the sub-elite.
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- 2021
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5. What's in a toon name?: player evaluations of toon names in Lord of the Rings Online and Toontown Rewritten.
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Hagiwara, Rob (Linguistics), Rosen, Nicole (Linguistics), Ghomeshi, Jila, Russell, Kevin, Mark, Connor, Hagiwara, Rob (Linguistics), Rosen, Nicole (Linguistics), Ghomeshi, Jila, Russell, Kevin, and Mark, Connor
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This thesis concerns attitudes toward player character (toon) names in two online video games: Lord of the Rings Online (LotRO) and Toontown Rewritten (TTR). In particular, this thesis aims to uncover what properties of good toon names are. While a little has been said about toon names in LotRO (Turkay 2012, Bainbridge 2016), nothing has been said about toon names in TTR. Moreover, there has been no research on either game concerning players’ opinions about what makes a name good. A combination of interviews and surveys was used to collect data. In addition to open questions, participants were tasked with comparing pairs of toons that differed in either name or appearance. In one task, participants saw only one toon from each pair and, in the survey, had to rank the name on a scale from 1 to 6. Conversely, in the second task, they saw both toons in each pair and had to select which one they preferred. The goal of the thesis is to build a foundation of knowledge on toon names in online video games, using two games in order to compare and contrast them, ideally giving some insight into what is game-specific and what could occur across online games more generally. The results indicate that while the games are different, many of the general attitudes among players of both games are the same. In particular, participants judged that some names are considered better on some toons than on others, that difficulty in pronunciation worsens the quality of the name, and that offensive names are dispreferred. Overall, players of LotRO are concerned with immersion and faithfulness towards Tolkien’s worldbuilding while TTR players enjoy names that are creative and humourous. Additionally, while some participants of both games are okay with or even enjoy names that generally do not match the toon named, LotRO players found these mismatches okay when it did not harm immersion and TTR players thought that mismatching names could be ironic, thus bringing humour to the names. This work
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- 2024
6. Optimizing Team Sport Training With Multi-Objective Evolutionary Computation.
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Mark Connor, David Fagan, Barry Watters, Fergal McCaffery, and Michael O'Neill 0001
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- 2021
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7. Synthesis and pharmacological evaluation of newly detected synthetic cannabinoid receptor agonists AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA, MDMB-4F-BUTINACA and their analogs
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Eric Sparkes, Rochelle Boyd, Shuli Chen, Jack W. Markham, Jia Lin Luo, Tahira Foyzun, Humayra Zaman, Charlotte Fletcher, Ross Ellison, Iain S. McGregor, Marina J. Santiago, Felcia Lai, Roy R. Gerona, Mark Connor, David E. Hibbs, Elizabeth A. Cairns, Michelle Glass, Adam Ametovski, and Samuel D. Banister
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synthetic cannabinoid ,cannabinoid receptor 1 agonists ,pharmacology ,cannabinoids ,SCRAs ,docking ,Psychiatry ,RC435-571 - Abstract
Synthetic cannabinoid receptor agonists (SCRAs) continue to make up a significant portion new psychoactive substances (NPS) detected and seized worldwide. Due to their often potent activation of central cannabinoid receptors in vivo, use of SCRAs can result in severe intoxication, in addition to other adverse health effects. Recent detections of AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA and MDMB-4F-BUTINACA mark a continuation in the appearance of SCRAs bearing novel tail substituents. The proactive characterization campaign described here has facilitated the detection of several new SCRAs in toxicological case work. Here we detail the synthesis, characterization, and pharmacological evaluation of recently detected SCRAs, as well as a systematic library of 32 compounds bearing head, tail, and core group combinations likely to appear in future. In vitro radioligand binding assays revealed most compounds showed moderate to high affinity at both CB1 (pKi = < 5 to 8.89 ± 0.09 M) and CB2 (pKi = 5.49 ± 0.03 to 9.92 ± 0.09 M) receptors. In vitro functional evaluation using a fluorescence-based membrane potential assay showed that most compounds were sub-micromolar to sub-nanomolar agonists at CB1 (pEC50 = < 5 to 9.48 ± 0.14 M) and CB2 (pEC50 = 5.92 ± 0.16 to 8.64 ± 0.15 M) receptors. An in silico receptor-ligand docking approach was utilized to rationalize binding trends for CB2 with respect to the tail substituent, and indicated that rigidity in this region (i.e., 4-cyanobutyl) was detrimental to affinity.
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- 2022
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8. Optimising Team Sport Training Plans With Grammatical Evolution.
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Mark Connor, David Fagan, and Michael O'Neill 0001
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- 2019
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9. Tapentadol shows lower intrinsic efficacy at µ receptor than morphine and oxycodone
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Preeti Manandhar, Mark Connor, and Marina Santiago
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µ receptor ,G protein ,intrinsic efficacy ,operational model ,opioids ,pain ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Tapentadol is a centrally acting analgesic with a dual mechanism of action. It acts as an agonist at the µ receptor and inhibitor of noradrenaline reuptake. Clinical trials suggest similar analgesic efficacy of tapentadol, oxycodone, and morphine in acute and chronic pain. Given the limited information about the molecular actions of tapentadol at the µ receptor, we investigated the intrinsic efficacy of tapentadol and compared it with other opioids. β‐chlornaltrexamine (β‐CNA, 100 nM, 20 min) was used to deplete spare receptors in AtT20 cells stably transfected with human µ receptor wild‐type (WT). Opioid‐mediated changes in membrane potential were measured in real‐time using a membrane potential‐sensitive fluorescent dye. Using Black and Leff’s operational model, intrinsic efficacy relative to DAMGO was calculated for each opioid. Tapentadol (0.05 ± 0.01) activated the GIRK channel with lesser intrinsic efficacy than morphine (0.17 ± 0.02) and oxycodone (0.16 ± 0.02). We further assessed the signaling of tapentadol in the common µ receptor variants (N40D and A6V) which are associated with altered receptor signaling. We found no difference in the response of tapentadol between these receptor variants.
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- 2022
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10. Quantifying the Kinetics of Signaling and Arrestin Recruitment by Nervous System G-Protein Coupled Receptors
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Sam R. J. Hoare, Paul H. Tewson, Shivani Sachdev, Mark Connor, Thomas E. Hughes, and Anne Marie Quinn
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arrestin ,biosensor ,cannabinoid ,dynamics ,G protein coupled receptor (GPCR) ,kinetics ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Neurons integrate inputs over different time and space scales. Fast excitatory synapses at boutons (ms and μm), and slow modulation over entire dendritic arbors (seconds and mm) are all ultimately combined to produce behavior. Understanding the timing of signaling events mediated by G-protein-coupled receptors is necessary to elucidate the mechanism of action of therapeutics targeting the nervous system. Measuring signaling kinetics in live cells has been transformed by the adoption of fluorescent biosensors and dyes that convert biological signals into optical signals that are conveniently recorded by microscopic imaging or by fluorescence plate readers. Quantifying the timing of signaling has now become routine with the application of equations in familiar curve fitting software to estimate the rates of signaling from the waveform. Here we describe examples of the application of these methods, including (1) Kinetic analysis of opioid signaling dynamics and partial agonism measured using cAMP and arrestin biosensors; (2) Quantifying the signaling activity of illicit synthetic cannabinoid receptor agonists measured using a fluorescent membrane potential dye; (3) Demonstration of multiplicity of arrestin functions from analysis of biosensor waveforms and quantification of the rates of these processes. These examples show how temporal analysis provides additional dimensions to enhance the understanding of GPCR signaling and therapeutic mechanisms in the nervous system.
