PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L‐associated PI3K activity

The Beclin1–VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L‐linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L‐ but not UVRAG‐linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise‐induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L‐associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro‐autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L‐linked VPS34 complex upon glucose starvation.     

Identification and Characterization of the Lysine-Rich Matrix Protein Family in <Emphasis Type="Italic">Pinctada fucata</Emphasis>: Indicative of Roles in Shell Formation

Mantle can secret matrix proteins playing key roles in regulating the process of shell formation. The genes encoding lysine-rich matrix proteins (KRMPs) are one of the most highly expressed matrix genes in pearl oysters. However, the expression pattern of KRMPs is limited and the functions of them still remain unknown. In this study, we isolated and identified six new members of lysine-rich matrix proteins, rich in lysine, glycine and tyrosine, and all of them are basic matrix proteins. Combined with four members of the KRMPs previously reported, all these proteins can be divided into three subclasses according to the results of phylogenetic analyses: KRMP1–3 belong to subclass KPI, KRMP4–5 belong to KPII, and KRMP6–10 belong to KPIII. Three subcategories of lysine-rich matrix proteins are highly expressed in the D-phase, the larvae and adult mantle. Lysine-rich matrix proteins are involved in the shell repairing process and associated with the formation of the shell and pearl. What’s more, they can cause abnormal shell growth after RNA interference. In detail, KPI subgroup was critical for the beginning formation of the prismatic layer; both KPII and KPIII subgroups participated in the formation of prismatic layer and nacreous layer. Compared with different temperatures and salinity stimulation treatments, the influence of changes in pH on KRMPs gene expression was the greatest. Recombinant KRMP7 significantly inhibited CaCO₃ precipitation, changed the morphology of calcite, and inhibited the growth of aragonite in vitro. Our results are beneficial to understand the functions of the KRMP genes during shell formation.     

Rapid Assessment of Tablet Film Coating Quality by Multispectral UV Imaging

Chemical imaging techniques are beneficial for control of tablet coating layer quality as they provide spectral and spatial information and allow characterization of various types of coating defects. The purpose of this study was to assess the applicability of multispectral UV imaging for assessment of the coating layer quality of tablets. UV images were used to detect, characterize, and localize coating layer defects such as chipped parts, inhomogeneities, and cracks, as well as to evaluate the coating surface texture. Acetylsalicylic acid tablets were prepared on a rotary tablet press and coated with a polyvinyl alcohol-polyethylene glycol graft copolymer using a pan coater. It was demonstrated that the coating intactness can be assessed accurately and fast by UV imaging. The different types of coating defects could be differentiated and localized based on multivariate image analysis and Soft Independent Modeling by Class Analogy applied to the UV images. Tablets with inhomogeneous texture of the coating could be identified and distinguished from those with a homogeneous surface texture. Consequently, UV imaging was shown to be well-suited for monitoring of the tablet coating layer quality. UV imaging is a promising technique for fast quality control of the tablet coating because of the high data acquisition speed and its nondestructive analytical nature.     

Metabolomic study of the bone trabecula of osteonecrosis femoral head patients based on UPLC–MS/MS

The severity and/or progression of osteonecrosis of the femoral head (ONFH) are commonly assessed by radiography, nuclear magnetic resonance image which aren’t invariably correlated to severity of disease and may be disturbed by other factors. Consequently, exploring the novel biochemical signatures of ONFH may be beneficial for diagnosing and understanding this disease. In this work, a bone trabecula metabolomics was undertaken to determine the expression pattern of low molecular mass metabolites in patients of femoral head necrosis based on the ultra-performance liquid chromatography/time-of-flight tandem mass spectrometry (UPLC/TOF MS/MS). Histological study showed that necrotic bone was characterized by necrosis, fibrosis and lacuna, but adjacent “normal” bone was pathologically normal. Principal component analysis in combination with orthogonal partial least-squares discrimination analysis was used to find out changed metabolites. MS/MS was used to speculate the corresponding molecule. Both osteonecrotic bone trabecula (ONBT) and adjacent “normal” bone trabecula (ANBT) showed higher levels of amino acids, such as proline, arginine, glutamine, dipeptides and lower levels of antioxidants. Most disrupted lipids, such as fatty acid esters, glycerophospholipids, sphingolipids, were found in osteonecrotic zone. The area under the receiver operating characteristic curve of combinational biomarkers (d-arginine, l-proline, l-carnitine, inosine) in ONBT and ANBT was 0.996 and 0.950, respectively. Our findings might provide a significant insight to understand the metabolic mechanism and diagnosis biomarkers of ONFH in the future.     

