CD36 aggravates podocyte injury by activating NLRP3 inflammasome and inhibiting autophagy in lupus nephritis

A major cause of proteinuria in lupus nephritis (LN) is podocyte injury, and determining potential therapeutic targets to prevent podocyte injury is important from a clinical perspective in the treatment of LN. CD36 is involved in podocyte injury in several glomerulopathies and was reported to be a vital candidate gene in LN. Here, we determined the role of CD36 in the podocyte injury of LN and the underlying mechanisms. We observed that CD36 and NLRP3 (NLR family pyrin domain containing 3) were upregulated in the podocytes of lupus nephritis patients and MRL/lpr mice with renal impairment. In vitro, CD36, NLRP3 inflammasome, and autophagy were elevated accompanied with increased podocyte injury stimulated by IgG extracted from lupus nephritis patients compared that from healthy donors. Knocking out CD36 with the CRISPR/cas9 system decreased the NLRP3 inflammasome levels, increased the autophagy levels and alleviated podocyte injury. By enhancing autophagy, NLRP3 inflammasome was decreased and podocyte injury was alleviated. These results demonstrated that, in lupus nephritis, CD36 promoted podocyte injury by activating NLRP3 inflammasome and inhibiting autophagy by enhancing which could decrease NLRP3 inflammasome and alleviate podocyte injury.Subject terms: Mechanisms of disease, Inflammasome, Lupus nephritis, Autophagy     

高原湖泊流域国土空间生态修复优先区诊断及修复研究

高原湖泊流域是高原地区人类活动的重要载体,兼具高生态价值和高脆弱性的特点。随着高原湖泊流域城市化和工业化发展加速,湖泊面积萎缩,污染加剧,流域生态环境受损严重,引发了一系列生态环境问题,如水土流失、水污染、湿地退化、生境质量下降等。亟需开展生态修复以平衡经济发展与生态环境保护之间关系,而基于整体保护与系统治理思维诊断并修复生态修复优先区,是科学有序推进国土空间生态保护与修复的重要抓手。基于此,研究以高原湖泊流域典型代表滇池流域为例,利用人类足迹和景观生态风险模型定量评估生态系统所受负向干扰,以最小累积阻力模型和电路理论构建流域生态网络;提取生态网络受负向干扰较高的关键区域为生态修复优先区并提出针对性修复措施。研究表明：(1)滇池流域人类干扰和生态风险整体较高,人类干扰整体呈核心—边缘递减的圈层式分布,中高生态风险占据了绝大部分区域。人类交通网络大幅扩展了人类干扰和生态风险的强度和深度;(2)区域生态网络呈典型湖泊生态网络特点,38条生态廊道呈放射状或环状分布,连通湖区、山区两大生态空间内共23块生态源地,保障区域生态安全;(3)研究共提取生态源地修复优先区73.83km²     

3年高氮添加对黄山松土壤真菌网络稳定性的影响

土壤真菌群落对维持生态系统功能至关重要,然而氮沉降等环境变化如何影响其稳定性尚不清楚。利用高通量测序和网络分析,探究了连续三年不同氮添加水平对土壤真菌群落特征的影响,并通过计算"内聚力"量化连通性以预测真菌网络的稳定性。结果表明,真菌多样性及其群落稳定性对氮添加的响应存在明显的时间效应。相比于前2年,第3年氮添加改变了真菌β多样性,且低氮添加显著提高了0-10 cm土层真菌Chao1和Shannon指数。网络分析发现,随着氮添加量的增加真菌网络正连接比例增加,平均聚类系数和模块性降低。内聚力分析表明,第3年高氮添加显著降低了两个土层的真菌负:正内聚力的绝对值,而低氮添加提高或不改变两者的比值。这说明高剂量氮添加将通过破坏真菌群落的稳定性影响其生态系统服务功能。研究为评价不同水平氮添加下森林土壤真菌群落稳定性提供了新的见解,对评价氮沉降的生态效应具有科学意义。     

Long noncoding RNA lncMREF promotes myogenic differentiation and muscle regeneration by interacting with the Smarca5/p300 complex

Long noncoding RNAs (lncRNAs) play important roles in the spatial and temporal regulation of muscle development and regeneration. Nevertheless, the determination of their biological functions and mechanisms underlying muscle regeneration remains challenging. Here, we identified a lncRNA named lncMREF (lncRNA muscle regeneration enhancement factor) as a conserved positive regulator of muscle regeneration among mice, pigs and humans. Functional studies demonstrated that lncMREF, which is mainly expressed in differentiated muscle satellite cells, promotes myogenic differentiation and muscle regeneration. Mechanistically, lncMREF interacts with Smarca5 to promote chromatin accessibility when muscle satellite cells are activated and start to differentiate, thereby facilitating genomic binding of p300/CBP/H3K27ac to upregulate the expression of myogenic regulators, such as MyoD and cell differentiation. Our results unravel a novel temporal-specific epigenetic regulation during muscle regeneration and reveal that lncMREF/Smarca5-mediated epigenetic programming is responsible for muscle cell differentiation, which provides new insights into the regulatory mechanism of muscle regeneration.     

Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways

Cardiac fibrosis is one of the common pathological processes in many cardiovascular diseases characterized by excessive extracellular matrix deposition. SerpinE2 is a kind of protein that inhibits peptidase in extracellular matrix and up-regulated tremendously in mouse model of cardiac fibrosis induced by pressure-overloaded via transverse aortic constriction (TAC) surgery. However, its effect on cardiac fibroblasts (CFs), collagen secretion and the underlying mechanism remains unclear. In this study, DyLight® 488 green fluorescent dye or His-tagged proteins were used to label the exogenous serpinE2 protein. It was showed that extracellular serpinE2 translocated into CFs by low-density lipoprotein receptor-related protein 1 (LRP1) and urokinase plasminogen activator receptor (uPAR) of cell membrane through endocytosis. Knockdown of LRP1 or uPAR reduced the level of serpinE2 in CFs and down-regulated the collagen expression. Inhibition of the endocytosis of serpinE2 could inhibit ERK1/2 and β-catenin signaling pathways and subsequently attenuated collagen secretion. Knockdown of serpinE2 attenuates cardiac fibrosis in TAC mouse. We conclude that serpinE2 could be translocated into cardiac fibroblasts due to endocytosis through directly interact with the membrane protein LRP1 and uPAR, and this process activated the ERK1/2, β-catenin signaling pathways, consequently promoting collagen production.     

Quantitative Proteomic Analysis Reveals Important Roles of the Acetylation of ER-Resident Molecular Chaperones for Conidiation in Fusarium oxysporum

Fusarium oxysporum is one of the most abundant and diverse fungal species found in soils and includes nonpathogenic, endophytic, and pathogenic strains affecting a broad range of plant and animal hosts. Conidiation is the major mode of reproduction in many filamentous fungi, but the regulation of this process is largely unknown. Lysine acetylation (Kac) is an evolutionarily conserved and widespread posttranslational modification implicated in regulation of multiple metabolic processes. A total of 62 upregulated and 49 downregulated Kac proteins were identified in sporulating mycelia versus nonsporulating mycelia of F. oxysporum. Diverse cellular proteins, including glycolytic enzymes, ribosomal proteins, and endoplasmic reticulum–resident molecular chaperones, were differentially acetylated in the sporulation process. Altered Kac levels of three endoplasmic reticulum–resident molecular chaperones, PDI^K70, HSP70^K604, and HSP40^K32 were identified that with important roles in F. oxysporum conidiation. Specifically, K70 acetylation (K70ac) was found to be crucial for maintaining stability and activity of protein disulphide isomerase and the K604ac of HSP70 and K32ac of HSP40 suppressed the detoxification ability of these heat shock proteins, resulting in higher levels of protein aggregation. During conidial formation, an increased level of PDI^K70ac and decreased levels of HSP70^K604ac and HSP40^K32ac contributed to the proper processing of unfolded proteins and eliminated protein aggregation, which is beneficial for dramatic cell biological remodeling during conidiation in F. oxysporum.     

基于实码遗传算法的湖泊水质模型参数优化

参数的合理取值决定着模型的模拟效果,因此确定研究区域的模型结构后,需要对模型的参数进行优化.湖泊水质模型(Simulation by means of an Analytical Lake Model,SALMO)利用常微分方程描述湖泊的营养物质循环和食物链动态,考虑了多个生态过程,包含104个参数.由于参数较多,不适宜采用传统参数优化方法进行优化.利用太湖梅梁湾2005年数据,采用实码遗传算法优化了SALMO模型中相对敏感的参数,运用优化后的模型,模拟了梅梁湾2006年的水质.对比分析参数优化前后模型的效果表明遗传算法能高效地对SALMO进行参数优化,优化后的模拟精度得到了显著提高,能更好地模拟梅梁湾的水质变化.     

A static pressure sensitive receptor APJ promote H9c2 cardiomyocyte hypertrophy via PI3K-autophagy pathway

This study is designed to investigate whether APJ receptor acts as a sensor in static pressure-induced cardiomyocyte hypertrophy and to investigate the mechanism of PI3K- autophagy pathway. The left ventricular hypertrophy rat model was established by coarctation of abdominal aorta. H9c2 rat cardiomyocytes were cultured in the presence of static pressure which was given by a custom-made pressure in- cubator. The results revealed that the expression of apelin/ APJ system, PI3K, Akt and their phosphorylation were sig- nificantly increased in the operation group. Static pressure up-regulated the APJ expression, PI3K phosphorylation, Akt phosphorylation, LC3-Ⅱ/Ⅰ and beclin-1 expression in cardio- myocytes. APJ shRNA pGPU6/Neo-rat-399, PI3K inhibitor LY294002, Akt inhibitor 1701-1 blocked the up-regulation of APJ, PI3K phosphorylation, Akt phosphorylation, LC3-H/I and beclin-1 expression, respectively. Moreover, static pres- sure increased the diameter, volume, protein content of cells, and these could be reversed when the cells were treated with pGPU6/Neo-rat-399, LY294002, and autop- hagy inhibitor 3-methyladenine, respectively. These results suggested that static pressure up-regulates APJ expression to promote cardiomyocyte hypertrophy by a PI3K-autop- hagy pathway.