Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones

Lessons learned from implementation of a demonstration program to reduce the burden of anemia and hookworm in women in Yen Bai Province, Viet Nam

Background Iron deficiency, anemia and hookworm disease are important public health problems for women of reproductive age living in developing countries and affect the health of newborns and infants. Iron supplementation and deworming treatment are effective in addressing these problems in both pregnant and non-pregnant women. Daily iron supplementation and deworming after the first trimester is recommended for pregnant women although these programs usually do not operate efficiently or effectively. Weekly iron-folic acid supplementation and regular deworming for non-pregnant women may be a viable approach for improving iron status and preventing anemia during the reproductive years. Addressing these diseases at a population level before women become pregnant could significantly improve women's health before and during pregnancy, as well as their infants' growth and development. Methods and Results This paper describes the major processes undertaken in a demonstration intervention of preventive weekly iron-folic acid supplementation with regular deworming for all 52,000 women aged 15–45 years in two districts of Yen Bai province, in northern Viet Nam. The intervention strategy included extensive consultation with community leaders and village, commune, district and provincial health staff, and training for village health workers. Distribution of the drugs was integrated with the existing health service infrastructure and the village health workers were the direct point of contact with women. Iron-folic acid tablets and deworming treatment were provided free of charge from May 2006. An independent Vietnamese NGO was commissioned to evaluate compliance and identify potential problems. The program resulted in effective distribution of iron-folic acid tablets and deworming treatment to all villages in the target districts, with full or partial compliance of 85%. Conclusion Training for health staff, the strong commitment of all partners and the use of appropriate educational materials led to broad support for weekly iron-folic acid supplementation and high participation in the regular deworming days. In March 2008 the program was expanded to all districts in the province, a target population of approximately 250,000 WRA, and management was handed over to provincial authorities

A free weekly iron-folic acid supplementation and regular deworming program is associated with improved hemoglobin and iron status indicators in Vietnamese women

Background Anemia due to iron deficiency is recognized as one of the major nutritional deficiencies in women and children in developing countries. Daily iron supplementation for pregnant women is recommended in many countries although there are few reports of these programs working efficiently or effectively. Weekly iron-folic acid supplementation (WIFS) and regular deworming treatment is recommended for non-pregnant women living in areas with high rates of anemia. Following a baseline survey to assess the prevalence of anemia, iron deficiency and soil transmitted helminth infections, we implemented a program to make WIFS and regular deworming treatment freely and universally available for all women of reproductive age in two districts of a province in northern Vietnam over a 12 month period. The impact of the program at the population level was assessed in terms of: i) change in mean hemoglobin and iron status indicators, and ii) change in the prevalence of anemia, iron deficiency and hookworm infections. Method Distribution of WIFS and deworming were integrated with routine health services and made available to 52,000 women. Demographic data and blood and stool samples were collected in baseline, and three and 12-month post-implementation surveys using a population-based, stratified multi-stage cluster sampling design. Results The mean Hb increased by 9.6 g/L (95% CI, 5.7, 13.5, p < 0.001) during the study period. Anemia (Hb<120 g/L) was present in 131/349 (37.5%, 95% CI 31.3, 44.8) subjects at baseline, and in 70/363 (19.3%, 95% CI 14.0, 24.6) after twelve months. Iron deficiency reduced from 75/329 (22.8%, 95% CI 16.9, 28.6) to 33/353 (9.3%, 95% CI 5.7, 13.0) by the 12-mnth survey, and hookworm infection from 279/366 (76.2%,, 95% CI 68.6, 83.8) to 66/287 (23.0%, 95% CI 17.5, 28.5) over the same period. Conclusion A free, universal WIFS program with regular deworming was associated with reduced prevalence and severity of anemia, iron deficiency and h

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI

Магнитные характеристики твердых растворов Ni1–xMxMnSb (M = Ti, V, Cr)

The results of an experiment on the study of the crystal and magnetic structures of substitutional solid solutions of the Ni0.90M0.10MnSb (M = Ti, V, Cr) systems using thermal neutron diffraction in the temperature range ~ 3–300 K are presented. It is found that all the studied compositions have ferromagnetic ordering along the c axis. In the spectra of Ni0.90V0.10MnSb and Ni0.90Cr0.10MnSb solid solutions, a reflection appears in the region 2Θ = 28.6°, which indicates the formation of antiferromagnetic ordering. It has been found that this reflection disappears at a temperature T = 75 K in Ni0.90V0.10MnSb, while it is observed in the spectrum of Ni0.90Cr0.10MnSb over the entire temperature range under study. Within the framework of density functional theory (DFT), an ab initio calculation of the crystal structure and magnetic moments for Ni1–xMxMnSb (M = Ti, V, Cr; x = 0; 0.125; 0.250) was carried out. It has been established that titanium, vanadium, and chromium ions participate in electron transfer only with Mn and Sb ions. The DFT results predict the existence of magnetic moments for Ti, V, and Cr ions. It was found that the spins of Ti, V, and Cr ions are antiferromagnetically coupled with the spins of Mn and Ni ions. The results obtained are of interest for the development of new concepts and models of structural design, which makes it possible to synthesize fundamentally new functional materials with already specified physical properties.Представлены результаты эксперимента по изучению кристаллической и магнитной структур твердых растворов замещения систем Ni0,90M0,10MnSb (M = Ti, V, Cr) с помощью дифракции тепловых нейтронов в интервале температур ~ 3–300 К. Обнаружено, что все исследуемые составы обладают ферромагнитным упорядочением вдоль оси с. На спектрах твердых растворов Ni0,90V0,10MnSb и Ni0,90Сr0,10MnSb в области 2Θ = 28,6° отмечено появление рефлекса, который указывает на формирование антиферромагнитного упорядочения. Установлено, что данный рефлекс исчезает при температуре T = 75 К в Ni0,90V0,10MnSb, а на спектре Ni0,90Cr0,10MnSb он наблюдается во всем исследуемом диапазоне температур. В рамках теории функционала плотности (DFT) проведен ab initio расчет кристаллической структуры и магнитных моментов для Ni1–xMxMnSb (M = Ti, V, Cr; x = 0; 0,125; 0,250). Установлено, что ионы титана, ванадия и хрома участвуют в переносе электрона только с ионами Mn и Sb. Результаты DFT предсказывают существование магнитных моментов у ионов Ti, V и Cr. Обнаружено, что спины ионов Ti, V и Cr антиферромагнитно связаны со спинами ионов Mn и Ni. Полученные результаты представляют интерес для разработки новых концепции и моделей структурного дизайна, при котором возможен синтез принципиально новых функциональных материалов с уже заданными физическими свойствами

Setting a baseline for global urban virome surveillance in sewage

The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective

Epidemiology of facial fractures: Incidence, prevalence and years lived with disability estimates from the Global Burden of Disease 2017 study

Background: The Global Burden of Disease Study (GBD) has historically produced estimates of causes of injury such as falls but not the resulting types of injuries that occur. The objective of this study was to estimate the global incidence, prevalence and years lived with disability (YLDs) due to facial fractures and to estimate the leading injurious causes of facial fracture. Methods: We obtained results from GBD 2017. First, the study estimated the incidence from each injury cause (eg, falls), and then the proportion of each cause that would result in facial fracture being the most disabling injury. Incidence, prevalence and YLDs of facial fractures are then calculated across causes. Results: Globally, in 2017, there were 7 538 663 (95% uncertainty interval 6 116 489 to 9 4