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Antisense oligonucleotides (ASONs)-based therapeutics offers tremendous promise for the treatment of diverse diseases. However, there is still a need to develop ASONs with enhanced stability against enzymes, improved drug delivery, and enhanced biological potency. In this study, we propose a novel anisamide (AA)-conjugated hairpin oligonucleotide prodrug loading with chemotherapeutic agent (doxorubicin, DOX) (AA-loop-ASON/DOX) for oncotherapy. Results indicated that the introduction of a hairpin conformation and AA ligand in prodrug significantly improved the stability against enzymatic hydrolysis, as well as the cellar uptake of ASONs and DOX. The incorporation of disulfide bonds could trigger mechanical opening, resulting in the release of ASON and DOX in response to the intracellular glutathione (GSH) in tumors. Moreover, the composite of DOX-loading ASONs prodrug exhibited a robust and selective inhibition of tumor cell proliferation. This paper introduces a novel design concept for nucleic acid-based therapeutics, aiming to enhance the delivery of drug and improve biological effectiveness.

Many migratory birds exhibit interannual consistency in migration schedules, routes and stopover sites. Detecting the interannual consistency in spatiotemporal characteristics helps understand the maintenance of migration and enables the implementation of targeted conservation measures. We tracked the migration of Whimbrel (Numenius phaeopus) in the East Asian–Australasian Flyway and collected spatiotemporal data from individuals that were tracked for at least two years. Wilcoxon non-parametric tests were used to compare the interannual variations in the dates of departure from and arrival at breeding/nonbreeding sites, and the interannual variation in the longitudes when the same individual across the same latitudes. Whimbrels exhibited a high degree of consistency in the use of breeding, nonbreeding, and stopover sites between years. The variation of arrival dates at nonbreeding sites was significantly larger than that of the departure dates from nonbreeding and breeding sites. Repeatedly used stopover sites by the same individuals in multiple years were concentrated in the Yellow Sea coast during northward migration, but were more widespread during southward migration. The stopover duration at repeatedly used sites was significantly longer than that at sites used only once. When flying across the Yellow Sea, Whimbrels breeding in Sakha (Yakutia) exhibited the highest consistency in migration routes in both autumn and spring. Moreover, the consistency in migration routes of Yakutia breeding birds was generally higher than that of birds breeding in Chukotka. Our results suggest that the northward migration schedule of the Whimbrels is mainly controlled by endogenous factors, while the southward migration schedule is less affected by endogenous factors. The repeated use of stopover sites in the Yellow Sea coast suggests this region is important for the migration of Whimbrel, and thus has high conservation value.

For the treatment of pain, the design of a bifunctional mu-opioid receptor (MOR)/delta-opioid receptor (DOR) agonist is an effective strategy to seek safer opioids with higher antinociceptive efficacy and diminished adverse side effects. Herein, we describe the design, synthesis, and evaluation of a novel bivalent ligand (SW-WL-2) with a methyl 1-(3-methoxy-3-oxopropyl)-4-(phenylamino) piperidine- 4-carboxylate moiety (remifentanil derivative) covalently linked to a dermorphin-like structure (H-Dmt-N-Me-D-Ala-Aba-Gly-NH2, BVD03) at the C-terminus. Our results showed that SW-WL-2 behaved as a potent dual agonist of MOR and DOR with significant and prolonged antinociceptive effects in acute pain models in vivo. Furthermore, SW-WL-2 exhibited reduced or no opioid-like side effects such as physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03. Thus, SW-WL-2 should be used as a new lead compound for the discovery of safer opioid drugs for the treatment of pain.

The cereals and their products, which have been easily infected by fungi and contaminated with mycotoxins, are serious threat to both human and animals alike. And yet, detection of these unknown fungal infection and mycotoxins contaminates remains a great challenge. In this work, a holistic approach based on multiple characteristic structure fragments scans and high-resolution mass spectrometry (HRMS) was proposed for discovering unknown structural analogues of mycotoxins. The structural similarity of the same class of compounds provides a direction for the discovery and identification of unknown structural analogues of mycotoxins. The following steps were carried out: the fragmentation pathways of four types of mycotoxins were elucidated through comprehensive fragment analysis. By the combination of fragmentation pathways, the multiple characteristic structure fragments were screened out, with the common fragments were obtained by Veen diagram. Finally multiple characteristic structure fragments scans were carried out to find the unknown structural analogues of mycotoxins. The approach, first proposed by us, was proved to be effective in discovering and identifying 5 structural analogues of mycotoxins in real samples. It was proved to be a simple, fast and accurate method for early detection of fungal infection and mycotoxin contaminants, even for trace amounts of chemicals in complex matrix, and is of great significance to prevent hazardous substances infection from the food supply chains worldwide.

Summary: Mouse embryonic stem cells (mESCs) can be directed to acquire cell-lineage-specific genetic programs and phenotypes by stepwise exposure to defined factors, allowing the development of in vitro models for studying disease and tissue generation. In this protocol, we describe the use of cultured mESCs to generate presomitic-like mesoderm cells undergoing further specification towards myogenic progenitors (MPs). Further, we describe here a procedure to obtain, dissect, and fluorescence-activated cell sorting (FACS)-isolate somitic cells from genetically labeled Pax7+/Cre; Rosa26YFP/+ embryos.For complete details on the use and execution of this protocol, please refer to Khateb et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Purpose – This study aims to analyze passenger service quality in Beijing West Railway Station from the perspective of passengers, to better understand the current service quality and obtain the areas of weakness for improvement. Design/methodology/approach – The research investigates the passenger experience of service in Beijing West Railway Station by using a questionnaire survey. The service quality (SERVQUAL) evaluation method is used to analyze the survey data, and it divides the passenger service into 5 attributes with 20 indicators. This research uses the Likert five-level scale method to process data and calculates the SERVQUAL value and weight difference of each attribute to evaluate the passenger service. Therefore, the deficiencies have been pointed out, so the station manager can improve the passenger service accordingly. Findings – It is indicated that among the five studied attributes, Beijing West Railway Station has the smallest service quality value in terms of timeliness, which means this part needs the largest improvement. To the five attributes, each lacks in station security check, ticketing efficiency, station identification accuracy, emergency processing of train delays and the restroom environment, respectively. Originality/value – The research can provide specific suggestions for the optimization of the passenger service of Beijing West Railway Station, and provide reference information for the formulation of policies.

