Transition metal-free, visible-light mediated synthesis of 1,10-phenanthroline derived ligand systems

A broad range of 1,10-phenanthroline substrates was efficiently C-H functionalised, providing rapid, gram-scale access to substituted heteroaromatic cores of broad utility. Furthermore, this C-H functionalisation pathway was extended to the synthesis of previously inaccessible, ultra-soluble, 2,9-bis-triazinyl-1,10-phenanthroline (BTPhen) ligands for advanced nuclear fuel cycles

Hydrophilic 2,9-bis-triazolyl-1,10-phenanthroline ligands enable selective Am(iii) separation: a step further towards sustainable nuclear energy

The first hydrophilic, 1,10-phenanthroline derived ligands consisting of only C, H, O and N atoms for the selective extraction of Am(iii) from spent nuclear fuel are reported herein. One of these 2,9-bis-triazolyl-1,10-phenanthroline (BTrzPhen) ligands combined with a non-selective extracting agent, was found to exhibit process-suitable selectivity for Am(iii) over Eu(iii) and Cm(iii), providing a clear step forward

Exploring electronic effects on the partitioning of actinides(III) from lanthanides(III) using functionalised bis-triazinyl phenanthroline ligands

The first examples of 4,7-disubstituted 2,9-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzo-triazin-3-yl)-1,10- phenanthroline (CyMe4 -BTPhen) ligands are reported herein. Evaluating the kinetics, selectivity and stoichiometry of actinide(III) and lanthanide(III) radiotracer extractions has provided a mechanistic insight into the extraction process. For the first time, it has been demonstrated that metal ion extraction kinetics can be modulated by backbone functionalisation and a promising new CHON compliant candidate ligand with enhanced metal ion extraction kinetics has been identified. The effects of 4,7- functionalisation on the equilibrium metal ion distribution ratios are far more pronounced than those of 5,6-functionalisation. The complexation of Cm(III) with two of the functionalised ligands was investigated by TRLFS and, at equilibrium, species of 1:2 [M:L] stoichiometry were observed exclusively. A direct correlation between the ELUMO-EHOMO energy gap and metal ion extraction potential is reported, with DFT studies reaffirming experimental findings

Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response

Selective small-molecule inhibitors represent powerful tools for the dissection of complex biological processes. ESI (eeyarestatin I) is a novel modulator of ER (endoplasmic reticulum) function. In the present study, we show that in addition to acutely inhibiting ERAD (ER-associated degradation), ESI causes production of mislocalized polypeptides that are ubiquitinated and degraded. Unexpectedly, our results suggest that these non-translocated polypeptides promote activation of the UPR (unfolded protein response), and indeed we can recapitulate UPR activation with an alternative and quite distinct inhibitor of ER translocation. These results suggest that the accumulation of non-translocated proteins in the cytosol may represent a novel mechanism that contributes to UPR activation

Social patterning of telephone health-advice for diarrhoea and vomiting: analysis of 24 million telehealth calls in England.

OBJECTIVES:Gastrointestinal (GI) infections are common and most people do not see a physician. There is conflicting evidence of the impact of socioeconomic status (SES) on risk of GI infections. We assessed the relationship between SES and GI calls to two National Health Service (NHS) telephone advice services in England. METHODS:Over 24 million calls to NHS Direct (2010-13) and NHS 111 (2013-15) were extracted from Public Health England (PHE) syndromic surveillance systems. The relationship between SES and GI calls was assessed using generalised linear models (GLM). RESULTS:Adjusting for rurality and age-sex interactions, in NHS Direct, children in disadvantaged areas were at lower risk of GI calls; in NHS 111 there was a higher risk of GI calls in disadvantaged areas for all ages (0-4 years RR 1.27, 95% CI 1.25-1.29; 5-9 years RR 1.43, 95% CI 1.36-1.51; 10-14 years RR 1.36, 95% CI 1.26-1.41; 15-19 years RR 1.59, 95% CI 1.52-1.67; 20-59 years RR 1.50, 95% CI 1.47-1.53, 60 years and over RR 1.12, 95% CI 1.09-1.14). CONCLUSIONS:Disadvantaged areas had higher risk of GI calls in NHS 111. This may relate to differences in exposure or vulnerability to GI infections, or propensity to call about GI infections

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study.