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- 2022
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11. Quantifying and Comparing the Match Demands of U18, U23, and 1ST Team English Professional Soccer Players
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James Reynolds, Mark Connor, Mikael Jamil, and Marco Beato
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football ,team sports ,GPS ,speed ,performance ,Physiology ,QP1-981 - Abstract
The aim of this study was to quantify and compare the match load demands of U18, U23, and 1ST team players during the official season. A total of 65 matches and 495 (U18 = 146, U23 = 146, and 1ST team = 203) individual player game observations were included in this analysis. A 10-Hz global navigation satellite systems (GNSS) and 100-Hz triaxial accelerometer (STATSports, Apex, Northern Ireland) were used to monitor the following metrics during official matches: total distance, high-speed running distance (HSR), sprint distance, high metabolic distance, explosive distance, high-intensity bursts distance, speed intensity, and dynamic stress load (DSL) were analyzed. A multivariate analysis of variance test reported significant (p < 0.001) differences among the groups. HSR during matches was lower (d = small) for U18 players than the U23 and 1ST team players. Sprint distance and high-intensity bursts distance were lower (small) in U18 compared with the U23 and 1ST team. DSL was greater in 1ST compared with U18 (small) and U23 (small). This study reported that the differences between groups were greater for HSR, sprint distance, high-intensity bursts distance, and DSL, while total distance, high metabolic load distance, explosive distance, and speed intensity did not differ between the groups. These findings could be used to design training programs in the academy players (i.e., U18) to achieve the required long-term physical adaptations that are needed to progress into the U23 and 1ST teams.
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- 2021
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12. Optimizing the parameters of a physical exercise dose-response model: an algorithmic comparison.
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Mark Connor and Michael O'Neill 0001
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- 2021
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13. Do gabapentin or pregabalin directly modulate the µ receptor?
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Preeti Manandhar, Bridin Patricia Murnion, Natasha L. Grimsey, Mark Connor, and Marina Santiago
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Pregabalin ,Gabapentin ,Opioid ,µ receptor ,Overdose ,Gabapentinoids ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background Pregabalin and gabapentin improve neuropathic pain symptoms but there are emerging concerns regarding their misuse. This is more pronounced among patients with substance use disorder, particularly involving opioids. Co-ingestion of gabapentinoids with opioids is increasingly identified in opioid related deaths, however, the molecular mechanism behind this is still unclear. We have sought to determine whether pregabalin or gabapentin directly modulates acute μ receptor signaling, or μ receptor activation by morphine. Methods The effects of pregabalin and gabapentin were assessed in HEK 293 cells stably transfected with the human μ receptor. Their effect on morphine induced hyperpolarization, cAMP production and ERK phosphorylation were studied using fluorescent-based membrane potential assay, bioluminescence based CAMYEL assay and ELISA assay, respectively. Pregabalin/gabapentin effects on morphine-induced hyperpolarization were also investigated in AtT20 cells. Results Pregabalin or gabapentin (1 µM, 100 µM each) did not activate the µ receptor or affect K channel activation or ERK phosphorylation produced by morphine. Neither drug affected the desensitization of K channel activation produced by prolonged (30 min) application of morphine. Gabapentin (1 µM, 100 µM) and pregabalin (1 µM) did not affect inhibition of forskolin-stimulated cAMP production by morphine. However, pregabalin (100 µM) potentiated forskolin mediated cAMP production, although morphine still inhibited cAMP levels with a similar potency to control. Discussion Pregabalin or gabapentin did not activate or modulate µ receptor signaling in three different assays. Our data do not support the hypothesis that gabapentin or pregabalin augment opioid effects through direct or allosteric modulation of the µ receptor. Pregabalin at a high concentration increases cAMP production independent of morphine. The mechanism of enhanced opioid-related harms from co-ingestion of pregabalin or gabapentin with opioids needs further investigation.
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- 2021
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14. Optimizing the Parameters of A Physical Exercise Dose-Response Model: An Algorithmic Comparison.
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Mark Connor and Michael O'Neill 0001
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- 2020
15. Differential activation of G protein‐mediated signaling by synthetic cannabinoid receptor agonists
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Shivani Sachdev, Samuel D. Banister, Marina Santiago, Chris Bladen, Michael Kassiou, and Mark Connor
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cannabinoid receptor ,G protein ,signaling ,synthetic cannabinoid receptor agonist ,toxicity ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Synthetic cannabinoid receptor agonists (SCRAs) are new psychoactive substances associated with acute intoxication and even death. However, the molecular mechanisms through which SCRAs may exert their toxic effects remain unclear—including the potential differential activation of G protein subtypes by cannabinoid receptor type 1 (CB1), a major target of SCRA. We measured CB1‐mediated activation of Gαs and Gαi/o proteins by SCRAs by examining stimulation (pertussis toxin, PTX treated) as well as inhibition (non‐PTX treated) of forskolin (FSK)‐induced cyclic adenosine monophosphate (cAMP) accumulation in human embryonic kidney (HEK) cells stably expressing CB1. Real‐time measurements of stimulation and inhibition of cAMP levels were made using a BRET biosensor. We found that the maximum concentration of SCRAs tested (10 µmol L−1), increased cAMP levels 12%‐45% above that produced by FSK alone, while the phytocannabinoid THC did not significantly alter cAMP levels in PTX‐treated HEK‐CB1 cells. All SCRAs had greater potency to inhibit FSK‐induced cAMP levels than to stimulate cAMP levels. The rank order of potencies for SCRA stimulation of cAMP (Gαs) was PB‐22 > 5F‐MDMB‐PICA > JWH‐018 ≈ AB‐FUBINACA > XLR‐11. By contrast, the potency of SCRAs for inhibition of cAMP (Gαi/o) was 5F‐MDMB‐PICA > AB‐FUBINACA > PB‐22 > JWH‐018 > XLR‐11. The different rank order of potency and EMax of the SCRAs to stimulate Gαs‐like signaling compared to Gαi/o signaling suggests differences in G protein preference between SCRAs. Understanding the apparent differences among these drugs may contribute to unravelling their complex effects in humans.
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- 2020
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16. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity
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Marjolein Soethoudt, Uwe Grether, Jürgen Fingerle, Travis W. Grim, Filomena Fezza, Luciano de Petrocellis, Christoph Ullmer, Benno Rothenhäusler, Camille Perret, Noortje van Gils, David Finlay, Christa MacDonald, Andrea Chicca, Marianela Dalghi Gens, Jordyn Stuart, Henk de Vries, Nicolina Mastrangelo, Lizi Xia, Georgios Alachouzos, Marc P. Baggelaar, Andrea Martella, Elliot D. Mock, Hui Deng, Laura H. Heitman, Mark Connor, Vincenzo Di Marzo, Jürg Gertsch, Aron H. Lichtman, Mauro Maccarrone, Pal Pacher, Michelle Glass, and Mario van der Stelt
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Science - Abstract
CB2 receptor agonists are developed as potential analgesics or immune-modulatory compounds. Here, the authors characterize the pharmacological properties of widely used CB2 receptor agonists and antagonists, recommending three that appear most suitable for in vitro and in vivostudies.
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- 2017
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17. Accelerating the search for the missing proteins in the human proteome
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Mark S. Baker, Seong Beom Ahn, Abidali Mohamedali, Mohammad T. Islam, David Cantor, Peter D. Verhaert, Susan Fanayan, Samridhi Sharma, Edouard C. Nice, Mark Connor, and Shoba Ranganathan
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Science - Abstract
The Human Proteome Project aims to catalogue the ∼20,000 proteins encoded by the human genome. In this review, Bakeret al. focus on the missing proteins, proteins that lack high stringency proteomic evidence, and launch MissingProteinPedia, a database aimed at accelerating the search for missing proteins.
