IGF2BP2 serves as a core m6A regulator in head and neck squamous cell carcinoma

Methylation of N6 adenosine (m6A) plays a crucial role in the development and progression of cancers. Its modification is regulated by three types of m6A-related regulators (methyltransferases (writers), demethylases (erasers), and RNA-binding proteins (readers)). Till now, the functions and roles of these regulators in head and neck squamous cell carcinoma (HNSC) remain largely unexplored. Therefore, we utilized the open HNSC dataset in The Cancer Genome Atlas (TCGA), four different cell lines, and our HNSC patient samples (n=40) to explore the clinical significance of 19 m6A regulators, and selected the most significant prognosis-related regulator. Authentic analyses based on online websites were also used in the study (Oncomine, UALCAN, Kaplan–Meier plotter, Human Protein Atlas (HPA), cBioPortal, LinkedOmics, String, etc.). From the results, general overexpression of m6A regulators was observed in pan-cancer, especially in HNSC. IGF2BP2 was recognized as the hub m6A regulator, which was an independent, unfavorable prognostic factor in HNSC. Its mRNA and protein expression in HNSC were significantly up-regulated. Gene mutation types of IGF2BP2 in HNSC (32%) were mainly mRNA High or Amplification, which represented the high expression of IGF2BP2. And these mutations were associated with a poor prognosis. In functional analysis, IGF2BP2 was negatively correlated to tumor immune infiltration in HNSC. Finally, HMGA2 might interact with the IGF2BP2 in HNSC. In conclusion, IGF2BP2 serves as a core m6A regulator among all regulators in HNSC, which has a high expression and predicts the poor prognosis of HNSC patients independently. IGF2BP2 might bring a new direction for HNSC treatment in the future.     

Barley GRIK1‐SnRK1 kinases subvert a viral virulence protein to upregulate antiviral RNAi and inhibit infection

Viruses often usurp host machineries for their amplification, but it remains unclear if hosts may subvert virus proteins to regulate viral proliferation. Here, we show that the 17K protein, an important virulence factor conserved in barley yellow dwarf viruses (BYDVs) and related poleroviruses, is phosphorylated by host GRIK1‐SnRK1 kinases, with the phosphorylated 17K (P17K) capable of enhancing the abundance of virus‐derived small interfering RNAs (vsiRNAs) and thus antiviral RNAi. Furthermore, P17K interacts with barley small RNA‐degrading nuclease 1 (HvSDN1) and impedes HvSDN1‐catalyzed vsiRNA degradation. Additionally, P17K weakens the HvSDN1‐HvAGO1 interaction, thus hindering HvSDN1 from accessing and degrading HvAGO1‐carried vsiRNAs. Importantly, transgenic expression of 17K phosphomimetics (17K^5D), or genome editing of SDN1, generates stable resistance to BYDV through elevating vsiRNA abundance. These data validate a novel mechanism that enhances antiviral RNAi through host subversion of a viral virulence protein to inhibit SDN1‐catalyzed vsiRNA degradation and suggest new ways for engineering BYDV‐resistant crops.     

Biochemical and structural characterization of hepatitis A virus 2C reveals an unusual ribonuclease activity on single-stranded RNA

The HAV nonstructural protein 2C is essential for virus replication; however, its precise function remains elusive. Although HAV 2C shares 24–27% sequence identity with other 2Cs, key motifs are conserved. Here, we demonstrate that HAV 2C is an ATPase but lacking helicase activity. We identified an ATPase-independent nuclease activity of HAV 2C with a preference for polyuridylic single-stranded RNAs. We determined the crystal structure of an HAV 2C fragment to 2.2 Å resolution, containing an ATPase domain, a region equivalent to enterovirus 2C zinc-finger (ZFER) and a C-terminal amphipathic helix (PBD). The PBD of HAV 2C occupies a hydrophobic pocket (Pocket) in the adjacent 2C, and we show the PBD–Pocket interaction is vital for 2C functions. We identified acidic residues that are essential for the ribonuclease activity and demonstrated mutations at these sites abrogate virus replication. We built a hexameric-ring model of HAV 2C, revealing the ribonuclease-essential residues clustering around the central pore of the ring, whereas the ATPase active sites line up at the gaps between adjacent 2Cs. Finally, we show the ribonuclease activity is shared by other picornavirus 2Cs. Our findings identified a previously unfound activity of picornavirus 2C, providing novel insights into the mechanisms of virus replication.     

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

Mitochondrial NAD⁺‐dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)‐dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR‐mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole‐body aerobic capacity but is dispensable for CR‐dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3 ^−/− ) yielded a longer overall and maximum lifespan as compared to Sirt3 ^+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3 ^−/− CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.     

