Nitric oxide produces HLA-G nitration and induces metalloprotease-dependent shedding creating a tolerogenic milieu

Human leucocyte antigen G (HLA-G) is a tolerogenic molecule that protects the fetus from maternal immune attack, may favour tumoral immunoescape and is up-regulated in viral and inflammatory diseases. The aim of this work was to discover if nitric oxide (NO) could affect HLA-G expression or function because NO is an important modulator of innate and adaptive immunity. For this purpose HLA-G expression and function were analysed following treatment with a NO donor or a peroxynitrite donor in various cell lines expressing HLA-G either spontaneously or upon transfection. Results showed NO-dependent nitration of both cellular and soluble HLA-G protein, but not all HLA-G moieties underwent nitration. Endogenous biosynthesis of NO by both U-937-HLA-G1 and M8-HLA-G5 stable transfectants also caused HLA-G nitration. The NO decreased total HLA-G cellular protein content and expression on the cell surface, while increasing HLA-G shedding into the culture medium. This effect was post-transcriptional and the result of metalloprotease activity. By contrast, NO pretreatment did not affect HLA-G capability to suppress NK cytotoxicity and lymphocyte proliferation. Our studies show that NO regulates the availability of HLA-G molecules without modifying their biological activities

Educational and social inequalities and cause-specific mortality in Mexico City: a prospective study

Background: Social inequalities in adult mortality have been reported across diverse populations, but there is no largescale prospective evidence from Mexico. We aimed to quantify social, including educational, inequalities in mortality among adults in Mexico City. Methods: The Mexico City Prospective Study recruited 150 000 adults aged 35 years and older from two districts of Mexico City between 1998 and 2004. Participants were followed up until Jan 1, 2021 for cause-specific mortality. Cox regression analysis yielded rate ratios (RRs) for death at ages 35–74 years associated with education and examined, in exploratory analyses, the mediating effects of lifestyle and related risk factors. Findings: Among 143 478 participants aged 35–74 years, there was a strong inverse association of education with premature death. Compared with participants with tertiary education, after adjustment for age and sex, those with no education had about twice the mortality rate (RR 1·84; 95% CI 1·71–1·98), equivalent to approximately 6 years lower life expectancy, with an RR of 1·78 (1·67–1·90) among participants with incomplete primary, 1·62 (1·53–1·72) with complete primary, and 1·34 (1·25–1·42) with secondary education. Education was most strongly associated with death from renal disease and acute diabetic crises (RR 3·65; 95% CI 3·05–4·38 for no education vs tertiary education) and from infectious diseases (2·67; 2·00–3·56), but there was an apparent higher rate of death from all specific causes studied with lower education, with the exception of cancer for which there was little association. Lifestyle factors (ie, smoking, alcohol drinking, and leisure time physical activity) and related physiological correlates (ie, adiposity, diabetes, and blood pressure) accounted for about four-fifths of the association of education with premature mortality. Interpretation: In this Mexican population there were marked educational inequalities in premature adult mortality, which appeared to largely be accounted for by lifestyle and related risk factors. Effective interventions to reduce these risk factors could reduce inequalities and have a major impact on premature mortality. Funding: Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, and the UK Medical Research Council Population Health Research Unit

A regulated deficit irrigation strategy for hedgerow olive orchards with high plant density

Background & Aims There is not a consensus on the best irrigation approach for super-high density (SHD) olive orchards. Our aim was to design and test a regulated deficit irrigation (RDI) strategy for a sustainable balance between water saving, tree vigour and oil production. Methods We tested our RDI strategy for 3 years in an ‘Arbequina’ orchard with 1,667 trees ha−1. Two levels of irrigation reduction were applied, 60RDI and 30RDI, scaled to replacing 60 % and 30 %, respectively, of the of irrigation needs (IN). We also had a full irrigation (FI) treatment as control, with IN totalling 4,701 m3 ha−1 Results The 30RDI treatment showed the best balance between water saving, tree vigour and oil production. With a yearly irrigation amount (IA) of 1,366 m3 ha−1, which meant 72 % water saving as compared to FI, the reduction in oil yield was 26 % only. Conclusions Our results, together with recent knowledge on the effect of water stress on fruit development, allowed us to suggest a potentially improved RDI strategy for which a total IA of ca. 2,100 m3 ha−1 was calculated. Both some management details and the benefits of this suggested RDI strategy are still to be tested

New Generation Cooperative and Cognitive Dual Satellite Systems: Performance Evaluation