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- 2017
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18. Brodifacoum does not modulate human cannabinoid receptor-mediated hyperpolarization of AtT20 cells or inhibition of adenylyl cyclase in HEK 293 cells
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Shivani Sachdev, Rochelle Boyd, Natasha L. Grimsey, Marina Santiago, and Mark Connor
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Synthetic cannabinoid ,Superwarfarin ,Overdose ,Cannabinoid receptor signaling ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background Synthetic cannabinoids are a commonly used class of recreational drugs that can have significant adverse effects. There have been sporadic reports of co-consumption of illicit drugs with rodenticides such as warfarin and brodifacoum (BFC) over the past 20 years but recently, hundreds of people have been reported to have been poisoned with a mixture of synthetic cannabinoids and BFC. We have sought to establish whether BFC directly affects cannabinoid receptors, or their activation by the synthetic cannabinoid CP55940 or the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Methods The effects of BFC on the hyperpolarization of wild type AtT20 cells, or AtT20 cells stably expressing human CB1- or CB2- receptors, were studied using a fluorescent assay of membrane potential. The effect of BFC on CB1- and CB2-mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) activation was measured using a BRET assay of cAMP levels in HEK 293 cells stably expressing human CB1 or CB2. Results BFC did not activate CB1 or CB2 receptors, or affect the hyperpolarization of wild type AtT20 cells produced by somatostatin. BFC (1 µM) did not affect the hyperpolarization of AtT20-CB1 or AtT20-CB2 cells produced by CP55940 or Δ9-THC. BFC (1 µM) did not affect the inhibition of forskolin-stimulated AC activity by CP55940 in HEK 293 cells expressing CB1 or CB2. BFC (1 µM) also failed to affect the desensitization of CB1 and CB2 signaling produced by prolonged (30 min) application of CP55940 or Δ9-THC to AtT20 cells. Discussion BFC is not a cannabinoid receptor agonist, and appeared not to affect cannabinoid receptor activation. Our data suggests there is no pharmacodynamic rationale for mixing BFC with synthetic cannabinoids; however, it does not speak to whether BFC may affect synthetic cannabinoid metabolism or biodistribution. The reasons underlying the mixing of BFC with synthetic cannabinoids are unknown, and it remains to be established whether the “contamination” was deliberate or accidental. However, the consequences for people who ingested the mixture were often serious, and sometimes fatal, but this seems unlikely to be due to BFC action at cannabinoid receptors.
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- 2019
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19. Monitoring Fatigue During Intermittent Exercise With Accelerometer-Derived Metrics
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Marco Beato, Kevin L. De Keijzer, Benjamin Carty, and Mark Connor
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training ,soccer ,team sports ,GPS ,football ,Physiology ,QP1-981 - Abstract
The aim of this study was to assess the sensitivity of accelerometer-derived metrics for monitoring fatigue during an intermittent exercise protocol. Fifteen university students were enrolled in the study (age 20 ± 1 years). A submaximal intermitted recovery test (Sub-IRT) with a duration of 6 min and 30 s (drill 1) was performed. In order to increase the participants’ fatigue, after that, a repeated sprint protocol (1×6 maximal 20 m sprints) was performed. Following that, participants repeated the Sub-IRT (drill 2) to evaluate the external and internal training load (TL) variations related to fatigue. Apex 10 Hz global navigation satellite system (GNSS) units were used to collect the variables total distance (TD), high metabolic distance (HMD), relative velocity (RV), average metabolic power (MP), heart rate maximal (HRmax) and mean (HRmean), muscular (RPEmus) and respiratory rating of perceived exertion (RPEres), dynamic stress load (DSL), and fatigue index (FI). A Bayesian statistical approach was used. A likelihood difference (between drill 1 and drill 2) was found for the following parameters: TD (BF10 = 0.33, moderate per H0), HMD (BF10 = 1.3, anecdotal), RV (BF10 = 0.29, moderate per H0), MP (BF10 = 1.3, anecdotal), accelerations (BF10 = 1.6, anecdotal ), FI (BF10 = 4.7, moderate), HRmax (BF10 = 2.2, anecdotal), HRmean (BF10 = 4.3, moderate), RPEmus (BF10 = 11.6, strong), RPEres (BF10 = 3.1, moderate), DSL (BF10 = 5.7, moderate), and DSL•m−1 (BF10 = 4.3, moderate). In conclusion, this study reports that DSL, DSL•m−1, and FI can be valid metrics to monitor fatigue related to movement strategy during a standardized submaximal intermittent exercise protocol.
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- 2019
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20. CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist
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Richard C. Kevin, Lyndsey Anderson, Iain S. McGregor, Rochelle Boyd, Jamie J. Manning, Michelle Glass, Mark Connor, and Samuel D. Banister
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novel psychoactive substance ,new psychoactive substance ,CUMYL ,synthetic cannabinoid ,seizure ,convulsant ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Synthetic cannabinoid receptor agonists (SCRAs) are the largest class of new psychoactive substances (NPS). New examples are detected constantly, and some are associated with a series of adverse effects, including seizures. CUMYL-4CN-BINACA (1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)indazole-3-carboxamide) is structurally related to potent, cumylamine-derived SCRAs such as 5F-CUMYL-PINACA, but is unusual due to a terminal aliphatic nitrile group not frequently encountered in SCRAs or pharmaceuticals. We report here that CUMYL-4CN-BINACA is a potent CB1 receptor agonist (Ki = 2.6 nM; EC50 = 0.58 nM) that produces pro-convulsant effects in mice at a lower dose than reported for any SCRA to date (0.3 mg/kg, i.p). Hypothermic and pro-convulsant effects in mice could be reduced or blocked, respectively, by pretreatment with CB1 receptor antagonist SR141716, pointing to at least partial involvement of CB1 receptors in vivo. Pretreatment with CB2 receptor antagonist AM-630 had no effect on pro-convulsant activity. The pro-convulsant properties and potency of CUMYL-4CN-BINACA may underpin the toxicity associated with this compound in humans.
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- 2019
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21. A Comparison of Training and Match Play External Load During a Congested In-Season Period in English League 2 Football
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Adam Fleming, Matthew Walker, Mark Armitage, Mark Connor, and Marco Beato
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Physical Therapy, Sports Therapy and Rehabilitation ,Orthopedics and Sports Medicine ,General Medicine - Published
- 2023
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22. Opioid receptors in GtoPdb v.2023.1
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Andreas Zimmer, Nurulain Zaveri, Yung H. Wong, Hiroshi Ueda, John R. Traynor, Lawrence Toll, Eric J. Simon, Toni S. Shippenberg, Stefan Schulz, Philip S. Portoghese, Jean-Claude Meunier, Dominique Massot, Davide Malfacini, Lee-Yuan Liu-Chen, Mary-Jeanne Kreek, Ian Kitchen, Brigitte Kieffer, Eamonn Kelly, Stephen Husbands, Graeme Henderson, Volker Höllt, Christopher Evans, Lakshmi A. Devi, Brian M. Cox, Mark Connor, Olivier Civelli, MacDonald J. Christie, Charles Chavkin, Girolamo Caló, Michael Bruchas, and Anna Borsodi
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General Medicine ,General Chemistry - Abstract
Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP [124, 101, 92]. However the acronyms MOR, DOR and KOR are still widely used in the literature. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [304], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone. The majority of clinically used opiates are relatively selective μ agonists or partial agonists, though there are some μ/κ compounds, such as butorphanol, in clinical use. κ opioid agonists, such as the alkaloid nalfurafine and the peripherally acting peptide difelikefalin, are in clinical use for itch.
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- 2023
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23. Inhibition of human recombinant T‐type calcium channels by phytocannabinoids in vitro
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Somayeh Mirlohi, Chris Bladen, Marina J. Santiago, Jonathon C. Arnold, Iain McGregor, and Mark Connor
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Pharmacology ,Calcium Channels, T-Type ,HEK293 Cells ,Patch-Clamp Techniques ,Cannabidiol ,Humans ,Calcium ,Membrane Potentials - Abstract
T-type Ca channels (IA fluorometric (fluorescence imaging plate reader [FLIPR]) assay was used to investigate modulation of human T-type IIn the FLIPR assay, all 11 phytocannabinoids tested modulated T-type IModulation of T-type calcium channels is a common property of phytocannabinoids, which all increase steady-state inactivation at physiological membrane potentials, with some also affecting channel activation. Thus, T-type I
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- 2022
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24. Putative Synthetic Cannabinoids MEPIRAPIM, 5F-BEPIRAPIM (NNL-2), and Their Analogues Are T-Type Calcium Channel (CaV3) Inhibitors
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Richard C. Kevin, Somayeh Mirlohi, Jamie J. Manning, Rochelle Boyd, Elizabeth A. Cairns, Adam Ametovski, Felcia Lai, Jia Lin Luo, William Jorgensen, Ross Ellison, Roy R. Gerona, David E. Hibbs, Iain S. McGregor, Michelle Glass, Mark Connor, Chris Bladen, Gerald W. Zamponi, and Samuel D. Banister
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Physiology ,Cognitive Neuroscience ,Cell Biology ,General Medicine ,Biochemistry - Published
- 2022
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25. Adaptive Athlete Training Plan Generation: An intelligent control systems approach
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Marco Beato, Mark Connor, and Michael O'Neill
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Decision support system ,Operations research ,Computer science ,Control (management) ,Proportional control ,Physical Therapy, Sports Therapy and Rehabilitation ,Optimal control ,Evolutionary computation ,Feedback ,Athletic training ,Artificial Intelligence ,Athletes ,Control system ,Humans ,Computer Simulation ,Orthopedics and Sports Medicine ,Design methods - Abstract
Objectives: The planning and control of team sport training activities is an extremely important aspect of athletic development and team performance. This research introduces a novel system which leverages techniques from the fields of control systems theory and artificial intelligence (AI) to construct optimal future training plans when unexpected disturbances and deviations from a training plan goal occur. Design: Simulation-based experimental design Methods: The adaptation of training load prescriptions was formulated as an optimal control problem where we seek to minimize the difference between a desired training plan goal and an observed training outcome. To determine the most suitable approach to optimise future training loads the performance of an AI based feedback controller was compared to random and proportional controllers. Robust computational simulations (N=1800) were conducted using a non-linear training plan spanning 60 days over a 12-week period, the control strategies were assessed on their ability to adapt future training loads when disturbances and deviations from an optimal planning policy have occurred. Statistical analysis was conducted to determine if significant difference existed between the three control strategies. Results: The results of a repeated-measures analysis of variance demonstrated that an intelligent feedback controller significantly outperforms the random (p
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- 2022
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26. A systematic literature review and meta-analysis of the effect of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders
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Steve Kisely, Mark Connor, Andrew A Somogyi, and Dan Siskind
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Psychiatry and Mental health ,General Medicine - Abstract
Objectives: There is an increasing interest in combining psilocybin or methylenedioxymethamphetamine with psychological support in treating psychiatric disorders. Although there have been several recent systematic reviews, study and participant numbers have been limited, and the field is rapidly evolving with the publication of more studies. We therefore conducted a systematic review of PubMed, MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, Embase, and CINAHL for randomised controlled trials of methylenedioxymethamphetamine and psilocybin with either inactive or active controls. Methods: Outcomes were psychiatric symptoms measured by standardised, validated and internationally recognised instruments at least 2 weeks following drug administration, Quality was independently assessed using the Cochrane risk of bias assessment tool and Grading of Recommendations Assessment, Development and Evaluation framework. Results: There were eight studies on methylenedioxymethamphetamine and six on psilocybin. Diagnoses included post-traumatic stress disorder, long-standing/treatment-resistant depression, obsessive-compulsive disorder, social anxiety in adults with autism, and anxiety or depression in life-threatening disease. The most information and strongest association was for the change in methylenedioxymethamphetamine scores compared to active controls in post-traumatic stress disorder ( k = 4; standardised mean difference = −0.86; 95% confidence interval = [−1.23, −0.50]; p Conclusion: Methylenedioxymethamphetamine and psilocybin may show promise in highly selected populations when administered in closely supervised settings and with intensive support.
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- 2022
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27. Modulation of Recombinant Human T-Type Calcium Channels by Δ9-Tetrahydrocannabinolic Acid In Vitro
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Marina Santiago, Chris Bladen, Somayeh Mirlohi, and Mark Connor
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Pharmacology ,Membrane potential ,Voltage-dependent calcium channel ,Chemistry ,medicine.medical_treatment ,T-type calcium channel ,In vitro ,law.invention ,Electrophysiology ,Complementary and alternative medicine ,law ,Tetrahydrocannabinolic acid ,Recombinant DNA ,medicine ,Biophysics ,Pharmacology (medical) ,Cannabinoid ,Steady state (chemistry) ,Patch clamp ,Δ9-tetrahydrocannabinol ,medicine.drug - Abstract
IntroductionLow voltage-activated T-type calcium channels (T-type ICa), CaV3.1, CaV3.2, and CaV3.3 are opened by small depolarizations from the resting membrane potential in many cells and have been associated with neurological disorders including absence epilepsy and pain. Δ9-tetrahydrocannabinol (THC) is the principal psychoactive compound in Cannabis and also directly modulates T-type ICa, however, there is no information about functional activity of most phytocannabinoids on T-type calcium channels, including Δ9-tetrahydrocannabinol acid (THCA), the natural non-psychoactive precursor of THC. The aim of this work was to characterize THCA effects on T-type calcium channels.Materials and MethodsWe used HEK293 Flp-In-TREx cells stably expressing CaV3.1, 3.2 or 3.3. Whole-cell patch clamp recordings were made to investigate cannabinoid modulation of ICa.ResultsTHCA and THC inhibited the peak current amplitude CaV3.1 with a pEC50s of 6.0 ± 0.7 and 5.6 ± 0.4, respectively. 1μM THCA or THC produced a significant negative shift in half activation and inactivation of CaV3.1 and both drugs prolonged CaV3.1 deactivation kinetics. THCA (10 μM) inhibited CaV3.2 by 53% ± 4 and both THCA and THC produced a substantial negative shift in the voltage for half inactivation and modest negative shift in half activation of CaV3.2. THC prolonged the deactivation time of CaV3.2 while THCA did not. THCA inhibited the peak current of CaV3.3 by 43% ± 2 (10μM) but did not notably affect CaV3.3 channel activation or inactivation, however, THC caused significant hyperpolarizing shift in CaV3.3 steady state inactivation.DiscussionTHCA modulated T-type ICa currents in vitro, with significant modulation of kinetics and voltage dependence at low μM concentrations. This study suggests that THCA may have potential for therapeutic use in pain and epilepsy via T-type channel modulation without the unwanted psychoactive effects associated with THC.
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- 2022
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28. Modulation of Recombinant Human T-Type Calcium Channels by Δ
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Somayeh, Mirlohi, Chris, Bladen, Marina, Santiago, and Mark, Connor
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Calcium Channels, T-Type ,HEK293 Cells ,Humans ,Pain ,Dronabinol ,Original Research - Abstract
Introduction: Low voltage-activated T-type calcium channels (T-type I(Ca)), Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3, are opened by small depolarizations from the resting membrane potential in many cells and have been associated with neurological disorders, including absence epilepsy and pain. Δ(9)-tetrahydrocannabinol (THC) is the principal psychoactive compound in Cannabis and also directly modulates T-type I(Ca); however, there is no information about functional activity of most phytocannabinoids on T-type calcium channels, including Δ(9)-tetrahydrocannabinolic acid (THCA), the natural nonpsychoactive precursor of THC. The aim of this work was to characterize THCA effects on T-type calcium channels. Materials and Methods: We used HEK293 Flp-In-TREx cells stably expressing Ca(V)3.1, 3.2, or 3.3. Whole-cell patch clamp recordings were made to investigate cannabinoid modulation of I(Ca). Results: THCA and THC inhibited the peak current amplitude Ca(V)3.1 with pEC(50)s of 6.0±0.7 and 5.6±0.4, respectively. THC (1 μM) or THC produced a significant negative shift in half activation and inactivation of Ca(V)3.1, and both drugs prolonged Ca(V)3.1 deactivation kinetics. THCA (10 μM) inhibited Ca(V)3.2 by 53%±4%, and both THCA and THC produced a substantial negative shift in the voltage for half inactivation and modest negative shift in half activation of Ca(V)3.2. THC prolonged the deactivation time of Ca(V)3.2, while THCA did not. THCA inhibited the peak current of Ca(V)3.3 by 43%±2% (10 μM) but did not notably affect Ca(V)3.3 channel activation or inactivation; however, THC caused significant hyperpolarizing shift in Ca(V)3.3 steady-state inactivation. Discussion: THCA modulated T-type I(Ca) currents in vitro, with significant modulation of kinetics and voltage dependence at low μM concentrations. This study suggests that THCA may have potential for therapeutic use in pain and epilepsy through T-type calcium channel modulation without the unwanted psychoactive effects associated with THC.
