The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

This work is licensed under a Creative Commons Attribution 4.0 International License.(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.NIDA grant P30 DA13429NIDA grant DA039997NIDA grant DA018151NIDA grant DA035857NIDA grant DA047574NIH Intramural Research Programs of the National Institute on Drug AbuseNational Institute of Alcohol Abuse and AlcoholismNIH Intramural Research Programs of the National Institute on Drug AbuseNIH Intramural Research Program through the Center for Information TechnologyNIH Intramural Research Programs of the National Institute on Drug Abus

Are we working towards global research priorities for management and conservation of sea turtles?

In 2010, an international group of 35 sea turtle researchers refined an initial list of more than 200 research questions into 20 metaquestions that were considered key for management and conservation of sea turtles. These were classified under 5 categories: reproductive biology, biogeography, population ecology, threats and conservation strategies. To obtain a picture of how research is being focused towards these key questions, we undertook a systematic review of the peer-reviewed literature (2014 and 2015) attributing papers to the original 20 questions. In total, we reviewed 605 articles in full and from these 355 (59%) were judged to substantively address the 20 key questions, with others focusing on basic science and monitoring. Progress to answering the 20 questions was not uniform, and there were biases regarding focal turtle species, geographic scope and publication outlet. Whilst it offers some meaningful indications as to effort, quantifying peer-reviewed literature output is ob viously not the only, and possibly not the best, metric for understanding progress towards informing key conservation and management goals. Along with the literature review, an international group based on the original project consortium was assigned to critically summarise recent progress towards answering each of the 20 questions. We found that significant research is being expended towards global priorities for management and conservation of sea turtles. Although highly variable, there has been significant progress in all the key questions identified in 2010. Undertaking this critical review has highlighted that it may be timely to undertake one or more new prioritizing exercises. For this to have maximal benefit we make a range of recommendations for its execution. These include a far greater engagement with social sciences, widening the pool of contributors and focussing the questions, perhaps disaggregating ecology and conservatio

Blending human and artificial intelligence to support Autistic children’s social communication skills

This paper examines the educational efficacy of a learning environment in which children diagnosed with Autism Spectrum Conditions (ASC) engage in social interactions with an artificially intelligent (AI) virtual agent and where a human practitioner acts in support of the interactions. A multi-site intervention study in schools across the UK was conducted with 29 children with ASC and learning difficulties, aged 4-14 years old. For reasons related to data completeness and amount of exposure to the AI environment, data for 15 children was included in the analysis. The analysis revealed a significant increase in the proportion of social responses made by ASC children to human practitioners. The number of initiations made to human practitioners and to the virtual agent by the ASC children also increased numerically over the course of the sessions. However, due to large individual differences within the ASC group, this did not reach significance. Although no evidence of transfer to the real-world post-test was shown, anecdotal evidence of classroom transfer was reported. The work presented in this paper offers an important contribution to the growing body of research in the context of AI technology design and use for autism intervention in real school contexts. Specifically, the work highlights key methodological challenges and opportunities in this area by leveraging interdisciplinary insights in a way that (i) bridges between educational interventions and intelligent technology design practices, (ii) considers the design of technology as well as the design of its use (context and procedures) on par with one another, and (iii) includes design contributions from different stakeholders, including children with and without ASC diagnosis, educational practitioners and researchers

Hidden inequalities amongst the international workforce

This chapter focuses on low status expatriates who have been largely ‘hidden’ from managerial scholarship. They are ‘hidden’ because they are ignored by the migrant literature which looks at people trying to remain in their new society and gain citizenship; and ignored by the expatriation literature which is mainly concerned with high-status ‘top’ talent. These hidden expatriates are typically maids, drivers, security guards, and construction workers - low status and low paid, unable to obtain citizenship, and liable to be sent home, unemployed, at the whim of their employer. If we, as scholars, are to contribute to the betterment of society by elevating the health and well-being of those who live in it, then we must recognise the existence of and address the management issues and concerns of those at the ‘bottom of the pyramid’. We use Organisational Justice theory and draw on examples from Turkey, Singapore and the Middle East to examine the position, the concerns, and the issues of such workers and their often-unequal place in the workforce

structuring and migration routes of an endangered marine turtle

1. The assessment of the composition and dynamics of endangered populations is crucial for management and conservation, and appropriate genetic markers are critical. 2. The genetic structuring of the Mediterranean green turtle ( Chelonia mydas) populations and the origin of the stranded animals found along the Israeli coast was investigated using new highly polymorphic short tandem repeat ( STR) markers. 3. The structuring of nesting populations was studied using pairwise genetic distances and a principal coordinates analysis ( PCoA). 4. The contribution of the different nesting populations to the stranded sample was assessed by using a mixed- stock analysis. 5. A clear population genetic structure, not detected before, has been revealed. The four nesting populations are genetically well differentiated, and thus should be considered as different management units. The populations from Turkey and Israel showed higher resemblance, despite residing at opposite ends of the Mediterranean distribution. TheTurkish nesting population is the main source of the stranded turtles sampled along the Israeli shore, confirming that individuals from this population migrate from north to south along the eastern shore of the Mediterranean, as previously shown by telemetry studies. 6. The use of a highly polymorphic haplotyping method enabled the detection of a clear genetic structuring of the green turtle populations in the eastern Mediterranean Sea that was not revealed in previous studies, demonstrating the importance of marker selection in population genetics. 7. The analysis of the genetic composition of the stranded turtles allowed us to investigate the migration patterns from nesting to foraging areas, supporting previous satellite- tracking and stable- isotope results. 8. These results will help to delineate conservation management units for the species in the Mediterranean, and reveal connectivity among beaches and mixed aggregations