Unraveling the molecular details of the complete mechanism that governs the synthesis of prostaglandin G2 catalyzed by cyclooxygenase-2

This is an open access article published under an ACS AuthorChoice License. See Standard ACS AuthorChoice/Editors' Choice Usage AgreementCyclooxygenase-2 (COX-2) is the key enzyme involved in the synthesis pathway of prostaglandin G₂ (PGG₂) by transformation of arachidonic acid (AA). Although COX-₂ is one of the principal pharmacological targets by the implication of PGG₂2 in several human diseases, the classical all-radical mechanism proposed for COX-₂ catalysis has never been validated at the molecular level. Herein, molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) calculations were combined to analyze the six steps of the all-radical mechanism. The results show that O₂ addition on C₁₁ of AA can follow an antarafacial or suprafacial approach with respect to tyrosine 385, but only the antarafacial addition leads to the product with the correct 11R stereochemistry as established in the mechanistic proposal. Moreover, only the reaction pathway coming from the antarafacial intermediate describes a viable 8,12-cyclization to form the prostaglandin-like bicyclo endoperoxide that finally leads, by kinetic control, to PGG₂ with the 15S stereochemistry found experimentally. The formation of the more stable trans ring isomer of natural PGG₂ in an enzymatic environment is also explained. Our molecular analysis shows how COX-2 uses its relatively narrow channel in the active site to restrain certain conformational changes of AA and of the reaction intermediates, so that the PGG2 enzymatic synthesis turns out to be highly regiospecific and stereospecific. A more recent 10-step carbocation-based mechanistic proposal has been discarded

The incidence of clinical fractures in adults aged 50 years and older in Spain

Objective. The aim of this study was to quantify the incidence of all clinical fractures, including traumatic and fragility fractures, in patients aged 50 years and older, and to describe their distribution by fracture location, sex and age. Methods. The incidence of clinical fractures at 10 hospitals in Catalonia, with a reference population of 3 155 000 inhabitants, was studied. For 1 week, from 30 May to 5 June 2016, we reviewed the discharge reports of the Traumatology section of the Emergency Department to identify all fractures diagnosed in patients ≥50 years of age. As a validation technique, data collection was carried out for 1 year at one of the centres, from 1 December 2015 to 30 November 2016. The fracture incidence, including the 95% CI, was estimated for the entire sample and grouped by fracture type, location, sex and age. Results. A total of 283 fractures were identified. Seventy per cent were in women, with a mean age of 72 years. The overall fracture incidence was 11.28 per 1000 person-years (95% CI: 11.10, 11.46), with an incidence of traumatic and fragility fractures of 4.15 (95% CI: 4.04, 4.26) and 7.13 per 1000 person-years (95% CI: 6.99, 7.28), respectively. The incidence of fractures observed in the validation sample coincided with that estimated for the whole of Catalonia. The most common fragility fractures were of the hip, forearm, humerus and vertebrae. Conclusion. The results of this study are the first to estimate the incidence of clinical fragility fractures in Spain, grouped by location, age and sex

Beyond the conflict: religion in the public sphere and deliberative democracy

Traditionally, liberals have confined religion to the sphere of the ‘private’ or ‘non-political’. However, recent debates over the use of religious symbols in public spaces, state financing of faith schools, and tax relief for religious organisations suggest that this distinction is not particularly useful in easing the tension between liberal ideas of equality among citizens and freedom of religion. This article deals with one aspect of this debate, which concerns whether members of religious communities should receive exemptions from regulations that place a distinctively heavy burden on them. For supporters of exemptions, protection for diverse practices and religious beliefs justifies such a special treatment. For others, this is a form of positive discrimination incompatible with equal citizenship. Drawing on Habermas’ understanding of churches as ‘communities of interpretation’ this article explores possible alternative solutions to both the ‘rule-andexemption’ approach and the ‘neutralist’ approach. Our proposal rests on the idea of mutual learning between secular and religious perspectives. On this interpretation, what is required is, firstly, generation and maintenance of public spaces in which there could be discussion and dialogue about particular cases, and, secondly, evaluation of whether the basic conditions of moral discourse are present in these spaces. Thus deliberation becomes a touchstone for the building of a shared democratic etho

Ambivalence toward men: comparing sexism among Polish, South African and British university students