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- 2023
29. Using multiple machine learning algorithms to classify elite and sub-elite goalkeepers in professional men’s football
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Ashwin Phatak, Mikael Jamil, Mark Connor, Daniel Memmert, Marco Beato, and Saumya Mehta
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Multidisciplinary ,Training set ,business.industry ,Computer science ,Mathematics and computing ,Science ,Scientific data ,Football ,Machine learning ,computer.software_genre ,Article ,Random forest ,Elite ,Medicine ,Artificial intelligence ,Gradient boosting ,business ,computer ,Algorithm - Abstract
This study applied multiple machine learning algorithms to classify the performance levels of professional goalkeepers (GK). Technical performances of GK’s competing in the elite divisions of England, Spain, Germany, and France were analysed in order to determine which factors distinguish elite GK’s from sub-elite GK’s. A total of (n = 14,671) player-match observations were analysed via multiple machine learning algorithms (MLA); Logistic Regressions (LR), Gradient Boosting Classifiers (GBC) and Random Forest Classifiers (RFC). The results revealed 15 common features across the three MLA’s pertaining to the actions of passing and distribution, distinguished goalkeepers performing at the elite level from those that do not. Specifically, short distribution, passing the ball successfully, receiving passes successfully, and keeping clean sheets were all revealed to be common traits of GK’s performing at the elite level. Moderate to high accuracy was reported across all the MLA’s for the training data, LR (0.7), RFC (0.82) and GBC (0.71) and testing data, LR (0.67), RFC (0.66) and GBC (0.66). Ultimately, the results discovered in this study suggest that a GK’s ability with their feet and not necessarily their hands are what distinguishes the elite GK’s from the sub-elite.
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- 2021
30. The influence of possession status on the physical output of male international hockey players
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Ulrik McCarthy Persson, Catherine Blake, Colin Boreham, Walter McConnell, Mark Connor, Marco Beato, Eoin Cunniffe, Eamonn Delahunt, and Adam Grainger
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Match analysis ,03 medical and health sciences ,0302 clinical medicine ,Field hockey ,Team sport ,Applied psychology ,030229 sport sciences ,Possession (law) ,Psychology ,030217 neurology & neurosurgery ,Social Sciences (miscellaneous) - Abstract
The aims of this investigation were to describe the physical output of hockey relative to possession status, and to identify differences in physical output during each possession category with respect of match result. Ten international matches were analysed utilizing Sportscode to identify in and not in possession instances. 24 players (age 26 ± 4) wore a 10 Hz GPS device to track physical output. Linear Mixed Models and post hoc pairwise comparisons were utilised to compare the physical output in each possession category within each position and relative to match result. Significant main effects were found for possession status on several physical output metrics (p ≤ 0.05). For all positions except forwards, not in possession instances were more physically demanding than in possession instances for metrics such as relative total distance, explosive distance, and high-speed running (>5.5 m.s−1). No significant difference was identified between possession category physical output aligned with match result (p > 0.05). This study shows for the first time that not in possession instances were more physically demanding than in possession instances for defenders, outside backs and midfielders. For not in possession instances, relative total distance and high-speed running was, on average, 13% and 41% higher compared to in possession instances. Furthermore, there was no statistical difference in physical output for any position during each possession category relative to the match result.
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- 2021
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31. Risks of mining to salmonid-bearing watersheds
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Christopher J. Sergeant, Erin K. Sexton, Jonathan W. Moore, Alana R. Westwood, Sonia A. Nagorski, Joseph L. Ebersole, David M. Chambers, Sarah L. O’Neal, Rachel L. Malison, F. Richard Hauer, Diane C. Whited, Jill Weitz, Jackie Caldwell, Marissa Capito, Mark Connor, Christopher A. Frissell, Greg Knox, Erin D. Lowery, Randal Macnair, Vicki Marlatt, Jenifer K. McIntyre, Megan V. McPhee, and Nikki Skuce
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Multidisciplinary - Abstract
Mining provides resources for people but can pose risks to ecosystems that support cultural keystone species. Our synthesis reviews relevant aspects of mining operations, describes the ecology of salmonid-bearing watersheds in northwestern North America, and compiles the impacts of metal and coal extraction on salmonids and their habitat. We conservatively estimate that this region encompasses nearly 4000 past producing mines, with present-day operations ranging from small placer sites to massive open-pit projects that annually mine more than 118 million metric tons of earth. Despite impact assessments that are intended to evaluate risk and inform mitigation, mines continue to harm salmonid-bearing watersheds via pathways such as toxic contaminants, stream channel burial, and flow regime alteration. To better maintain watershed processes that benefit salmonids, we highlight key windows during the mining governance life cycle for science to guide policy by more accurately accounting for stressor complexity, cumulative effects, and future environmental change.
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- 2022
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32. Wound Care: A Palm Pilot-Based Expert System for the Treatment of Pressure Ulcers.
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Douglas D. Dankel II, Mark Connor, and Zulma Chardon
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- 2003
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33. Optimizing Team Sport Training With Multi-Objective Evolutionary Computation
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Michael O'Neill, David Faganan, Fergal McCaffery, Barry Watters, and Mark Connor
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General Computer Science ,Team sport ,Computer science ,Management science ,Biomedical Engineering ,Training (civil) ,Evolutionary computation - Abstract
This research introduces a new novel method for mathematically optimizing team sport training models to enhance two measures of athletic performance using an evolutionary computation based approach. A common training load model, consisting of daily training load prescriptions, was optimized using an evolutionary multi-objective algorithm to produce improvements in the mean match-day running intensity across a competitive season. The optimized training model was then compared to real-world observed training and performance data to assess the potential improvements in performance that could be achieved. The results demonstrated that it is possible to increase and maintain a stable level of match-day running performance across a competitive season whilst adhering to model-based and real-world constraints, using an intelligently optimized training design compared a to standard human design, across multiple performance criteria (BF+0 = 5651, BF+0 = 11803). This work demonstrates the value of evolutionary algorithms to design and optimize team sport training models and provides support staff with an effective decision support system to plan and prescribe optimal strategies to enhance in-season athlete performance.
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- 2021
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34. Defining Steric Requirements at CB
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Jack, Markham, Eric, Sparkes, Rochelle, Boyd, Shuli, Chen, Jamie J, Manning, David, Finlay, Felcia, Lai, Eila, McGregor, Callan J, Maloney, Roy R, Gerona, Mark, Connor, Iain S, McGregor, David E, Hibbs, Michelle, Glass, Richard C, Kevin, and Samuel D, Banister
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Cannabinoid Receptor Agonists ,Receptor, Cannabinoid, CB2 ,Mice ,Indazoles ,Receptor, Cannabinoid, CB1 ,Cannabinoids ,Animals ,Valine ,Receptors, Cannabinoid ,Central Nervous System Agents - Abstract
Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS). They commonly comprise
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- 2022
35. Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels
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Jonathon C. Arnold, Jordyn Stuart, Mark Connor, Marina Santiago, Charlotte Fletcher, Iain S. McGregor, and Marika Heblinski
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Pharmacology ,Entourage effect ,Complementary and alternative medicine ,TRPV1 ,Pharmacology (medical) ,Biology ,Cannabis sativa ,Endocannabinoid system ,Terpenoid - Abstract
Introduction: Cannabis sativa produces hundreds of bioactive compounds, including cannabinoids and terpenoids. It has been proposed that cannabinoids act in synergy with terpenoids to produce the e...
