Molecular characterization and expression of the SiUCP2 gene in sea urchin Strongylocentrotus intermedius

Uncoupling protein 2 (UCP2) is a proton transporter located in the inner mitochondrial membrane, and inhibits the formation of adenosine triphosphate and reactive oxygen species by uncoupling oxidative phosphorylation. To provide a theoretical basis for the role of SiUCP2 in lipid metabolism, a 2 341-bp full-length cDNA of SiUCP2 from sea urchin Strongylocentrotus intermedius , which encodes 323 amino acids (predicted MW 36.11 kDa) was obtained, and the structure and function of the SiUCP2 gene and its expression at the mRNA and protein level were studied. SiUCP2 had high homology with UCP2 of other species. Expression of SiUCP2 was detected in the order of tube feet > gonads > coelomocytes > intestines. The expression level was the highest in prismatic larvae and lowest in the two-cell stage. Moreover, using in-situ hybridization, we found that SiUCP2 protein was expressed in the gonads and intestine. This study provided a theoretical basis for subsequent studies on the role of SiUCP2 and its regulatory mechanism in lipid metabolism, and for the improvement of gonad quality to obtain a higher economic value from sea urchins.

地球深部过程与极热和极冷事件

地球气候以频繁冷暖波动为特征,在百万年时间尺度上可划分为温室期和冰室期,期间发生持续时间相对短的极热和极冷事件.大多数学者将这些温室期、冰室期以及极热和极冷事件归因于大气CO_(2)浓度变化,即地球深部碳释放和表层碳消耗之间的动态平衡.地球深部碳是CO_(2)的主要来源,通过大火成岩省、俯冲带、裂谷岩浆活动等过程释放到大气中,从而引发全球增温.但是,深部过程又可通过4种途径引发降温:(1)火山活动释放SO_(2)形成硫酸盐气溶胶,导致“火山冬天”;(2)岩浆活动峰期之后的化学风化消耗大气CO_(2),其中,镁铁质岩化学风化速率高于长英质岩,降温作用更显著;(3)火山喷发及岩浆岩化学风化释放营养元素,促进大洋初级生产力,加快碳埋藏;(4)板块运动增大陆地面积以及使大陆聚集于高温、湿润的低纬地区,增强化学风化对CO_(2)的消耗.大体上,温室和冰室气候与俯冲带大陆弧岩浆活动强度(通常用大陆弧长度和年轻碎屑锆石相对丰度指代)及低纬地区弧-陆碰撞带长度有关,如果大陆弧活跃且低纬地区弧-陆碰撞带规模小,易形成温室气候,反之则形成冰室气候.极热事件普遍由镁铁质大火成岩省的快速巨量碳释放引发;极冷事件成因较为复杂,例如低纬地区大火成岩省强烈化学风化(如前寒武纪斯图特雪球地球)和硅质大火成岩省或大规模长英质火山活动的“火山冬天”效应(如晚古生代冰期极盛期).目前,从发生时间一致和关联机制合理性这两个角度考虑,大部分极热和极冷事件的发生都可归因于大规模岩浆活动,但是岩浆活动引发的系列反馈过程以及对极热和极冷事件的触发与维持机制仍缺乏深入理解.就此而论,高精度定年、岩浆活动过程及其气候反馈的数值模拟应该是今后研究的重点.

上新世数值模拟揭示气候周期空间差异的机理

上新世(5.33~2.58 Ma)是距今最近的大气CO_(2)浓度超过400 ppmv的暖期,是理解未来气候变化的地质历史相似型.地质记录显示,上新世气候主要响应地球倾角和岁差变化,比如深海氧同位素和高纬陆相记录表现出强的倾角周期(41 ka),低纬和地中海地区的粉尘和花粉记录以岁差周期(21 ka)为主.然而,这些气候周期空间差异的机制尚不清楚.我们使用全球海气耦合模式HadCM3,开展了轨道参数极值实验.结果表明:(1)倾角变化主要对高纬温度影响显著(>5℃),很好地解释了高纬记录和受高纬冰量调节的深海氧同位素记录的41 ka周期;(2)岁差变化主要影响低纬降水(>2 mm d-1),很好地解释了低纬和地中海地区与季风活动相关的21 ka气候周期.

Repurposing carrimycin as an antiviral agent against human coronaviruses,including the currently pandemic SARS-CoV-2

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development.No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections.We report herein that a macrolide antibiotic,carrimycin,potently inhibited the cytopathic effects(CPE)and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229 E,OC43,and SARS-CoV-2.Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection.In support of this notion,metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA.Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

Tumor extracellular vesicles mediate anti-PD-L1 therapyresistance by decoying anti-PD-L1

PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is unknown.Here,we show that PD-L1+TEVs substantially decoyαPD-L1 and that TEV-boundαPD-L1 is more rapidly cleared by macrophages,causing insufficient blockade of tumor PD-L1 and subsequentαPD-L1 therapy resistance.Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reversesαPD-L1 therapy resistance.Either an increasedαPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishesαPD-L1 therapy resistance.Moreover,in the treatment cycle with the same total treatment dose ofαPD-L1,high-dose and low-frequency treatment had better antitumor effects than low-dose and highfrequency treatment,induced stronger antitumor immune memory,and eliminatedαPD-L1 therapy resistance.Notably,in humanized immune system mice with human xenograft tumors,both increasedαPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects ofαPD-L1.Furthermore,increased doses ofαPD-L1 andαPD-1 had comparable antitumor effects,butαPD-L1 amplified fewer PD-1+Treg cells,which are responsible for tumor hyperprogression.Altogether,our results reveal a TEV-mediated mechanism ofαPD-L1-specific therapy resistance,thus providing promising strategies to improveαPD-L1 efficacy.

Reciprocal regulation between lunapark and atlastin facilitates ER three-way junction formation

Three-way junctions are characteristic structures of the tubular endoplasmic reticulum (ER) network. Junctions are formed through atlastin (ATL)-mediated membrane fusion and stabilized by lunapark (Lnp). However, how Lnp is preferentially enriched at three-way junctions remains elusiveHere, we showed that Lnp loses its junction localization when ATLs are deleted. Reintroduction of ATL1 R77A and ATL3, which have been shown to cluster at the junctions, but not wild-type ATL1, relocates Lnp to the junctions. Mutations in the Nmyristoylation site or hydrophobic residues in the coiled coil (CC1) of Lnp N-terminus (NT) cause mis-targeting of LnpConversely, deletion of the lunapark motif in the C-terminal zinc fin ger domain, which affects the homooligomerization of Lnp, does not alter its localizationPurified Lnp-NT attaches to the membrane in a myristoylation- dependent manner. The mutation of hydrophobic residues in CC1 does not affect membrane association, but compromises ATL interactionsIn addition, Lnp-NT inhibits ATL-mediated vesicle fusion in vitro. These results suggest that CC1 in Lnp-NT contacts junction-enriched ATLs for proper localization;subsequently, further ATL activity is limited by Lnp after the junction is formed. The proposed mechanism ensures coordinated actions of ATL and Lnp in generating and maintaining three-way junctions.