人NFE2基因上游增强子lncRNA调控NFE2基因转录和K562细胞增殖

目的 转录因子NFE2的异常表达在许多骨髓增殖性肿瘤患者中被观察到,然而造成这种异常的转录调控机制尚不明确,本研究旨在探究参与NFE2转录调控的元件和分子机制。方法 首先通过公共数据库中ChIP-seq数据和ATAC-seq数据预测NFE2基因的潜在增强子元件,并通过双荧光素酶报告实验进行体外验证。随后,通过PRO-seq和GRO-seq数据结合RACE技术克隆这些增强子RNA转录本,经在线编码潜能预测工具分析认为其为lncRNA,通过RT-qPCR检测该lncRNA在不同白血病细胞系中和这些细胞诱导分化前后的表达变化及其亚细胞定位。最后,通过慢病毒系统在K562细胞中过表达和敲降该lncRNA以探究其功能。结果 鉴定出调控NFE2转录的3个增强子元件,分别位于NFE2转录起始位点-3.6k,-6.2k和+6.3k区域,这些元件插入NFE2启动子上游均能增强下游萤火虫荧光素酶的表达。克隆出-3.6k增强子负链方向的转录本,将其鉴定为-3.6k-lncRNA。本研究发现,该lncRNA在K562、U937和HL-60这3种白血病细胞系中均有一定程度的表达,且均定位于细胞核内。当该lncRNA在K562细胞中过表达,NFE2水平随之提高,细胞增殖和细胞迁移能力受到抑制;当其被敲降时,NFE2水平相应降低而K562细胞增殖能力随之升高。结论 本文鉴定了调控人NFE2基因转录的3个增强子元件和一条增强子lncRNA转录本,并验证了该lncRNA对NFE2转录的正调控作用以及对K562细胞增殖能力具有抑制作用。     

BMI1基因下调使宫颈癌和子宫内膜癌对紫杉醇敏感

目的 研究B细胞特异性莫洛尼鼠白血病病毒插入位点1（BMI1）基因对宫颈癌及子宫内膜癌增殖浸润及紫杉醇耐受的影响及其机制。方法 首先利用Cbioportal、TCGA和CPTAC数据库分析BMI1基因在宫颈癌和子宫内膜癌中的突变及表达情况。接着对人宫颈癌组织样本和人子宫内膜癌组织样本中BMI1的蛋白质表达水平进行免疫组化分析。采用蛋白质印迹法（Western blot)检测BMI1敲低后宫颈癌及子宫内膜癌细胞中BMI1下游调控因子的蛋白质水平变化。此外,通过细胞功能实验研究了BMI1在宫颈癌HeLa及子宫内膜癌HEC-1-A细胞中的功能。最后,通过实验评估siBMI1联合紫杉醇治疗的协同抗生长作用。结果 数据库分析结果显示,BMI1在1.5%的子宫颈癌患者及1.9%的子宫内膜癌的患者中存在不同程度的扩增、错义及剪接突变。此外,高mRNA水平的BMI1与宫颈癌的病理类型相关,且高蛋白质水平的BMI1与子宫内膜癌的病理类型和肿瘤分级及较低的生存率相关。进一步的免疫组化分析发现,与正常组织相比,宫颈癌和子宫内膜癌组织中BMI1蛋白水平表达升高,且与肿瘤的病理分化及浸润深度相关。药物敏感性实验显示,BMI1过表达导致HeLa及HEC-1-A细胞对多种抗癌药物的敏感性下降,其中包括紫杉醇。为了进一步分析BMI1与紫杉醇耐受的关系,通过Western blot检测BMI1敲除后HeLa及HEC-1-A细胞中BMI1下游因子的蛋白质水平变化。结果显示,抗凋亡相关蛋白Bcl-2随着BMI1的敲低而表达水平下降,而促凋亡相关蛋白BAX则显著升高。此外,细胞功能实验结果显示,体外过表达BMI1可促进HeLa及HEC-1-A细胞的增殖和迁移,且BMI1低表达的HeLa及HEC-1-A细胞对紫杉醇更敏感。结论 BMI1在宫颈癌和子宫内膜癌患者的肿瘤组织中过表达,BMI1的下调通过调控凋亡通路使CC和EC细胞对紫杉醇更加敏感。     

核因子E2相关因子2在运动改善非酒精性脂肪性肝病中的作用

核因子E2相关因子2 (nuclear factor erythroid 2-related factor 2,Nrf2)信号通路在维持心血管疾病、神经系统退行性疾病以及慢性代谢性疾病中的细胞稳态方面起关键作用。研究表明,以氧化应激、炎症和线粒体功能失调为特征的慢性疾病可通过增加Nrf2表达来恢复机体氧化还原状态,治疗或预防疾病。非酒精性脂肪性肝病（nonalcoholic fatty liver disease,NAFLD）是一种由除酒精以外的其他多种因素导致的以肝脏脂肪变性为特征的慢性代谢性肝脏疾病,其患病率近年来在全球范围内逐渐增加。运动是防治NAFLD的有效手段,可通过运动方式、运动强度、运动环境和运动疲劳等因素影响Nrf2信号通路。本文通过阐述Nrf2信号通路的激活、其调控抗氧化的相关机制以及运动对Nrf2信号通路的影响,以NAFLD的发病机制为基础,探讨运动、Nrf2和NAFLD之间的关系,综述Nrf2在运动改善NAFLD中的作用及相关机制。为运动改善NAFLD的分子机制研究提供理论参考依据。     

Multi-Shell Copper Catalysts for Selective Electroreduction of CO2 to Multicarbon Chemicals

Electrocatalytic CO₂ reduction (CO₂R) coupled with renewable electricity has been considered as a promising route for the sustainability transition of energy and chemical industries. However, the unsatisfactory yield of desired products, particularly multicarbon (C₂₊) products, has hindered the implementation of this technology. This work describes a strategy to enhance the yield of C₂₊ product formation in CO₂R by utilizing spatial confinement effects. The finite element simulation results suggest that increasing the number of shells in the catalyst wil lead to a high local concentration of *CO and promotes the formation of C₂₊ products. Inspired by this, Cu nanoparticles are synthesized with desired hollow multi-shell structures. The CO₂ reduction results confirm that as the number of shells increase, the hollow multi-shell copper catalysts exhibit improved selectivity toward C₂₊ products. Specifically, the Cu catalyst with 4.4-shell achieved a high selectivity of over 80% toward C₂₊ at a current density of 900 mA cm⁻². Evidence from in situ attenuated total reflection surface-enhanced infrared absorption spectroscopy unveils that the multi-shell Cu catalyst exhibits an enhanced *CO_atop coverage and the stronger interaction with *CO_atop compared to commercial Cu, confirming the simulation results. Overall, the work promises an effective approach for boosting CO₂R selectivity toward value-added chemicals.     

Mechanistic Understanding of Additive Reductive Degradation and SEI Formation in High-Voltage NMC811||SiOx-Containing Cells via Operando ATR-FTIR Spectroscopy

The implementation of silicon (Si)-containing negative electrodes is widely discussed as an approach to increase the specific capacity of lithium-ion batteries. However, challenges caused by severe volume changes and continuous (re-)formation of the solid-electrolyte interphase (SEI) on Si need to be overcome. The volume changes lead to electrolyte consumption and active lithium loss, decaying the cell performance and cycle life. Herein, the additive 2-sulfobenzoic acid anhydride (2-SBA) is utilized as an SEI-forming electrolyte additive for SiO_x-containing anodes. The addition of 2-SBA to a state-of-the-art carbonate-based electrolyte in high-voltage LiNi_0.8Mn_0.1Co_0.1O₂, NMC811||artificial graphite +20% SiO_x pouch cells leads to improved electrochemical performance, resulting in a doubled cell cycle life. The origin of the enhanced cell performance is mechanistically investigated by developing an advanced experimental technique based on operando attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy. The operando ATR-FTIR spectroscopy results elucidate the degradation mechanism via anhydride ring-opening reactions after electrochemical reduction on the anode surface. Additionally, ion chromatography conductivity detection mass spectrometry, scanning electron microscopy, energy dispersive X-ray analysis, and quantum chemistry calculations are employed to further elucidate the working mechanisms of the additive and its degradation products.     

Boundary-Free Metal–Organic Framework Glasses Enable Highly Stable All-Solid-State Lithium–Oxygen Battery

Rechargeable lithium–oxygen batteries (LOBs) are considered to be one of the most promising energy storage systems. However, the use of reactive lithium (Li) metal and the formation of Li dendrites during battery operation would lead to serious safety concerns, especially when flammable liquid electrolytes are utilized. Herein, superior metal–organic framework (MOF) glass-based solid-state electrolytes (SSEs) is developed for stable all-solid-state LOBs (SSLOBs). These non-flammable and boundary-free MOF glass SSEs are capable of suppressing the dendrite growth and exhibiting long-term Li stripping/plating stability, contributing to superior Li⁺ conductivity (5 × 10⁻⁴ S cm⁻¹ at 20 °C), high Li⁺ transference number (0.86), and good electrochemical stability. It is discovered that discharge product deposition behavior in the solid-solid interface can be well regulated by the ion/electron mixed conducted cathode fabricated with MOF glass SSEs and electronic conductive polymers. As a result, the SSLOBs can be stably recharged for 400 cycles with a low polarization gap and deliver a high capacity of 13552 mAh g⁻¹. The development of this proposed MOF glass displays great application potential in energy storage systems with good safety and high energy density.     