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- 2020
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36. Analysing the physical output of international field hockey players through the lens of the phase of play
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Eoin Cunniffe, Mark Connor, Marco Beato, Adam Grainger, Walter Mcconnell, and Catherine Blake
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Social Sciences (miscellaneous) - Abstract
The purpose of this study was to describe the locomotor activity of men's hockey based on the phase of play and to identify if differences in locomotor activity exist between phases. Twenty-four players (age 26 ± 4) wore a 10 Hz Global Positioning System device to track locomotor activity during 10 international matches. The locomotor activity of players was allocated to five different phases: (1) established attack, (2) opposition counterattack, (3) established defence, (4) attacking counterattack and (5) offensive pressing, utilising a video analysis-based system. Linear mixed models and post-hoc pairwise comparisons, using estimated marginal means, were utilised to compare the locomotor activity in each phase of play within each position. Significant main effects were found for the phase of play on several locomotor activity metrics ( p ≤ 0.05). With respect to max speed and relative total distance across positions, counterattacks present a unique challenge compared to other phases. Established attack phases evoke lower max speed values than offensive pressing phases for all playing positions as well as compared to opposition counterattacks for defenders, midfielders, and forwards. Positional differences existed during attacking counterattack phases, with defenders producing lower values than both midfielders and forwards for high-speed running, high-speed running efforts, max speed and relative total distance. Depending on the metric, this approach captured 22%–70% of a player's locomotor activity providing valuable insight into the current dynamics of international hockey. This investigation demonstrated positional differences based on the phase of play, which may explain previous research findings regarding positional differences.
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- 2023
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37. Tapentadol shows lower intrinsic efficacy at µ receptor than morphine and oxycodone
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Marina Junqueira Santiago, Preeti Manandhar, and Mark Connor
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Morphine ,Receptors, Opioid, mu ,opioids ,G protein ,RM1-950 ,Analgesics, Opioid ,Tapentadol ,Mice ,Neurology ,µ receptor ,Cell Line, Tumor ,Animals ,Humans ,pain ,intrinsic efficacy ,Therapeutics. Pharmacology ,General Pharmacology, Toxicology and Pharmaceutics ,operational model ,Oxycodone - Abstract
Tapentadol is a centrally acting analgesic with a dual mechanism of action. It acts as an agonist at the µ receptor and inhibitor of noradrenaline reuptake. Clinical trials suggest similar analgesic efficacy of tapentadol, oxycodone, and morphine in acute and chronic pain. Given the limited information about the molecular actions of tapentadol at the µ receptor, we investigated the intrinsic efficacy of tapentadol and compared it with other opioids. β‐chlornaltrexamine (β‐CNA, 100 nM, 20 min) was used to deplete spare receptors in AtT20 cells stably transfected with human µ receptor wild‐type (WT). Opioid‐mediated changes in membrane potential were measured in real‐time using a membrane potential‐sensitive fluorescent dye. Using Black and Leff’s operational model, intrinsic efficacy relative to DAMGO was calculated for each opioid. Tapentadol (0.05 ± 0.01) activated the GIRK channel with lesser intrinsic efficacy than morphine (0.17 ± 0.02) and oxycodone (0.16 ± 0.02). We further assessed the signaling of tapentadol in the common µ receptor variants (N40D and A6V) which are associated with altered receptor signaling. We found no difference in the response of tapentadol between these receptor variants.
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- 2021
38. Context is key: normalization as a novel approach to sport specific preprocessing of KPI's for match analysis in soccer
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Ashwin A. Phatak, Saumya Mehta, Franz-Georg Wieland, Mikael Jamil, Mark Connor, Manuel Bassek, and Daniel Memmert
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Multidisciplinary ,Science ,Computational science ,Statistics ,Medicine ,human activities ,Article - Abstract
Key Performance Indicators (KPIs) have been investigated, validated and applied in multitude of sports for recruiting, coaching, opponent, self-analysis etc. Although a wide variety of in game performance indicators have been used as KPIs, they lack sports specific context. With the introduction of artificial intelligence and machine learning (AI/ML) in sports, the need for building intrinsic context into the independent variables is even greater as AI/ML models seem to perform better in terms of predictability but lack interpretability. The study proposes domain specific feature preprocessing method (normalization) that can be utilized across a wide range of sports and demonstrates its value through a specific data transformation by using team possession as a normalizing factor while analyzing defensive performance in soccer. The study performed two linear regressions and three gradient boosting machine models to demonstrate the value of normalization while predicting defensive performance. The results demonstrate that the direction of correlation of the relevant variables changes post normalization while predicting defensive performance of teams for the whole season. Both raw and normalized KPIs showing significant correlation with defensive performance (p
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- 2021
39. Employing the Operational Model to Measure System-Independent OTR Efficacy
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Kiyan Afzali and Mark Connor
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Measure (data warehouse) ,Multivariate analysis ,Scope (project management) ,Computer science ,Drug discovery ,business.industry ,Machine learning ,computer.software_genre ,Drug activity ,Basic research ,Artificial intelligence ,Robust analysis ,business ,computer - Abstract
Ideally, pharmacological analysis is based on quantitative measurements applied toward unveiling biological mechanisms and guiding medicinal chemistry efforts in drug discovery and basic research. The most robust analysis frameworks generate findings which can be dissociated from the specific experimental setting to provide insights of a broader scope. With insufficient efficacy being the leading cause of drug failures in late-stage clinical trials, more rigorous preclinical definitions might assist in better translation. This chapter details a new method for accessing the Black and Leff operational model of agonism using a stable Flp-In™ T-REx™ HEK293 cell line under tetracycline-dependent control of OTR expression. We cover steps for performing the Gq-coupled HTRF® IP-One assay, curve-fitting data, calculating and statistically representing system-independent drug activity, predicting responses in different sensitivities, and plotting of multivariate analyses.
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- 2021
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40. Employing the Operational Model to Measure System-Independent OTR Efficacy
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Kiyan, Afzali and Mark, Connor
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HEK293 Cells ,Genetic Techniques ,Pharmaceutical Preparations ,Drug Discovery ,Humans - Abstract
Ideally, pharmacological analysis is based on quantitative measurements applied toward unveiling biological mechanisms and guiding medicinal chemistry efforts in drug discovery and basic research. The most robust analysis frameworks generate findings which can be dissociated from the specific experimental setting to provide insights of a broader scope. With insufficient efficacy being the leading cause of drug failures in late-stage clinical trials, more rigorous preclinical definitions might assist in better translation. This chapter details a new method for accessing the Black and Leff operational model of agonism using a stable Flp-In™ T-REx™ HEK293 cell line under tetracycline-dependent control of OTR expression. We cover steps for performing the G
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- 2021
41. Opioid receptors in GtoPdb v.2021.3
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Eric J. Simon, Nurulain T. Zaveri, Dominique Massot, Brian M. Cox, Lawrence Toll, Lakshmi A. Devi, Toni S. Shippenberg, Eamonn Kelly, John R. Traynor, Philip S. Portoghese, Mary Jeanne Kreek, Brigitte L. Kieffer, Hiroshi Ueda, Andreas Zimmer, Volker Höllt, Graeme Henderson, Charles Chavkin, Stephen M. Husbands, MacDonald J. Christie, Michael R. Bruchas, Mark Connor, Ian Kitchen, Girolamo Calò, Anna Borsodi, Stefan Schulz, Olivier Civelli, Jean-Claude Meunier, Lee-Yuan Liu-Chen, Yung Hou Wong, and Christopher J. Evans
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chemistry.chemical_compound ,Nociceptin receptor ,chemistry ,Enkephalin ,Opioid ,Dynorphin B ,medicine ,Dynorphin A ,(+)-Naloxone ,Pharmacology ,Receptor ,Big dynorphin ,medicine.drug - Abstract
Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [121, 100, 91]. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [294], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone, however only for the μ receptor.
