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ABSTRACTMacroautophagy/autophagy and apoptosis are pivotal interconnected host cell responses to viral infection, including picornaviruses. Here, the VP3 proteins of picornaviruses were determined to trigger autophagy, with the autophagic flux being triggered by the TP53-BAD-BAX axis. Using foot-and-mouth disease virus (FMDV) as a model system, we unraveled a novel mechanism of how picornavirus hijacks autophagy to bolster viral replication and enhance pathogenesis. FMDV infection induced both autophagy and apoptosis in vivo and in vitro. FMDV VP3 protein facilitated the phosphorylation and translocation of TP53 from the nucleus into the mitochondria, resulting in BAD-mediated apoptosis and BECN1-mediated autophagy. The amino acid Gly129 in VP3 is essential for its interaction with TP53, and crucial for induction of autophagy and apoptosis. VP3-induced autophagy and apoptosis are both essential for FMDV replication, while, autophagy plays a more important role in VP3-mediated pathogenesis. Mutation of Gly129 to Ala129 in VP3 abrogated the autophagic regulatory function of VP3, which significantly decreased the viral replication and pathogenesis of FMDV. This suggested that VP3-induced autophagy benefits viral replication and pathogenesis. Importantly, this Gly is conserved and showed a common function in various picornaviruses. This study provides insight for developing broad-spectrum antivirals and genetic engineering attenuated vaccines against picornaviruses.Abbreviations: 3-MA, 3-methyladenine; ATG, autophagy related; BAD, BCL2 associated agonist of cell death; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X, apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCL2, BCL2 apoptosis regulator; BID, BH3 interacting domain death agonist; BIP-V5, BAX inhibitor peptide V5; CFLAR/FLIP, CASP8 and FADD like apoptosis regulator; CPE, cytopathic effects; CQ, chloroquine; CV, coxsackievirus; DAPK, death associated protein kinase; DRAM, DNA damage regulated autophagy modulator; EV71, enterovirus 71; FMDV, foot-and-mouth disease virus; HAV, hepatitis A virus; KD, knockdown; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MOI, multiplicity of infection; MTOR, mechanistic target of rapamycin kinase; PML, promyelocytic leukemia; PV, poliovirus; SVA, Seneca Valley virus; TCID50, 50% tissue culture infectious doses; TOR, target of rapamycin. TP53/p53, tumor protein p53; WCL, whole-cell lysate.

Abdominal complications following cardiac surgery are rare events, but can be fatal if not diagnosed and managed in time. Aggressive treatments offer a better chance for survival in patients with risk factors. This case report describes the clinical presentation and details of 3 recently operated patients who suffered acute abdominal pain after cardiac surgery. The underlying causes were Crohn disease-associated ileal perforation, intestinal necrosis, and diverticulitis-associated colonic perforation. The presentation and management of these severe conditions are discussed.

Restoring confidence in Chinese exports requires a cooperative response from the Chinese government and the governments of importing countries. Chinese export sales declined as a result of product safety incidents in 2007, reducing sales even for firms with no safety problems.

ABSTRACTThe foot-and-mouth disease virus (FMDV) is the causative agent of FMD, a highly infectious and devastating viral disease of domestic and wild cloven-hoofed animals. FMD affects livestock and animal products’ national and international trade, causing severe economic losses and social consequences. Currently, inactivated vaccines play a vital role in FMD control, but they have several limitations. The genetic code expansion technology provides powerful strategies for generating premature termination codon (PTC)-harbouring virus as a live but replication-incompetent viral vaccine. However, this technology has not been explored for the design and development of new FMD vaccines. In this study, we first expanded the genetic code of the FMDV genome via a transgenic cell line containing an orthogonal translation machinery. We demonstrated that the transgenic cells stably integrated the orthogonal pyltRNA/pylRS pair into the genome and enabled efficient, homogeneous incorporation of unnatural amino acids into target proteins in mammalian cells. Next, we constructed 129 single-PTC FMDV mutants and four dual-PTC FMDV mutants after considering the tolerance, location, and potential functions of those mutated sites. Amber stop codons individually substituted the selected amino acid codons in four viral proteins (3D, L, VP1, and VP4) of FMDV. We successfully rescued PTC-FMDV mutants, but the amber codon unexpectedly showed a highly degree of mutation rate during PTC-FMDV packaging and replication. Our findings highlight that the genetic code expansion technology for the generation of PTC-FMD vaccines needs to be further improved and that the genetic stability of amber codons during the packaging and replication of FMDV is a concern.

Takeda G protein-coupled receptor 5 (TGR5) is a promising target for treating metabolic syndrome and inflammatory diseases. Herein, we identified a new series of betulinic acid derivatives as potent TGR5 agonists, which show remarkable activity on human (h) and canine (c) TGR5 but exhibit unpromising activity on murine (m) TGR5. Species difference was also observed with many other reported TGR5 agonists. Therefore, we screened 29 amino acids which were conserved in hTGR5 and cTGR5 but different in mTGR5 and found a key amino acid, H88 in mTGR5 (Y89 in hTGR5), which contributed to the species difference. With the CRISPR/Cas9 system, the mTGR5H88Ymutation was introduced into mice, and the optimized compound 11d-Nadisplayed a significant glucose-lowering effect and stimulated GLP-1 and insulin secretion in TGR5H88Ymice but not in wild-type animals. Taken together, our study provides a useful tool to bridge the gap of species difference and discovers a potent TGR5 agonist for further investigation.

Parameter identification of the proton exchange membrane fuel cell (PEMFC) is a good way of increasing their efficiency in the next designs. In this study, an optimized improved Elman neural network based on a new hybrid optimization algorithm is proposed for this purpose. The proposed algorithm is a hybrid algorithm based on a combination of two newly algorithms, the world cup optimization (WCO) and the fluid Search Optimization (FSO) algorithms. The proposed method is applied to improve the method efficiency for estimating the PEMFC model parameters. The method is then validated by four different operational conditions. The optimization algorithm efficiency is also analyzed by comparison with some popular algorithms. Simulation results showed that using the designed method gives higher accuracy forecast for the PEMFC model parameters.

The rapid pace of both economic growth and transition from a command to market economy has required a major restructuring of food safety institutions in the People's Republic of China (PRC). The institutional transformation has consistently lagged behind the changes demanded by economic transformation. The declining ability to control both information and integration into the global food economy has brought scrutiny of institutional deficiencies and spurred reforms. Incentives to invest in food safety in the private sector and food safety training of workers all along food supply chains and in the inspection service remain the major public health challenges.

Adenosine 5′-monophosphate-activated protein kinase (AMPK) activator YLF466D is a promising preclinical drug candidate to treat metabolic diseases and myocardial ischemia-reperfusion injury (MIRI). Herein, we report our efforts on optimization and development of a practical and scalable process for the preparation of YLF466D in kilogram scale. The process features a palladium-catalyzed C–H activation under mild reaction conditions, geometry selectivity, effective impurities purging, and low levels of residual solvents in the final active pharmaceutical ingredient (API). We applied this process successfully to prepare more than 17 kg (3.0–3.6 kg per batch) of YLF466D to support its preclinical study.

In order to strengthen the community energy interconnection and promote the optimization and complementation of various energy sources, the scheduling of the integrated community energy system (ICES) has become the basic work of the development of community energy systems. At the same time, the economic dispatch of ICES is an important measure to accept new energy and improve the economic performance of community energy consumption. Without a suitable economic dispatching method, the system cannot fully accept new energy, which will cause the decrease of overall efficiency of the integrated energy system. For the object of economic optimization, this work proposes a holistic optimization dispatching method of several energy devices (electric boilers, hot water tanks and heat pumps) to minimize the operation cost of ICES. Considering that under low temperature the utilization rate of heating equipment is relatively high, a typical season, winter is selected to build operation constraints models. Example analysis shows that the proposed ICES optimization dispatching method provides an appropriate dispatching scheme for the planner of the ICES. This optimization dispatching method not only reduces the operation cost, but also promotes the consumption of renewable energy.