Single-Atom Immobilization Boosting Oxygen Redox Kinetics of High-Entropy Perovskite Oxide Toward High-Performance Lithium-Oxygen Batteries

Understanding and modulating the unique electronic interaction between single-metal atoms and high entropy compounds are of great significance to enable their high-efficiency oxygen electrocatalysis for aprotic lithium-oxygen (Li-O₂) batteries. Herein, a novel bi-functional electrocatalyst is for the first time created by immobilizing single-atom ruthenium (Ru) on lanthanum-based high entropy perovskite oxide La(Mn_0.2Co_0.2Fe_0.2Ni_0.2Cr_0.2)O₃ (Ru@HEPO), which demonstrates high activity and stability in Li-O₂ batteries. The heteronuclear coordination between single-atom Ru and HEPO facilitates fast electron transfer from Ru to HEPO by establishing Ru-O-M (M stands for Mn, Co, Fe, Ni) bridges, which well redistributes electrons within the Ru@HEPO hence significantly improving its interfacial charge transfer kinetics and electrocatalytic activity. Additionally, the strong electron coupling between Ru and Mn atoms enhances the hybridization between Mn 3d and O 2p orbitals, which promotes the inherent affinity of Ru@HEPO toward the LiO₂ intermediate, thereby reducing the reaction energy barrier of the oxygen electrode. As a result, the Ru@HEPO-based Li-O₂ batteries deliver remarkable electrochemical performances, such as high energy efficiency (87.3% at 100 mA g⁻¹), excellent rate capability (low overpotential of 0.52 V at 100 mA g⁻¹) and durable cyclability (345 cycles at 300 mA g⁻¹). This work opens up a promising avenue for the development of high entropy-based electrocatalysts for Li-O₂ batteries by precisely tailoring the electronic distributions at an atomic scale.     

Deubiquitinase USP2 stabilizes the MRE11–RAD50–NBS1 complex at DNA double-strand break sites by counteracting the ubiquitination of NBS1

The MRE11–RAD50–NBS1 (MRN) complex plays essential roles in the cellular response to DNA double-strand breaks (DSBs), which are the most cytotoxic DNA lesions, and is a target of various modifications and controls. Recently, lysine 48-linked ubiquitination of NBS1, resulting in premature disassembly of the MRN complex from DSB sites, was observed in cells lacking RECQL4 helicase activity. However, the role and control of this ubiquitination during the DSB response in cells with intact RECQL4 remain unknown. Here, we showed that USP2 counteracts this ubiquitination and stabilizes the MRN complex during the DSB response. By screening deubiquitinases that increase the stability of the MRN complex in RECQL4-deficient cells, USP2 was identified as a new deubiquitinase that acts at DSB sites to counteract NBS1 ubiquitination. We determined that USP2 is recruited to DSB sites in a manner dependent on ATM, a major checkpoint kinase against DSBs, and stably interacts with NBS1 and RECQL4 in immunoprecipitation experiments. Phosphorylation of two critical residues in the N terminus of USP2 by ATM is required for its recruitment to DSBs and its interaction with RECQL4. While inactivation of USP2 alone does not substantially influence the DSB response, we found that inactivation of USP2 and USP28, another deubiquitinase influencing NBS1 ubiquitination, results in premature disassembly of the MRN complex from DSB sites as well as defects in ATM activation and homologous recombination repair abilities. These results suggest that deubiquitinases counteracting NBS1 ubiquitination are essential for the stable maintenance of the MRN complex and proper cellular response to DSBs.     

Liquid–liquid phase separation of amyloid-β oligomers modulates amyloid fibrils formation

Soluble amyloid-β oligomers (AβOs) are proposed to instigate and mediate the pathology of Alzheimer’s disease, but the mechanisms involved are not clear. In this study, we reported that AβOs can undergo liquid–liquid phase separation (LLPS) to form liquid-like droplets in vitro. We determined that AβOs exhibited an α-helix conformation in a membrane-mimicking environment of SDS. Importantly, SDS is capable of reconfiguring the assembly of different AβOs to induce their LLPS. Moreover, we found that the droplet formation of AβOs was promoted by strong hydrated anions and weak hydrated cations, suggesting that hydrophobic interactions play a key role in mediating phase separation of AβOs. Finally, we observed that LLPS of AβOs can further promote Aβ to form amyloid fibrils, which can be modulated by (−)-epigallocatechin gallate. Our study highlights amyloid oligomers as an important entity involved in protein liquid-to-solid phase transition and reveals the regulatory role of LLPS underlying amyloid protein aggregation, which may be relevant to the pathological process of Alzheimer’s disease.