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- 2021
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42. Optimizing the parameters of a physical exercise dose-response model
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Michael O'Neill and Mark Connor
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FOS: Computer and information sciences ,Nonlinear system ,Mathematical optimization ,Response model ,Optimization algorithm ,Robustness (computer science) ,Computer science ,Differential evolution ,Computer Science - Neural and Evolutionary Computing ,Neural and Evolutionary Computing (cs.NE) ,Least squares ,Field (computer science) ,Evolutionary computation - Abstract
The purpose of this research was to compare the robustness and performance of a local and global optimization algorithm applied to the problem of fitting the parameters of a non-linear dose-response model utilized in the field of exercise physiology. Traditionally the parameters of dose-response models utilised in exercise physiology have been fit with non-linear least squares procedures in combination with local optimization algorithms. These algorithms have demonstrated limitations in their ability to converge on a globally optimal solution. This research purposes the use of an evolutionary computation based algorithm as an alternative method to fit a nonlinear dose-response model. The results of our comparison over 1000 experimental runs demonstrated the superior performance of the evolutionary computation based algorithm to consistently achieve a more consistent model fit and holdout evaluation performance in comparison to the local search algorithm. This initial research would suggest that global evolutionary computation based optimization algorithms are a fast and more robust alternative to local optimization algorithms when fitting the parameters of nonlinear dose-response models.
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- 2021
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43. Quantifying and Comparing the Match Demands of U18, U23, and 1ST Team English Professional Soccer Players
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Marco Beato, Mikael Jamil, Mark Connor, and James Reynolds
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football ,Computer science ,business.industry ,Physiology ,GPS ,Triaxial accelerometer ,speed ,030229 sport sciences ,Football ,Northern ireland ,Brief Research Report ,03 medical and health sciences ,0302 clinical medicine ,Digital subscriber line ,Multivariate analysis of variance ,Sprint ,GNSS applications ,Physiology (medical) ,Statistics ,Global Positioning System ,QP1-981 ,030212 general & internal medicine ,team sports ,business ,performance - Abstract
The aim of this study was to quantify and compare the match load demands of U18, U23, and 1ST team players during the official season. A total of 65 matches and 495 (U18 = 146, U23 = 146, and 1ST team = 203) individual player game observations were included in this analysis. A 10-Hz global navigation satellite systems (GNSS) and 100-Hz triaxial accelerometer (STATSports, Apex, Northern Ireland) were used to monitor the following metrics during official matches: total distance, high-speed running distance (HSR), sprint distance, high metabolic distance, explosive distance, high-intensity bursts distance, speed intensity, and dynamic stress load (DSL) were analyzed. A multivariate analysis of variance test reported significant (p < 0.001) differences among the groups. HSR during matches was lower (d = small) for U18 players than the U23 and 1ST team players. Sprint distance and high-intensity bursts distance were lower (small) in U18 compared with the U23 and 1ST team. DSL was greater in 1ST compared with U18 (small) and U23 (small). This study reported that the differences between groups were greater for HSR, sprint distance, high-intensity bursts distance, and DSL, while total distance, high metabolic load distance, explosive distance, and speed intensity did not differ between the groups. These findings could be used to design training programs in the academy players (i.e., U18) to achieve the required long-term physical adaptations that are needed to progress into the U23 and 1ST teams.
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- 2021
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44. Cannabichromene is a cannabinoid CB2receptor agonist
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Iain S. McGregor, Mark Connor, Michael Philip Udoh, Marina Santiago, and Steven O. Devenish
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0301 basic medicine ,Agonist ,Indoles ,Cannabinoid receptor ,medicine.drug_class ,medicine.medical_treatment ,Pharmacology ,Pertussis toxin ,Receptor, Cannabinoid, CB2 ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Cannabichromene ,chemistry.chemical_compound ,0302 clinical medicine ,Cell surface receptor ,parasitic diseases ,Tumor Cells, Cultured ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Tetrahydrocannabinol ,Receptor ,Cannabinoid Receptor Agonists ,Dose-Response Relationship, Drug ,Molecular Structure ,Cannabinoids ,Research Papers ,030104 developmental biology ,Pertussis Toxin ,chemistry ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - Abstract
BACKGROUNDCannabichromene (CBC) is one of the most abundant phytocannabinoids inCannabis spp. It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ9-tetrahydrocannabinol (THC)in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.EXPERIMENTAL APPROACHAtT20 cells stably expressing HA-tagged human CB1 and CB2 receptors were used. Assays of cellular membrane potential and loss of cell surface receptors were performed.KEY RESULTSCBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. Activation of CB2 receptors was antagonised by the CB2 antagonist AM630 and sensitive to pertussis toxin. Co-application of CBC reduced activation of CB2 receptors CP55,940, a potent CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.CONCLUSIONS AND IMPLICATIONSCannabichromene is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.
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- 2019
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45. Strategies to develop selective CB2 receptor agonists from indole carboxamide synthetic cannabinoids
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Mark Connor, Michael Moir, Michael Kassiou, Felcia Lai, David E. Hibbs, and Samuel Lane
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Pharmacology ,Indole test ,0303 health sciences ,Cannabinoid receptor ,010405 organic chemistry ,medicine.drug_class ,Chemistry ,medicine.medical_treatment ,Organic Chemistry ,Carboxamide ,General Medicine ,01 natural sciences ,0104 chemical sciences ,Designer drug ,03 medical and health sciences ,Docking (molecular) ,Drug Discovery ,Synthetic cannabinoids ,medicine ,Cannabinoid receptor type 2 ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,030304 developmental biology ,medicine.drug - Abstract
Activation of the CB2 receptor is an attractive therapeutic strategy for the treatment of a wide range of inflammatory diseases. However, receptor subtype selectivity is necessary in order to circumvent the psychoactive effects associated with activation of the CB1 receptor. We aimed to use potent, non-selective synthetic cannabinoids designer drugs to develop selective CB2 receptor agonists. Simple structural modifications such as moving the amide substituent of 3-amidoalkylindole synthetic cannabinoids to the 2-position and bioisosteric replacement of the indole core to the 7-azaindole scaffold are shown to be effective and general strategies to impart receptor subtype selectivity. 2-Amidoalkylindole 16 (EC50 CB1 > 10 μM, EC50 CB2 = 189 nM) and 3-amidoalkyl-7-azaindole 21 (EC50 CB1 > 10 μM, EC50 = 49 nM) were found to be potent and selective agonists with favourable physicochemical properties. Docking studies were used to elucidate the molecular basis for the observed receptor subtype selectivity for these compounds.
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- 2019
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46. New-generation azaindole-adamantyl-derived synthetic cannabinoids
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Rochelle Boyd, Michael Kassiou, Karen Blakey, Mitchell Longworth, Mark Connor, and Tristan A. Reekie
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Cannabinoid receptor ,Bicyclic molecule ,Chemistry ,010401 analytical chemistry ,Biochemistry (medical) ,Toxicology ,Mass spectrometry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,APICA ,Synthetic cannabinoids ,medicine ,030216 legal & forensic medicine ,Gas chromatography–mass spectrometry ,Divergent synthesis ,Plate reader ,medicine.drug - Abstract
This work reports the synthesis and pharmacological and analytical data for a new series of recently identified azaindole-adamantyl-derived synthetic cannabinoids (SCs). Each SC was synthesised using an efficient and divergent synthesis, and assessed by electron ionisation mass spectrometry (EIMS). The cannabimimetic activity of each compound was conducted using a fluorometric imaging plate reader (FLIPR) assay. The described EIMS method and retention time by gas chromatography were able to effectively differentiate each of the analogues regardless of the bicyclic core. For the first time in these SC structures, the bicyclic ring system was shown to have an impact on the cannabimimetic activities in the fluorometric assay of membrane potential. Analogues ranged from moderately potent at both CB1 and CB2 (e.g., AP4AIC EC50 = 160 nM and EC50 = 64 nM, respectively) to not active at either cannabinoid receptor (AP4AICA, AP5AICA, and APIC). Further investigation into receptor selectivity surrounding these bicyclic cores could prove useful for future therapeutic applications.
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- 2019
- Full Text
- View/download PDF
47. Dark Classics in Chemical Neuroscience: Δ9-Tetrahydrocannabinol
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Jonathon C. Arnold, Michelle Glass, Samuel D. Banister, Mark Connor, and Iain S. McGregor
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Drug ,medicine.medical_specialty ,Physiology ,Cognitive Neuroscience ,media_common.quotation_subject ,medicine.medical_treatment ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,Dementia ,Tetrahydrocannabinol ,Psychiatry ,030304 developmental biology ,media_common ,0303 health sciences ,biology ,organic chemicals ,Addiction ,Cell Biology ,General Medicine ,medicine.disease ,biology.organism_classification ,Anorexia nervosa (differential diagnoses) ,Cannabis ,Cannabinoid ,Cannabidiol ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Cannabis ( Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally. The main psychoactive component of cannabis is (-)- trans-Δ9-tetrahydrocannabinol (Δ9-THC), a compound with a diverse range of pharmacological actions. The unique and distinctive intoxication caused by Δ9-THC primarily reflects partial agonist action at central cannabinoid type 1 (CB1) receptors. Δ9-THC is an approved therapeutic treatment for a range of conditions, including chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis, and is being investigated in indications such as anorexia nervosa, agitation in dementia, and Tourette's syndrome. It is available as a regulated pharmaceutical in products such as Marinol, Sativex, and Namisol as well as in an ever-increasing range of unregistered medicinal and recreational cannabis products. While cannabis is an ancient medicament, contemporary use is embroiled in legal, scientific, and social controversy, much of which relates to the potential hazards and benefits of Δ9-THC itself. Robust contemporary debate surrounds the therapeutic value of Δ9-THC in different diseases, its capacity to produce psychosis and cognitive impairment, and the addictive and "gateway" potential of the drug. This review will provide a profile of the chemistry, pharmacology, and therapeutic uses of Δ9-THC as well as the historical and societal import of this unique, distinctive, and ubiquitous psychoactive substance.
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- 2019
- Full Text
- View/download PDF
48. Ligand determinants of fatty acid activation of the pronociceptive ion channel TRPA1
- Author
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William John Redmond, Liuqiong Gu, Maxime Camo, Peter McIntyre, and Mark Connor
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Arachidonic acid ,TRP channel ,Pain ,Inflammation ,Arachidonoyl amino acid/neurotransmitter conjugate ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background and purpose. Arachidonic acid (AA) and its derivatives are important modulators of cellular signalling. The transient receptor potential cation channel subfamily A, member 1 (TRPA1) is a cation channel with important functions in mediating cellular responses to noxious stimuli and inflammation. There is limited information about the interactions between AA itself and TRPA1, so we investigated the effects of AA and key ethanolamide and amino acid/neurotransmitter derivatives of AA on hTRPA1.Experimental approach. HEK 293 cells expressing hTRPA1 were studied by measuring changes in intracellular calcium ([Ca]i) with a fluorescent dye and by standard whole cell patch clamp recordings.Key results. AA (30 μM) increased fluorescence in hTRPA1 expressing cells by 370% (notional EC50 13 μM). The covalent TRPA1 agonist cinnamaldehyde (300 μM) increased fluorescence by 430% (EC50, 11 μM). Anandamide (230%) and N-arachidonoyl tyrosine (170%) substantially activated hTRPA1 at 30 μM, however, N-arachidonoyl conjugates of glycine and taurine were less effective while N-acyl conjugates of 5-HT did not affect hTRPA1. Changing the acyl chain length or the number and position of double bonds reduced fatty acid efficacy at hTRPA1. Mutant hTRPA1 (Cys621, Cys641 and Cys665 changed to Ser) could be activated by AA (100 μM, 40% of wild type) but not by cinnamaldehyde (300 μM).Conclusions and implications. AA is a more potent activator of TRPA1 than its ethanolamide or amino acid/neurotransmitter derivatives and acts via a mechanism distinct from that of cinnamaldehyde, further underscoring the likelyhood of multiple pharmacologically exploitable sites on hTRPA1.
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- 2014
- Full Text
- View/download PDF
49. Lifetime-Engineered Ruby Nanoparticles (Tau-Rubies) for Multiplexed Imaging of μ-Opioid Receptors
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Varun K. A. Sreenivasan, Marina Santiago, Alireza Maleki, Xianlin Zheng, Yiqing Lu, Judith M. Dawes, Xiaohong Yang, Mark Connor, Nikolay A. Lipey, and Andrei V. Zvyagin
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Diagnostic Imaging ,Materials science ,Photoluminescence ,Nanoparticle ,Bioengineering ,02 engineering and technology ,Biosensing Techniques ,01 natural sciences ,Multiplexing ,Nanomaterials ,Instrumentation ,Fluid Flow and Transfer Processes ,Dopant ,Scattering ,business.industry ,Process Chemistry and Technology ,010401 analytical chemistry ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Nanostructures ,Click chemistry ,Optoelectronics ,Nanoparticles ,0210 nano-technology ,business ,Excitation - Abstract
To address the growing demand for simultaneous imaging of multiple biomarkers in highly scattering media such as organotypic cell cultures, we introduce a new type of photoluminescent nanomaterial termed "tau-ruby" composed of ruby nanocrystals (Al2O3:Cr3+) with tunable emission lifetime. The lifetime tuning range from 2.4 to 3.2 ms was achieved by varying the Cr3+ dopant concentration from 0.8% to 0.2%, affording facile implementation of background-free detection. We developed inexpensive scalable production of tau-ruby characterized by bright emission, narrow spectrum (693 ± 2 nm), and virtually unlimited photostability upon excitation with affordable excitation/detection sources, noncytotoxic and insensitive to microenvironmental fluctuations. By functionalizing the surface of tau-rubies with targeting antibodies, we obtained different biomarkers suitable for multiplexed lifetime imaging. As a proof of principle, three tau-ruby bioprobes, characterized by three mean lifetimes, were deployed to label three μ-opioid receptor species expressed on transfected cancer cells, each fused to a unique epitope, so that three types of cells were lifetime-encoded. Robust decoding of photoluminescent signals that report on each cell type was achieved by using a home-built lifetime imaging system and resulted in high-contrast multiplexed lifetime imaging of the cells.
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- 2021
50. Quantifying and modelling the game speed outputs of English Championship soccer players
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Dylan Mernagh, Marco Beato, and Mark Connor
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Male ,Applied psychology ,ComputingMilieux_PERSONALCOMPUTING ,Physical Therapy, Sports Therapy and Rehabilitation ,030229 sport sciences ,Football ,League ,Athletic Performance ,Running ,03 medical and health sciences ,0302 clinical medicine ,Soccer ,Humans ,Orthopedics and Sports Medicine ,Sociology ,Seasons ,Championship ,human activities ,030217 neurology & neurosurgery - Abstract
This study aims to quantify and model the game-speed demands of professional soccer players competing in the English Championship league, to compare the effect of match location and to examine the effect of playing position on game-speed outputs across the season. Twenty-eight male professional soccer players were enrolled. Moving average calculations were applied to the raw GNSS (STATSports) speed data of each player's duration matches (home = 14 and away = 9). Positional groups were centre-back (CB), full-back (FB), centre-midfield (CM), wing-midfield (WM) and centre-forward (CF). The maximum value across each of the moving average window durations was extracted and converted to units of metres per minute. Power-law models were fitted to all observations (R2 = 0.64), home only (R2 = 0.98), and away only (R2 = 0.98). No significant effects are observed in game-speed outputs when home and away games are analysed. Significant differences were seen between the following positional groups; CBvs.CF (
- Published
- 2021
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