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It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl‐tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock‐in mouse models through the CRISPR‐Cas9 system. Kars knock‐in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase‐3‐mediated apoptosis were observed in the brain white matter of Kars knock‐in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady‐state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock‐in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock‐in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock‐in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)‐related diseases. [ABSTRACT FROM AUTHOR]

Extreme heat events (EHEs) often hit North China, resulting in significant losses. The devastating EHE in the 1743 summer, marked as the highest temperature in the past 300 years, led to ∼11,000 fatalities. These historical EHEs prompt us to explore potential mechanisms beyond anthropogenic influences. We employ the Norwegian Earth System Model here to simulate the past millennium climate and then dynamically downscale the July 1743 event using the Weather Research and Forecasting Model. The successful simulation of warming in North China, although it has been a fortunate outcome, is supported by tree‐ring records, providing a compelling case study for the event. Through composite and case analyses, we discover a connection between EHEs and active Northeast China Vortexes (NCVs) which induce warm advection, consequently heating the lower atmosphere. Reanalysis further confirms the connection in the modern era. Our study suggests modeling past EHEs, while challenging, is indeed feasible. Plain Language Summary: Nowadays, heat waves have a significant impact on our society and result in substantial economic losses. Climate projections indicate that extreme heat events (EHEs) will become more frequent. However, heat waves have also often occurred in the past 300 years during periods with much lower anthropogenic forcing. One notable example is the severe heat event in the summer of 1743, which killed more than 10 thousand people in North China. The mechanism behind such events remains uncertain, making it exciting and valuable to investigate such heat waves in the past. In this study, we use a global model, a nested regional model, and tree‐ring records to explore the mechanisms driving EHEs. The statistical robustness of the connection between EHEs in North China and Northeast China Vortexes is supported by modern observations. Notably, from 1950 to 2021, 63.6% of EHEs in North China coincide with active Northeast China Vortexes. Key Points: Our simulation, supported by tree‐ring, shows that warm advection linked to Northeast China Vortex likely drove the 1743 extreme heat event (EHE)Reanalysis data from 1950 to 2021 indicate that 63.6% of EHEs in North China coincide with active Northeast China VortexesOur study implies that modeling past extreme climate events is feasible to gain insights into their causes and dynamics [ABSTRACT FROM AUTHOR]

The potential of reactive oxygen species (ROS) cancer therapy in tumor treatment has been greatly enhanced by the introduction of catalytically superior polyoxometalate (POM)‐based nanoplatforms, mainly composed of atomic clusters consisting of pre‐transition metals and oxygen. These nanoplatforms have unique advantages, such as Fenton activity at neutral pH, induction of cellular ferroptosis instead of just apoptosis, and sensitivity to external field stimulation. However, there are also inevitable challenges such as neutralization of ROS by the antioxidant system of the tumor microenvironment (TME), hypoxia, and limited hydrogen peroxide concentrations. This review article aims to provide an overview of recent research advancements in POM‐based nanoplatforms for ROS therapy from the perspective of chemical reactions and biological processes, addressing endogenous and exogenous factors that affect the antitumor efficacy. Endogenous factors include the mechanism of ROS generation by POM, the impact of pH and antioxidant systems on POM, and the various manners of tumor cell death. Exogenous stimuli mainly include light, heat, X‐rays, and electricity. The article analyzes the specific mechanisms of action of each influencing factor in the first two sections, concluding with the limitations of the present study and some possible directions for future research. [ABSTRACT FROM AUTHOR]