Trisomy 21-induced Dysregulation of Microglial Homeostasis in Alzheimer’s Brains is Mediated by USP25

阿尔茨海默病（Alzheimer’s disease, AD）是一种最为常见的与记忆、认知能力退化相关的渐进性神经退行性疾病。唐氏综合征（Down’s syndrome, DS）是早发型阿尔茨海默病的一个重要风险因素，作为最常见的智力障碍遗传疾病，厦门大学医学院神经科学研究所王鑫教授团队揭示了治疗阿尔茨海默病和唐氏综合征新的治疗靶点，并且在小鼠模型上利用USP25小分子抑制剂成功地改善了阿尔茨海默病小鼠的认知功能，缓解了神经退行性病变的病理进程。该研究工作由王鑫教授指导完成，厦门大学医学院助理教授郑秋阳和博士生李桂林完成主要实验工作，王世华、朱琳、高月、邓青芳、张洪峰、张丽珊、吴美玲、狄安洁参与了部分研究工作。厦门大学医学院许华曦、赵颖俊和孙灏教授在研究过程中给予大力帮助和支持，清华大学董晨教授提供了Usp25基因敲除小鼠，厦门大学附属妇女儿童医院周裕林教授和郑良楷博士帮助收集了脑组织样品。Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer’s disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of USP25, a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of Usp25 reduces neuroinflammation and rescues synaptic and cognitive function in 5×FAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5×FAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased USP25 dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.This work was supported by the National Natural Science Foundation of China (31871077, 81822014, and 81571176 to X.W.; 81701130 to Q.Z.), the National Key R&D Program of China (2016YFC1305900 to X.W.), the Natural Science Foundation of Fujian Province of China (2017J06021 to X.W.), the Fundamental Research Funds for the Chinese Central Universities (20720150061 to X.W.), and the BrightFocus Foundation (A2018214F to Yingjun Zhao). 该研究工作得到国家重点研发计划项目、国家自然科学基金、福建省自然科学基金、厦门大学校长基金的资助和支持

植物中褪黑素的研究进展

植物褪黑素自20世纪90年代被发现以来,初期的研究多为测定方法,而后褪黑素生理功能的研究成为热点。植物中褪黑素含量的测定方法有放射免疫测定(RIA)、高效液相色谱(HPLC)、气相色谱(GC)、高效液相色谱-质谱(HPLC-MS)和气相色谱-质谱(GC-MS)等,而高效液相色谱与荧光检测器(HPLC-FD)和电化学检测器(HPLC-EC)联用是植物中褪黑素定量研究的较常用方法。褪黑素含量因植物种类、器官不同而异,并以繁殖器官种子和花中较高。褪黑素在植物中具有调节光周期、促进植物种子萌发及生根、提高植物抵御外界环境压力如重金属、紫外辐射、温度变化等功能,而这些生理功能的作用机制、合成位点等尚待进一步研究。该文对国内外近年来有关褪黑素在植物中的检测方法、生物合成途径及生理功能等几个方面的研究进展进行综述,并提出今后的研究方向

The Denitrification Rate and Its Influence Factors in the Surface Sediment of Yellow River Estuary in Autumn

用乙炔抑制法和现场静态箱法对黄河口附近海域秋季的反硝化速率进行了研究,该海域反硝化速率在3.8~19.3μmol/(m2.h)之间,平均10.27μmol/(m2.h)。影响其反硝化速率的主要因素为反硝化细菌的数量。黄河口的反硝化速率低于珠江口和长江口海域。 &nbsp

Mechanism Underlying the Brain-specific Membrane-anchored Protein TMEM59L-mediated Apoptosis

TMEM59l为近年来新发现的脑特异性高表达蛋白,具有促凋亡效果,但其具体的凋亡机制还不清楚.构建了TMEM59l重组质粒,并在HEk293T细胞中过表达TMEM59l,用AnnEXIn V-fITC/PI双染法确定了TMEM59l可以诱导细胞凋亡,之后用免疫印迹方法检测细胞内凋亡相关分子激活情况.结果显示,外源TMEM59l可以降低bCl-2的蛋白表达水平,诱导细胞色素C从线粒体释放进入细胞质,并且激活CASPASE-9、CASPASE-7和CASPASE-3,但不激活CASPASE-8;活化的CASPASE-7和CASPASE-3进一步酶解死亡底物PArP,导致细胞凋亡;此外,用广谱CASPASE抑制剂z-VAl-AlA-ASP-fMk(z-VAd-fMk)抑制CASPASE-7和CASPASE-3活性后,死亡底物PArP的酶解也基本被抑制.由此可见,TMEM59l是通过CASPASE依赖的线粒体途径诱导HEk293T细胞凋亡.Apoptosis plays a key role in multiple biological functions and dysregulation of apoptosis leads to disease pathogenesis.Therefore,identification of new proteins mediating apoptosis and elucidation of the underlying mechanism is important not only for basic research but also for disease intervention.TMEM59L is a newly-found brain-specific anchored protein with very limited information.One study reported that TMEM59L could induce apoptosis.But the underlying mechanism remains elusive.In this paper,TMEM59L recombinant plasmid was constructed and transfected into HEK293 cells.Through Annexin V-FITC/ propidium iodide double staining and flow cytometry assay,it was confirmed that overexpression of TMEM59L could dramatically induce cell apoptosis.Through Westen blotting study,it was also found that overexpression of TMEM59L could reduce the protein level of Bcl-2,induce cytochrome c release from mitochondria to the cytosol,and activate caspase-9,caspase-3 and caspase-7,but not caspase-8.Consistently,overexpression of TMEM59L promoted the cleavage of death substrate PARP by activated caspases.While cleavage of PARP upon TMEM59L overexpression was dramatically decreased when cells were treated with a caspase inhibitor Z-Val-Ala-Asp-FMK(Z-VAD-FMK).Together these results suggest that TMEM59L can induce apoptosis through a caspase-dependent mitochondrial pathway.Because of its high abundance in the brain,TMEM59L might participate in the physiological apoptosis during neural development and/or pathological apoptosis during neurodegenerative diseases,and these deserve further investigation.国家自然科学基金项目(30973150);国家重点基础研究发展计划(973)前期研究专项项目(2010CB535004);国家科技重大专项项目(2009ZX09103-731);福建省自然科学杰出青年基金项目(2009J06022

中亚增生造山演化与成矿预测应用研究

本成果结合中亚增生造山带的基本特征,以解剖增生楔的组成、构造样式和时代及其时空分布规律为切入点,在全球最大的增生造山带的一些关键薄弱环节进行构造解析和年代学分析,全面理解增生造山作用和其所蕴含的大陆动力学意义,建立中亚成矿域的大陆动力学与成矿系统演化模型,在此基础上开展大型矿集区预测,建立大型矿集区预测的理论和方法技术平台,为中亚成矿域找矿工作提供理论基础和技术支撑。 本成果主要创新点： (1)通过对增生楔岩石的物质成分分析,岩石组合分析以及高精度的地质年代学测试阐明其大地构造背景和演化历史,从空间和时间两个方面构建了大陆边缘增生构造带的精细结构,集约古生代的俯冲增生过程与..