This study extends the literature on attitudes toward gender roles by exploring whether the nature of sexism (i.e., benevolence and hostility directed at men) differs among university students from two under-researched countries, Poland (n = 190) and South Africa (n = 188), in a comparison with students in the United Kingdom (n = 166). Based on empirical literature applying Ambivalent Sexism Theory, and in the light of the socio-political context, it was hypothesized that: (1) both hostile and benevolent attitudes toward men in Poland would be more liberal than in South Africa and more conservative than in the United Kingdom, and (2), women would exhibit more hostile but less benevolent attitudes than men in relatively more conservative South Africa. The Ambivalence to Men Inventory was used to measure the two types of sexist attitudes about men. Findings supported the first hypothesis for hostile attitudes and partially for benevolent attitudes. South African and Polish students were more benevolent and hostile to men than British students, and students from South Africa were more hostile than those from Poland. Moreover, as predicted, a significant country-by-gender interaction revealed that South African women had more hostile and less benevolent attitudes to men than South African men. No such gender gap was present in the case of hostile attitudes in Poland and benevolent attitudes in the United Kingdom. Findings are discussed in terms of Ambivalent Sexism Theory and the countries’ socio-cultural context

Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE - The UK National Cohort Study

Background: Children with intellectual disability (ID) frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aimed to determine the impact of genomics, inheritance and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared to the general population. Methods: IMAGINE is a prospective study using online mental health and medical assessments in a cohort of 2770 children with ID and pathogenic genomic variants, identified by the UK’s National Health Service. Outcomes: Assessments completed on 2397 young people with ID (4-19 years, M 9·2, SD 3·9) with a rare pathogenic genomic variant. 1339 (55·9%) were male. 1771 (73·9%) of participants had a pathogenic copy number variant (CNV), 626 (26·1%) a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk of co-occurring neuropsychiatric diagnoses, compared with the UK national population, was high: Autism Spectrum Disorder 29·2 (95% CI 23·9 to 36·5), Attention Deficit Hyperactivity Disorder 13·5 (95% CI 11·1 to 16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV. Interpretation: Children with genomic variants and ID are at a greatly enhanced risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk

Cross-Cultural Sexism and the Effectiveness of Gender (Non)Traditional Advertising: A Comparison of Purchase Intentions in Poland, South Africa, and the United Kingdom.

Findings regarding the effectiveness of (non)traditionally gendered advertisements are mixed and largely emanate from the United States. We tested the stereotype content model and ambivalent sexism theory cross-nationally in an advertising context and predicted that paternalistic (vs. envious) female stereotypes will trigger higher purchase intent (PI) irrespective of country (Hypothesis 1), viewers’ benevolent sexism will positively predict PI for paternalistic housewife advertisements (Hypothesis 2a), viewers’ hostile sexism will negatively predict PI for envious businesswoman advertisements (Hypothesis 2b), and these relationships with sexism will be confined to less gender egalitarian countries (i.e., Poland and South Africa) (Hypothesis 3). Statistical analyses of data from 468 Polish, South African, and British university students supported Hypothesis 1 and partially supported Hypotheses 2 and 3. The predicted patterns held for South Africa, but in Poland, viewers’ benevolence positively predicted PI for both advertisement types, with the exception of highly hostile women. British viewers’ hostility positively predicted PI for the housewife advertisement. Our findings support the cross-cultural applicability of the stereotype content model to advertising and suggest that the predictive role of sexism changes depending on its type, advertisement type, country, and gender. We recommend that advertisers should adopt a nuanced approach in predicting the effectiveness of gendered advertisements

Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study

Background Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population. Methods IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ. Findings We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV. Interpretation Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services

[Appel à contribution] Table ronde "Convertir un lieu". Jeudi 10 et vendredi 11 mars 2022, Université Côte d'Azur (Nice). Date limite : 20 septembre 2021

Le Programme Espace et Religieux, programme de recherche informel lancé en novembre 2021 dans le cadre de réflexions doctorales et adossé à des UMR, organise une première table ronde à l'université Côte d'Azur les 11 et 12 mars 2022. Ce programme vise à développer et à rendre visibles les travaux de jeunes chercheuses et chercheurs en sciences humaines et sociales autour des notions d’espace et de religieux. Afin de promouvoir des échanges sur la longue durée, cette première Table ronde à Nic..