BackgroundThe Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.MethodsThe COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.ResultsThe CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.ConclusionAvailability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years

Pacific Ocean–wide profile of CYP1A1 expression, stable carbon and nitrogen isotope ratios, and organic contaminant burden in sperm whale skin biopsies

This paper is not subject to U.S. copyright. The definitive version was published in Environmental Health Perspectives 119 (2011): 337-343, doi:10.1289/ehp.0901809.Background: Ocean pollution affects marine organisms and ecosystems as well as humans. The International Oceanographic Commission recommends ocean health monitoring programs to investigate the presence of marine contaminants and the health of threatened species and the use of multiple and early-warning biomarker approaches. Objective: We explored the hypothesis that biomarker and contaminant analyses in skin biopsies of the threatened sperm whale (Physeter macrocephalus) could reveal geographical trends in exposure on an oceanwide scale. Methods: We analyzed cytochrome P450 1A1 (CYP1A1) expression (by immunohistochemistry), stable nitrogen and carbon isotope ratios (as general indicators of trophic position and latitude, respectively), and contaminant burdens in skin biopsies to explore regional trends in the Pacific Ocean. Results: Biomarker analyses revealed significant regional differences within the Pacific Ocean. CYP1A1 expression was highest in whales from the Galapagos, a United Nations Educational, Scientific, and Cultural Organization World Heritage marine reserve, and was lowest in the sampling sites farthest away from continents. We examined the possible influence of the whales’ sex, diet, or range and other parameters on regional variation in CYP1A1 expression, but data were inconclusive. In general, CYP1A1 expression was not significantly correlated with contaminant burdens in blubber. However, small sample sizes precluded detailed chemical analyses, and power to detect significant associations was limited. Conclusions: Our large-scale monitoring study was successful at identifying regional differences in CYP1A1 expression, providing a baseline for this known biomarker of exposure to aryl hydrocarbon receptor agonists. However, we could not identify factors that explained this variation. Future oceanwide CYP1A1 expression profiles in cetacean skin biopsies are warranted and could reveal whether globally distributed chemicals occur at biochemically relevant concentrations on a global basis, which may provide a measure of ocean integrity.Funding was provided by National Institute of Environmental Health Sciences grant P42-ES-0469, Superfund Basic Research Program grant P42ES007381, NOAA Sea Grant NA86RG0075 R/B-162, and the Ocean Alliance

Introduction: building the history of language learning and teaching (HoLLT)

The papers presented in this issue are the result of a workshop held at the University of Nottingham in December 2012 as part of an Arts and Humanities Research Council research network Towards a History of Modern Foreign Language Teaching and Learning (2012–14) intended to stimulate historical research into language teaching and learning. This, the first workshop in the programme, focused on exchanging information on the history of language learning and teaching (HoLLT) across the different language traditions, for it had become clear to us that scholars working within their own language disciplines were often relatively unaware of work outside these. We hope that this special issue — with overview articles on the history of English, French, German, and Spanish as second/foreign languages — will help overcome that lack of awareness and facilitate further research collaboration. Charting the history of language teaching and learning will, in turn, make us all better informed in facing challenges and changes to policy and practice now and in the future. It is instructive in the current climate, for example, to realize that grave doubts were held about whether second foreign languages could survive alongside French in British schools in the early twentieth century (McLelland, forthcoming), or to look back at earlier attempts to establish foreign languages in primary schools (Bayley, 1989; Burstall et al., 1974; Hoy, 1977). As we write, language learning in England is undergoing yet more radical change. Language teaching for all children from the age of seven is being made compulsory in primary schools from 2014, while at Key Stage 3 (up to age 16), where a foreign language has not been compulsory since 2002, the most recent programme of study for England has virtually abandoned the recent focus on intercultural competence and now requires learners to ‘read great literature in the original language’,1 a radical change in emphasis compared to the previous half-century, which seems to reflect a very different view of what language learning is for. We seem to be little closer in 2014 than we were at the dawn of the twentieth century to answering with any certainty the questions that lie at the very foundations of language teaching: who should learn a foreign language, why learners learn, what they need to learn, and what we want to teach them — answers that we need before we can consider how we want to teach. The research programme begun under our research network is intended to help us to take ‘the long view’ on such questions

Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their effect on brain structure