Investigating innovative satellite architectures with enhanced system through- put is one of the most important challenges towards realizing the next generation of satellite communication systems. In this context, we study two advanced architectures, namely cooperative and cognitive satellite systems. These designs allow the spectral coexistence of two multibeam satellites over a common coverage area with the overlapping beam patterns. In the cooperative dual satellite system, we consider coordination between two coexisting transmitters in order to reduce the intersatellite interference. This is achieved by employing adequate user scheduling, based on the channel state information of each user. To this end, a semi-orthogonal interference aware scheduling algorithm is applied. Further, in the cognitive dual satellite system, we employ a cognitive beamhopping technique assuming that the secondary gateway is aware of the primary's beamhopping pattern. Moreover, we compare the performances of these schemes with those of the conventional multi- beam and overlapping dual satellite systems in terms of spectral efficiency, power efficiency and user fairness. Finally, we provide several insights on the performance of these schemes and provide interesting future works in these domains

Overview of recent TJ-II stellarator results

The main results obtained in the TJ-II stellarator in the last two years are reported. The most important topics investigated have been modelling and validation of impurity transport, validation of gyrokinetic simulations, turbulence characterisation, effect of magnetic configuration on transport, fuelling with pellet injection, fast particles and liquid metal plasma facing components. As regards impurity transport research, a number of working lines exploring several recently discovered effects have been developed: the effect of tangential drifts on stellarator neoclassical transport, the impurity flux driven by electric fields tangent to magnetic surfaces and attempts of experimental validation with Doppler reflectometry of the variation of the radial electric field on the flux surface. Concerning gyrokinetic simulations, two validation activities have been performed, the comparison with measurements of zonal flow relaxation in pellet-induced fast transients and the comparison with experimental poloidal variation of fluctuations amplitude. The impact of radial electric fields on turbulence spreading in the edge and scrape-off layer has been also experimentally characterized using a 2D Langmuir probe array. Another remarkable piece of work has been the investigation of the radial propagation of small temperature perturbations using transfer entropy. Research on the physics and modelling of plasma core fuelling with pellet and tracer-encapsulated solid-pellet injection has produced also relevant results. Neutral beam injection driven Alfvénic activity and its possible control by electron cyclotron current drive has been examined as well in TJ-II. Finally, recent results on alternative plasma facing components based on liquid metals are also presentedThis work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 under Grant Agreement No. 633053. It has been partially funded by the Ministerio de Ciencia, Inovación y Universidades of Spain under projects ENE2013-48109-P, ENE2015-70142-P and FIS2017-88892-P. It has also received funds from the Spanish Government via mobility grant PRX17/00425. The authors thankfully acknowledge the computer resources at MareNostrum and the technical support provided by the Barcelona S.C. It has been supported as well by The Science and Technology Center in Ukraine (STCU), Project P-507F

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

This is the final version. Available from Nature Research via the DOI in this record. Data availability: The UK Biobank phenotype and WES data described here are publicly available to registered researchers through the UK Biobank data access protocol. Information about registration for access to the data is available at https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. Data for this study were obtained under resource applications 26041 and 9905. The MCPS welcomes open-access and collaboration data requests from bona fide researchers. For more details on accessibility, the study’s data and sample sharing policy can be downloaded (in English or Spanish) from https://www.ctsu.ox.ac.uk/research/mcps. Available study data can be examined in detail through the study’s Data Showcase, available at https://datashare.ndph.ox.ac.uk/mexico/. SCOOP and INTERVAL WES data are accessible from the European Genome-phenome Archive with accession numbers EGAS00001000124 (SCOOP) and EGAS00001000825 (INTERVAL). snRNA-seq data are available from the NCBI Gene Expression Omnibus (GEO), under accession number: GSE243112. Source data are provided with this paper.Code availability: The pipeline code for processing, filtering, annotating and burden testing UK Biobank WES data using the UK Biobank RAP is publicly available (https://github.com/mrcepid-rap). No custom code for analyzing the UK Biobank WES data was developed for this study. The analysis code for single-nucleus sequencing is available on GitHub (https://github.com/mariachukanova1/BSN_paper) and has been deposited on Zenodo at https://doi.org/10.5281/zenodo.10687754.Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.Medical Research CouncilMedical Research CouncilMedical Research CouncilMedical Research CouncilWellcome TrustMedical Research CouncilWellcome TrustWellcome Trust and Royal SocietyChan Zuckerberg InitiativeBiotechnology and Biological Sciences Research Council (BBSRC)Mexican Health MinistryNational Council of Science and Technology for MexicoCancer Research UKBritish Heart FoundationNational Institute for Health ResearchCambridge Biomedical Research CentreBotnar FoundationBernard Wolfe Health Neuroscience EndowmentResearch Englan

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate