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

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

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

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

Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling

Objective: Mangiferin (MGF) is a natural xanthone, with regulation effect on lipid metabolism. However, the molecular mechanism remains unclear. We purposed after oral administration, MGF is converted to its active metabolite(s), which contributes to the effects on lipid metabolism.Methods: KK-Ay mice were used to validate the effects of MGF on lipid metabolic disorders. Liver biochemical indices and gene expressions were determined. MGF metabolites were isolated from MGF administrated rat urine. Mechanism studies were carried out using HepG2 cells treated by MGF and its metabolite with or without inhibitors or small interfering RNA (siRNA). Western blot and immunoprecipitation methods were used to determine the lipid metabolism related gene expression. AMP/ATP ratios were measured by HPLC. AMP-activated protein kinase (AMPK) activation were identified by homogeneous time resolved fluorescence (HTRF) assays.Results: MGF significantly decreased liver triglyceride and free fatty acid levels, increased sirtuin-1 (SIRT-1) and AMPK phosphorylation in KK-Ay mice. HTRF studies indicated that MGF and its metabolites were not direct AMPK activators. Norathyriol, one of MGF’s metabolite, possess stronger regulating effect on hepatic lipid metabolism than MGF. The mechanism was mediated by activation of SIRT-1, liver kinase B1, and increasing the intracellular AMP level and AMP/ATP ratio, followed by AMPK phosphorylation, lead to increased phosphorylation level of sterol regulatory element-binding protein-1c.Conclusion: These results provided new insight into the molecular mechanisms of MGF in protecting against hepatic lipid metabolic disorders via regulating SIRT-1/AMPK pathway. Norathyriol showed potential therapeutic in treatment of non-alcoholic fatty liver disease

Multifunctional antibacterial bioactive nanoglass hydrogel for normal and MRSA infected wound repair

Abstract Large-scale skin damage brings potential risk to patients, such as imbalance of skin homeostasis, inflammation, fluid loss and bacterial infection. Moreover, multidrug resistant bacteria (MDRB) infection is still a great challenge for skin damage repair. Herein, we developed an injectable self-healing bioactive nanoglass hydrogel (FABA) with robust antibacterial and anti-inflammatory ability for normal and Methicillin-resistant Staphylococcus aureus (MRSA) infected skin wound repair. FABA hydrogel was fabricated facilely by the self-crosslinking of F127-CHO (FA) and alendronate sodium (AL)-decorated Si-Ca-Cu nanoglass (BA). FABA hydrogel could significantly inhibit the growth of Staphylococcus aureus, Escherichia coli and MRSA in vitro, while showing good cytocompatibility and hemocompatibility. In addition, FABA hydrogel could inhibit the expression of proinflammatory factor TNF-α and enhance the expression of anti-inflammatory factor IL-4/ IL-10. Based on its versatility, FABA hydrogel could complete wound closure efficiently (75% at day 3 for normal wound, 70% at day 3 for MRSA wound), which was almost 3 times higher than control wound, which was related with the decrease of inflammatory factor in early wound. This work suggested that FABA hydrogel could be a promising dressing for acute and MRSA-infected wound repair. Graphical Abstrac