Macrophage autophagy regulates mitochondria‐mediated apoptosis and inhibits necrotic core formation in vulnerable plaques

The vulnerable plaque is a key distinguishing feature of atherosclerotic lesions that can cause acute atherothrombotic vascular disease. This study was designed to explore the effect of autophagy on mitochondria‐mediated macrophage apoptosis and vulnerable plaques. Here, we generated the mouse model of vulnerable carotid plaque in ApoE^?/? mice. Application of ApoE^?/? mice with rapamycin (an autophagy inducer) inhibited necrotic core formation in vulnerable plaques by decreasing macrophage apoptosis. However, 3‐methyladenine (an autophagy inhibitor) promoted plaque vulnerability through deteriorating these indexes. To further explore the mechanism of autophagy on macrophage apoptosis, we used macrophage apoptosis model in vitro and found that 7‐ketocholesterol (7‐KC, one of the primary oxysterols in oxLDL) caused macrophage apoptosis with concomitant impairment of mitochondria, characterized by the impairment of mitochondrial ultrastructure, cytochrome c release, mitochondrial potential dissipation, mitochondrial fragmentation, excessive ROS generation and both caspase‐9 and caspase‐3 activation. Interestingly, such mitochondrial apoptotic responses were ameliorated by autophagy activator, but exacerbated by autophagy inhibitor. Finally, we found that MAPK‐NF‐κB signalling pathway was involved in autophagy modulation of 7‐KC–induced macrophage apoptosis. So, we provide strong evidence for the potential therapeutic benefit of macrophage autophagy in regulating mitochondria‐mediated apoptosis and inhibiting necrotic core formation in vulnerable plaques.     

CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer

CD73 is a glycosylphosphatidylinositol (GPI)‐anchored protein that attenuates tumour immunity via cooperating with CD39 to generate immunosuppressive adenosine. Therefore, CD73 blockade has been incorporated into clinical trials for cancers based on preclinical efficacy. However, the biological role and underlying mechanism of CD73 in pancreatic cancer (PC) microenvironment and its prognostic impact have not been comprehensively studied. In this article, we found that the expression of CD73 was up‐regulated in PC tissues and patients with higher CD73 expression had poorer overall survival (OS) and disease‐free survival (DFS) in multiple publicly available databases. Higher CD73 expression was significantly associated with its reduced methylation, and only the hypomethylation of CpG site at cg23172664 was obviously correlated with poorer OS. Then, Metascape analysis and GSEA showed that CD73 may play an important role in PC progression and immune regulations. Notably, CD73 was verified to be negatively correlated with infiltrating levels of CD8⁺ T cells and γδ⁺ T cells in both TCGA and GEO cohorts via the CIBERSORT algorithm. In addition, patients with higher CD73 expression also tended to have higher PD‐L1 expression and tumour mutation load. It seemed that CD73 might be a promising biomarker for the response to the anti‐PD‐1/PD‐L1 treatment in PC. In conclusion, these results reveal that CD73 may function as a promotor in cancer progression and a regulator in immune patterns via CD73‐related pathways. Blockade of CD73 might be a promising therapeutic strategy for PC.     

东亚钳蝎毒液透明质酸酶全基因序列的克隆和结构分析

本研究通过以东亚钳蝎毒腺为研究材料,采用TRIzol法分离透明质酸酶的全基因序列,并从中分离出4个东亚钳蝎透明质酸酶序列,分别命名为BmHYⅠ、BmHYⅡ、BmHYⅢ和BmHYⅣ。BmHYⅠcDNA全长是1423 bp,包括42 bp的5’非翻译区,1230 bp的开放阅读框,编码了一个410个氨基酸,还有151 bp的3’非翻译区;BmHYⅠ中包含5个糖基化位点;与其它物种蛋白质比对结果显示,BmHYⅠ中有10个高度保守半胱氨酸残基形成5个二硫键。BmHYⅠ在二级结构中形成了13个螺旋和14个折叠,其中折叠主要分布在N端和C端。系统进化树结构表明,东亚钳蝎BmHYⅠ与其它蝎子物种透明质酸酶亲缘关系最近,其次是蜘蛛,最后是脊椎动物。而BmHYⅡ、BmHYⅢ和BmHYⅣ序列缺少终止密码子,蛋白序列与BmHYⅠ具有高度同源性。本研究结果为进一步透明质酸酶的功能提供数据参考。     