The insights of Let‐7 miRNAs in oncogenesis and stem cell potency

The ability of the classic tumour‐suppressive let‐7 family to inhibit carcinogenesis, tumour progression, recurrence and pluripotency of cancer stem cells has generated significant interest in the field of cancer research. Through suppressing and degrading downstream‐targeted mRNAs, let‐7 affected most aspects of cell biology. It is perplexing how let‐7 affects oncogenesis, as the large influx of new miRNAs and other kinds of non‐coding RNAs are continuously defined. In this review, we delineate the complex functions of let‐7 and discuss the future direction of let‐7 research.     

小叶兜兰的果实生长和雌配子体发育

为了解濒危兰科植物小叶兜兰(Paphiopedilum barbigerum Tang et Wang)胚珠和雌配子体的发育过程,采用常规石蜡切片技术对其果实的生长动态进行了研究。结果表明,授粉后60~75 d的蒴果内种子数量迅速增加,到授粉后120 d时种子充满整个蒴果。授粉后40 d的胎座上分化形成多数由1层表皮细胞包被1列细胞的胚珠原基;授粉后60 d时位于胎座指状结构末端处紧靠表皮细胞下方的孢原细胞分化为大孢子母细胞。之后,大孢子母细胞经过减数分裂和有丝分裂最终形成成熟胚囊;授粉后135 d胚囊发育成熟,附着在胎座上的种子个体分化明显。小叶兜兰胚囊的发育类型为双孢子葱型,胚珠为倒生胚珠,薄珠心,单珠被,成熟胚囊为8核。这为小叶兜兰的生殖生物学及繁殖体系的建立提供理论依据。     

医药 CRO 专题报告——蓝海市场，强者恒强

随着全球制药企业研发投资成本加大、研发周期变长、研发成功率降低,作为社会分工专业化的产物,CRO 企业凭借其低成本、高效率、 多服务的特点,快速发展,且服务范畴已涵盖药物研发的整个过程,成为医药研发产业链中不可缺少的环节。报告采用文献调研、数据库检索、 数据统计与分析等定性定量研究方法,从发展概况、发展策略、竞争格局、企业布局等角度对国内外医药 CRO 领域进行多角度、多层次的 分析,旨在为相关企业确定产品研发思路、制定市场策略提供线索和参考。     

土荆芥挥发性化感物质对蚕豆叶表皮保卫细胞的影响

化感作用是外来植物土荆芥( Chenopodium ambrosioides)成功入侵的机制之一。为了探讨土荆芥挥发油的化感作用机制,该文以蚕豆( Vicia faba)叶的下表皮为材料,将表皮条孵育在分别含土荆芥挥发油、α-萜品烯和对伞花素的MES [2-( N-morpholino) ethanesulfonic acid]缓冲液中,25℃下光照培养30 min,采用吖啶橙/溴乙锭( AO/EB)双荧光染色法和Feulgen染色法,研究土荆芥挥发油、α-萜品烯和对伞花素对保卫细胞活性和细胞核形态的影响。结果表明：在土荆芥挥发油、α-萜品烯和对伞花素的作用下,蚕豆气孔保卫细胞活性降低,细胞核出现固缩、畸形或降解等细胞凋亡特征。随着处理剂量增加,保卫细胞活性显著下降,核异常率显著增加,表明土荆芥挥发油、α-萜品烯和对伞花素均对蚕豆保卫细胞具有细胞毒性,其中,挥发油毒性最大,α-萜品烯的毒性次之,对伞花素的毒性最小;Caspase抑制剂Z-VAD-FMK可缓解挥发油、α-萜品烯和对伞花素对保卫细胞的毒性,提高细胞活性,这种缓解效应随着抑制剂浓度的增加而增大。由此可见,土荆芥挥发油、α-萜品烯和对伞花素诱导蚕豆保卫细胞发生了Caspase依赖性的细胞凋亡。     

尿液作为新型生物标志物来源的探索

机体各种变化是生物标志物研究的核心内容.因为机体固有的稳态调控机制,在血液中早期产生的变化容易被清除.而在尿液中不存在稳态调控机制,允许容纳更多的变化因素存在.尤其在疾病发生的早期阶段,从尿液中更有可能发现新型的早期生物标志物.在尿液生物标志物研究中,亦应当考虑药物的影响.使用尿液生物标志物研究路线图,能够有效规避各种影响因素对于尿液生物标志物研究的干扰;同时,结合膜处理新技术,有利于经济、高效地大规模收集尿液样本,促进尿液生物标志物的大规模研究.另外,本文介绍了最容易在尿液中体现出变化的肾脏疾病生物标志物的研究进展.尿液生物标志物的研究,将赋予人类在疾病预防、诊断、治疗及预后监测等诸多方面实现更多进步的可能性.