One night of sleep deprivation induces release of small extracellular vesicles into circulation and promotes platelet activation by small EVs

Extracellular vesicles (EVs) are emerging as key players in intercellular communication. Few studies have focused on EV levels in subjects with sleep disorders. Here, we aimed to explore the role of acute sleep deprivation on the quantity and functionality of circulating EVs, and their tissue distribution. EVs were isolated by ultracentrifugation from the plasma of volunteers and animals undergoing one night of sleep deprivation. Arterio‐venous shunt, FeCl₃ thrombus test and thrombin‐induced platelet aggregation assay were conducted to evaluate the in vivo and in vitro bioactivity of small EVs. Western blotting was performed to measure the expression of EV proteins. The fate and distribution of circulating small EVs were determined by intravital imaging. We found that one night of sleep deprivation triggers release of small EVs into the circulation in both healthy individuals and animals. Injection of sleep deprivation‐liberated small EVs into animals increased thrombus formation and weight in thrombosis models. Also, sleep deprivation‐liberated small EVs promoted platelet aggregation induced by thrombin. Mechanistically, sleep deprivation increased the levels of HMGB1 protein in small EVs, which play important roles in platelet activation. Furthermore, we found sleep deprivation‐liberated small EVs are more readily localize in the liver. These data suggested that one night of sleep deprivation is a stress for small EV release, and small EVs released here may increase the risk of thrombosis. Further, small EVs may be implicated in long distance signalling during sleep deprivation‐mediated adaptation processes.     

北方农牧交错带多伦县生态系统服务权衡与协同关系研究

科学理解生态系统服务的权衡/协同关系,对于正确指导生态系统可持续管理实践具有重要意义。以位于北方农牧交错带的多伦县为研究区,基于土地利用/覆被、气象、土壤类型、归一化植被指数(NDVI)以及社会经济统计资料等多种数据,分析了2000年、2015年食物供给、碳固持、土壤保持、防风固沙及产水量5种生态系统服务的时空变化,识别了5种服务的供给热点区,并基于相关分析法从县域、乡镇及不同地类3种尺度上对生态系统服务间的权衡/协同关系进行分析。结果表明:(1)2000—2015年,食物供给与土壤保持量增幅较大,产水量与碳固持的供给量增幅较小,防风固沙量大幅下降,5种服务的空间格局基本保持不变;(2)多伦县1类热点区面积明显增加,3类热点区面积明显减少;面积占比超过50%的草地提供5种服务的能力强于耕地;(3)多伦县生态系统服务的权衡关系主要存在于产水量与土壤保持、产水量与碳固持、产水量与食物供给三对服务中;由于研究区生态系统环境的空间异质性较强,各乡镇和两种地类(草地和耕地)上分别只有4对和3对生态系统服务的权衡/协同关系与县域保持一致;(4)不同土地利用类型、海拔、土壤类型等因素的组合使多伦县乡...     

生态系统服务功能与景观格局耦合协调度研究——以武陵山区退耕还林工程为例

生态系统服务功能与景观格局演变关系极为密切,研究生态系统服务功能与景观格局的耦合协调度对于区域发展具有重要意义。以武陵山区退耕还林工程为例,参照国家标准和行业标准,采用分布式测算方法、景观格局指数分析和耦合协调度模型等方法,旨在揭示武陵山区退耕还林工程生态系统服务功能与景观格局二者耦合协调关系。结果表明:(1)2005—2017年间武陵山区退耕还林工程各项生态服务功能物质量均以15倍左右速度增长,生态系统服务空间分布格局最佳区域由西部地区逐渐向东南扩大;(2)武陵山区景观演变存在时空差异,1995—2005年景观格局变化更为明显,变化区域集中在中西部地区,2005—2015年与之相比,景观格局变化空间上更为分散;(3)武陵山区退耕还林工程生态系统服务与景观格局演变存在较高水平的耦合以及高水平的协调性。研究结果可为武陵山区土地利用规划及退耕还林工程进一步实施提供科学依据。     

气候因素对黑线姬鼠种群动态影响的非线性效应

受全球气候变化的影响,气候因素与害鼠种群变化之间的关系成为害鼠防治研究中的热点问题。以西安市长安区周边分布的黑线姬鼠为研究对象,通过标志重捕法进行种群动态监测,掌握其种群数量的动态变化规律,并结合非线性的统计方法广义可加模型,对该地区2015—2018年黑线姬鼠种群密度和气候因素数据进行分析,探讨该鼠种群变化与气候因素之间的关系。结果表明,该地区黑线姬鼠种群数量总体显现为下降趋势。黑线姬鼠种群密度存在显著的正向自我调节效应(F_{1.00, 5.77}=27.062,P<0.01),且与上一月种群密度存在线性的正相关。当月平均温度与该鼠种群密度之间存在显著的非线性效应(F_{1.90, 5.77} =4.696,P<0.05),两者之间显现为钟型关系,当温度<21℃时,两者之间显现为正相关,黑线姬鼠种群密度随温度的升高而升高,反之显现为负相关。当月累计降雨量与其种群密度之间也存在显著的非线性效应(F_{1.87, 5.77}=3.879,P<0.05),同样,两者之间也显现为钟型关系,当降雨量>90 mm时,...