Osa‐miR167d facilitates infection of Magnaporthe oryzae in rice

MicroRNAs (miRNAs) play important roles in rice response to Magnaporthe oryzae, the causative agent of rice blast disease. Studying the roles of rice miRNAs is of great significance for the disease control. Osa‐miR167d belongs to a conserved miRNA family targeting auxin responsive factor (ARF) genes that act in developmental and stress‐induced responses. Here, we show that Osa‐miR167d plays a negative role in rice immunity against M. oryzae by suppressing its target gene. The expression of Osa‐miR167d was significantly suppressed in a resistant accession at and after 24 h post inoculation (hpi), however, its expression was significantly increased at 24 hpi in the susceptible accession upon M. oryzae infection. Transgenic rice lines over‐expressing Osa‐miR167d were highly susceptible to multiple blast fungal strains. By contrast, transgenic lines expressing a target mimicry to block Osa‐miR167d enhanced resistance to rice blast disease. In addition, knocking out the target gene ARF12 led to hyper‐susceptibility to multiple blast fungal strains. Taken together, our results indicate that Osa‐miR167d negatively regulate rice immunity to facilitate the infection of M. oryzae by downregulating ARF12. Thus, Osa‐miR167d‐ARF12 regulatory module could be valuable in improvement of blast‐disease resistance.     

Osa‐miR1873 fine‐tunes rice immunity against Magnaporthe oryzae and yield traits

MicroRNAs (miRNAs) are known to fine‐tune growth, development, and stress‐induced responses. Osa‐miR1873 is a rice‐specific miRNA targeting LOC_Os05g01790. Here, we show that Osa‐miR1873 fine‐tunes rice immunity against Magnaporthe oryzae and yield traits via LOC_Os05g01790. Osa‐miR1873 was significantly upregulated in a susceptible accession but downregulated in a resistance accession at 24 h post‐inoculation (hpi) of M. oryzae. Overexpressing Osa‐miR1873 enhanced susceptibility to M. oryzae and compromised induction of defense responses. In contrast, blocking Osa‐miR1873 through target mimicry compromised susceptibility to M. oryzae and enhanced induction of defense responses. Altered expression of Osa‐miR1873 also resulted in some defects in yield traits, including grain numbers and seed setting rate. Moreover, overexpression of the target gene LOC_Os05g01790 increased rice blast disease resistance but severely penalized growth and yield. Taken together, we demonstrate that Osa‐miR1873 fine‐tunes the rice immunity‐growth trade‐off via LOC_Os05g01790, and blocking Osa‐miR1873 could improve blast disease resistance without significant yield penalty. Thus, the Osa‐miR1873‐LOC_Os05g01790 regulatory module is valuable in balancing yield traits and blast resistance.     

Emergence of breeding tubercles and puberty onset in male zebrafish: evidence for a dependence on body growth

The presence of breeding tubercles (BTs) on the pectoral fins has been investigated as a typical male secondary sexual characteristic (SSC) that distinguish males from females in adult zebrafish. Nonetheless, the earliest occurrence of these tubercles and its association with puberty onset and body growth remain unclear. In this study, using morphological, histological and statistical analyses, the authors examined the first appearance of BTs and puberty onset in male zebrafish, with particular emphasis on the potential impact of body growth on them. The results of this study revealed that BTs distributed along the first five branched pectoral fin rays were the earliest manifestation of male SSCs, which is significantly strongly correlated with body weight (R² = 0.9609, P < 0.001), and could be used as a “gold standard” for the earliest sex distinction (<0.1 g in weight). Using the first appearance of BTs (<0.20 mm²) as a metric, the authors established that male puberty commenced at a body weight of c. 0.056 ± 0.015 g or a standard length of 10.99 ± 1.051 mm (mean ± S.D. ). In this study, the authors thus established a simple method that can be used to sex live zebrafish at the pubertal stage and provides the first evidence for the relationship of BTs and male puberty initiation with body growth. These findings will accordingly lay a foundation for exploring mechanisms of the SSCs and male puberty onset in zebrafish and other teleost fish.