Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo

Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification

Efficient and bright warm-white electroluminescence from lead-free metal halides.

Solution-processed metal-halide perovskites are emerging as one of the most promising materials for displays, lighting and energy generation. Currently, the best-performing perovskite optoelectronic devices are based on lead halides and the lead toxicity severely restricts their practical applications. Moreover, efficient white electroluminescence from broadband-emission metal halides remains a challenge. Here we demonstrate efficient and bright lead-free LEDs based on cesium copper halides enabled by introducing an organic additive (Tween, polyethylene glycol sorbitan monooleate) into the precursor solutions. We find the additive can reduce the trap states, enhancing the photoluminescence quantum efficiency of the metal halide films, and increase the surface potential, facilitating the hole injection and transport in the LEDs. Consequently, we achieve warm-white LEDs reaching an external quantum efficiency of 3.1% and a luminance of 1570 cd m-2 at a low voltage of 5.4 V, showing great promise of lead-free metal halides for solution-processed white LED applications

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Optimizing Cross-Dock Terminal Location Selection: A Multi-Step Approach Based on CI-DEA–IDOCRIW–MABAC for Enhanced Supply Chain Efficiency—A Case Study

Thedistribution of products stands out as one of the pivotal activities for logistics companies in recent years, particularly in the aftermath of the COVID-19 pandemic and other geopolitical events. Intense competition compels companies to efficiently execute their logistical processes, with cross-docking emerging as a frequently applied solution. However, the location of cross-dock terminals in urban areas remains a problem insufficiently addressed in the literature, with a dearth of studies and models tackling this issue. This paper introduces a novel and innovative model for locating cross-dock terminals based on the CI-DEA–IDOCRIW–MABAC (Composite Indicators–Data Envelopment Analysis-Integrated Determination of Objective Criteria Weights–Multi-Attributive Border Approximation Area Comparison) methods. In the process of defining input indicators, the following three sources were utilized: relevant literature, practical insights from logistics experts, and the knowledge and experience of the authors. Eight inputs and three outputs were considered (the number of users in the observed channel; the area served by the channel; the average distance a vehicle travels in one delivery; the required number of vehicles; labor availability; competition; construction, and expansion possibilities; proximity to the main infrastructure and traffic facilities; the average number of deliveries; average delivered quantity; and service level). The model underwent testing in a case study analyzing nine distribution channels (areas within the observed urban zone). The results indicated that alternative A4 (in the southwest area) ranked the highest since it was the best-ranked in accordance with the most important criteria, suggesting that the terminal is best located in the southwest zone. The accuracy of the results was confirmed by company management. By developing a completely new model and addressing the identified gap in the literature, this paper provides unequivocal scientific contributions

国际鱼道适应性管理体系综述及对中国的启示

为便于目标鱼类能够在河流系统中顺利通过大坝等障碍物,已有大量的人力、物力投入到鱼道等过鱼设施的开发、建设以及修复中。如今,鱼道科学已逐步发展成为以工程学为中心,涵盖鱼类行为学、社会经济学和复杂建模(河流网络通道优先选择)等多学科交叉的一门学科。建设高效的鱼道等过鱼设施(延迟洄游时间短,洄游后负面影响小),需要适应性的管理和连续的创新。中国过鱼设施建设如火如荼,但是完善的过鱼设施全过程管理体系亟待建立。文章对1991年至2017年国外鱼道适应性管理体系相关文献(包括开发、建设和管理等方面)进行了综述。其中检索词为“鱼道(Fishway)”、“鱼类通道(Fish passage)”、“鱼(Fish)”和“大坝(Dam)”。研究表明,国外的过鱼设施逐步由经济种群保护向生物多样性保护发展、上行通道向下行通道发展、单一工程建设向流域整体发展、单一过鱼功能向生境补充发展、单纯工程建设向适应性管理发展。最后,文章讨论并展望了中国鱼道等过鱼设施的全过程适应性管理体系的发展前景

国际鱼道适应性管理体系综述及对中国的启示

为便于目标鱼类能够在河流系统中顺利通过大坝等障碍物,已有大量的人力、物力投入到鱼道等过鱼设施的开发、建设以及修复中。如今,鱼道科学已逐步发展成为以工程学为中心,涵盖鱼类行为学、社会经济学和复杂建模(河流网络通道优先选择)等多学科交叉的一门学科。建设高效的鱼道等过鱼设施(延迟洄游时间短,洄游后负面影响小),需要适应性的管理和连续的创新。中国过鱼设施建设如火如荼,但是完善的过鱼设施全过程管理体系亟待建立。文章对1991年至2017年国外鱼道适应性管理体系相关文献(包括开发、建设和管理等方面)进行了综述。其中检索词为“鱼道(Fishway)”、“鱼类通道(Fish passage)”、“鱼(Fish)”和“大坝(Dam)”。研究表明,国外的过鱼设施逐步由经济种群保护向生物多样性保护发展、上行通道向下行通道发展、单一工程建设向流域整体发展、单一过鱼功能向生境补充发展、单纯工程建设向适应性管理发展。最后,文章讨论并展望了中国鱼道等过鱼设施的全过程适应性管理体系的发展前景

国际鱼道适应性管理体系综述及对中国的启示

为便于目标鱼类能够在河流系统中顺利通过大坝等障碍物,已有大量的人力、物力投入到鱼道等过鱼设施的开发、建设以及修复中。如今,鱼道科学已逐步发展成为以工程学为中心,涵盖鱼类行为学、社会经济学和复杂建模(河流网络通道优先选择)等多学科交叉的一门学科。建设高效的鱼道等过鱼设施(延迟洄游时间短,洄游后负面影响小),需要适应性的管理和连续的创新。中国过鱼设施建设如火如荼,但是完善的过鱼设施全过程管理体系亟待建立。文章对1991年至2017年国外鱼道适应性管理体系相关文献(包括开发、建设和管理等方面)进行了综述。其中检索词为“鱼道(Fishway)”、“鱼类通道(Fish passage)”、“鱼(Fish)”和“大坝(Dam)”。研究表明,国外的过鱼设施逐步由经济种群保护向生物多样性保护发展、上行通道向下行通道发展、单一工程建设向流域整体发展、单一过鱼功能向生境补充发展、单纯工程建设向适应性管理发展。最后,文章讨论并展望了中国鱼道等过鱼设施的全过程适应性管理体系的发展前景

Hydrocyanation of Sulfonylimines Using Potassium Hexacyanoferrate(II) as an Eco-Friendly Cyanide Source

An efficient and eco-friendly method for hydrocyanation of sulfonylimines via one-pot two-step procedure using potassium hexacyanoferrate(II) as a cyanide source, benzoyl chloride as a promoter, and potassium carbonate as a base is described. This protocol has the features of using nontoxic, nonvolatile and inexpensive cyanide source, high yield, and simple work-up procedure

Polyphenol Compound 18a Modulates UCP1-Dependent Thermogenesis to Counteract Obesity

Recent studies increasingly suggest that targeting brown/beige adipose tissues to enhance energy expenditure offers a novel therapeutic approach for treating metabolic diseases. Brown/beige adipocytes exhibit elevated expression of uncoupling protein 1 (UCP1), which is a thermogenic protein that efficiently converts energy into heat, particularly in response to cold stimulation. Polyphenols possess potential anti-obesity properties, but their pharmacological effects are limited by their bioavailability and distribution within tissue. This study discovered 18a, a polyphenol compound with a favorable distribution within adipose tissues, which transcriptionally activates UCP1, thereby promoting thermogenesis and enhancing mitochondrial respiration in brown adipocytes. Furthermore, in vivo studies demonstrated that 18a prevents high-fat-diet-induced weight gain and improves insulin sensitivity. Our research provides strong mechanistic evidence that UCP1 is a complex mediator of 18a-induced thermogenesis, which is a critical process in obesity mitigation. Brown adipose thermogenesis is triggered by 18a via the AMPK-PGC-1α pathway. As a result, our research highlights a thermogenic controlled polyphenol compound 18a and clarifies its underlying mechanisms, thus offering a potential strategy for the thermogenic targeting of adipose tissue to reduce the incidence of obesity and its related metabolic problems