Reexamination of the Ergothioneine Biosynthetic Methyltransferase EgtD from Mycobacterium tuberculosis as a Protein Kinase Substrate

Ergothioneine has emerged as a crucial cytoprotectant in the pathogenic lifestyle of Mycobacterium tuberculosis. Production of this antioxidant from primary metabolites may be regulated by phosphorylation of Thr213 in the active site of the methyltransferase EgtD. The structure of mycobacterial EgtD suggests that this post-translational modification would require a large-scale change in conformation to make the active-site residue accessible to a protein kinase. In this report, we show that, under in vitro conditions, EgtD is not a substrate of protein kinase PknD.     

microRNA在亨廷顿病中的研究进展

亨廷顿病(Huntington's disease, HD)是神经退行性疾病(neurodegenerative disorders)中一种单基因遗传病,由亨廷顿基因(the huntingtin gene, HTT)第一个外显子中的CAG三核苷酸序列重复扩增引起,尚无法治愈。HTT编码的蛋白产物被称为亨廷顿蛋白(Huntingtin protein, Htt)。突变亨廷顿蛋白(mutated huntingtin protein, mHtt)容易形成聚集体,具有毒性,导致一系列细胞学异常和神经元功能障碍。microRNA(miRNA)在基因转录后水平调控中起重要作用,其表达的改变与HD病理过程有关,成为治疗HD的潜在生物标志物。近年来,对一些特定miRNA在HD中调控机制及靶基因预测方面的研究可为HD提供潜在的治疗方法。本文就miRNA在HD中的相关研究进展进行综述。     

A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia

Targeting protein-protein interactions (PPIs) with small-molecule inhibitors has become a hotbed of modern drug development. In this review, we describe a new class of PPI inhibitors that block menin from binding to MLL proteins. Menin is encoded by the MEN1 tumor suppressor, but acts as an essential cofactor for MLL/KMT2A-rearranged leukemias. The most promising menin-MLL inhibitors belong to the thienopyrimidine class and have recently entered phase I/II clinical trials for treating acute leukemias characterized by MLL/KMT2A translocations or NPM1 mutations. As single agents, thienopyrimidine compounds eradicate leukemia in a xenograft models of primary leukemic cells belonging to the MLL-rearranged or NPM1-mutant subtypes. These compounds are well tolerated with few or no side effects, which is remarkable given the tumor-suppressor function of menin. The menin-MLL inhibitors highlight how leukemia patients could benefit from a targeted epigenetic therapy with novel PPI inhibitors obtained by directed chemical evolution.     

Service quality,technical efficiency and total factor productivity growth in Pakistan's post-reform electricity distribution companies

Pakistan's energy sector has undergone substantial reforms during the last three decades with the aim to improve its operational performance and to cater to the growing energy needs of the economy. In the wake of these reforms, the WAPDA Act was passed in 1998 to achieve operational and financial efficiencies. Pakistan's electricity market is still hampered by issues like extended blackouts, electricity thefts, high circular debt and poor service quality. The electricity distribution sector is thus an interesting case to investigate its efficiency in the post-reform period by examining the impact of service-quality parameters (SQPs), which have generally been neglected in the literature. Stochastic frontier analysis has been used to estimate technical efficiency, while the Malmquist Productivity Index is implemented to decompose total factor productivity (TFP) into scale change, technical change and efficiency change from 2006 to 2016. We conclude that the technical efficiency score declines from 98 percent to 36 percent with the inclusion of SQPs in the models. The results also indicate a negative trend in scale change, implying that distribution companies are not operating at the technically optimal scale. We propose that the regulatory body should change its governance regime and focus on incentive-based regulation instead of rate-of-return regulation.     

The (In)efficiency of the retail-minus rule

The Retail-Minus Rule (RMR) specifies that the rate for a mandated wholesale service is set by subtracting from the vertically integrated provider's (VIP's) retail price the costs it avoids by selling the wholesale service rather than the retail service. While the RMR offers regulators an expedient method for setting wholesale prices, we show that it is efficient only under restrictive conditions. The proper test for a price squeeze inquires whether the VIP's retail price is greater than or equal to the sum of the direct cost and the opportunity cost of supplying the retail service. The RMR passes this test only when the competing retail services are perfect substitutes.     

数字经济时代网络市场监管创新的思考

数字经济时代,新技术、新产业、新业态、新模式加速孕育,网络市场竞争态势愈加复杂、多变,监管创新成为重要课题。网络市场监管工作应当确立稳定、可预期的监管原则,并落实好包容审慎、事中事后监管、协同监管等原则;对关系到国家安全、社会稳定和公众生命健康等底线性问题,监管不能缺位,而应继续严格审查监管。从创新监管原则的宏观研究,以及大数据监管、提升电子取证能力等监管手段的具体研究等维度,对监管创新进行了深度思考。