Background: Drosophila melanogaster is a well-studied and highly tractable genetic model system for deciphering the molecular mechanisms underlying various biological processes. Although being one of the most critical post-translational modifications of proteins, the understanding of glycosylation in Drosophila is still lagging behind compared with that of other model organisms. Methods: In this study, we systematically investigated the site-specific N-glycan profile of Drosophila melanogaster using intact glycopeptide analysis technique. This approach identified the glycans, proteins, and their glycosites in Drosophila, as well as information on site-specific glycosylation, which allowed us to know which glycans are attached to which glycosylation sites. Results: The results showed that the majority of N-glycans in Drosophila were high-mannose type (69.3%), consistent with reports in other insects. Meanwhile, fucosylated N-glycans were also highly abundant (22.7%), and the majority of them were mono-fucosylated. In addition, 24 different sialylated glycans attached with 16 glycoproteins were identified, and these proteins were mainly associated with developmental processes. Gene ontology analysis showed that N-glycosylated proteins in Drosophila were involved in multiple biological processes, such as axon guidance, N-linked glycosylation, cell migration, cell spreading, and tissue development. Interestingly, we found that seven glycosyltransferases and four glycosidases were N-glycosylated, which suggested that N-glycans may play a regulatory role in the synthesis and degradation of N-glycans and glycoproteins. Conclusions: To our knowledge, this work represents the first comprehensive analysis of site-specific N-glycosylation in Drosophila, thereby providing new perspectives for the understanding of biological functions of glycosylation in insects.

The Hooded Crane (Grus monacha) is listed as a Vulnerable species in the IUCN red list. Tidal wetland (tideland), the major habitat for wintering Hooded Cranes at East China's Chongming Dongtan, has dramatically changed in the past two decades, but there is limited knowledge about the population and habitat changes of the Hooded Cranes. This study investigated the population size and distribution of wintering Hooded Cranes at Chongming Dongtan from 2000 to 2021. We used remote sensing images combined with a vegetation classification algorithm to analyse the distribution of saltmarsh vegetation. The quadrat method was used to investigate the density and weight of the underground corms of Sea Bulrush (Scirpus mariquter), the main food on tideland for the Hooded Cranes. From 2000 to 2021, the population number of wintering Hooded Cranes at Chongming Dongtan remained stable at approximately 100. In 2000, the area of Scirpus spp. and Common Reed (Phragmites australis) accounted for approximately half of the total saltmarsh area at Chongming Dongtan, respectively. The invasive Smooth Cordgrass (Spartina alterniflora) rapidly expanded on tideland in the 2000s while the Scirpus spp. was competed out and thus significantly reduced in area. After the implementation of an ecological project to control Smooth Cordgrass and to restore Scirpus spp. in the 2010s, the area of the Smooth Cordgrass decreased considerably while the area of Scirpus spp. increased. The corms of Sea Bulrush decreased on the southeastern tideland during the study period, which might be the cause of the northward movement of the foraging Hooded Cranes on tideland. We also found Hooded Cranes foraged crops in the nearby farmland in mid-winter, causing human-bird conflicts in the recent decade. Our results found that changes in habitat and food conditions on tideland impacted wintering Hooded Cranes. Foraging in farmland with human disturbance in the recent decade might be related to insufficient food on tideland. We suggest active intervention to accelerate the restoration of Sea Bulrush on tideland and reduce human disturbance in farmland to improve the habitat quality of the wintering Hooded Crane at Chongming Dongtan.

Antisense oligonucleotides (ASONs) have proven potential for the treatment of various diseases. However, their limited bioavailability restricts their clinical application. New structures with improved enzyme resistance stability and efficient drug delivery are needed. In this work, we propose a novel category of ASONs bearing anisamide conjugation at phosphorothioate sites for oncotherapy. ASONs can be conjugated with the ligand anisamide very efficiently and flexibly in a solution. The conjugation sites and the ligand amount both influence anti-enzymatic stability and cellular uptake, resulting in changes in antitumor activity that are detectable by cytotoxicity assay. The conjugate with double anisamide (T6) was identified as the optimal conjugate, and its antitumor activity and the underlying mechanism were examined further in vitro and in vivo. This paper presents a new strategy for the design of nucleic acid-based therapeutics with improved drug delivery and biophysical and biological efficacy.

Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have made treatment options for TNBC more selective. However, there are still problems, such as poor patient tolerance, large administration doses, high dosing frequency, and toxic side effects, necessitating the development of more efficient and less toxic treatment strategies. High expression of Nrf2, a vital antioxidant transcription factor, often promotes tumor progression, and it is also one of the most effective targets in BC therapy. We found that in MDA-MB-231 cells and SUM159 cells, brusatol (BRU) combined with polydatin (PD) could significantly inhibit cell proliferation in vitro, significantly downregulate the expression of Nrf2 protein as well as the expression of downstream related target genes Heme Oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1), and promote reactive oxygen species (ROS) levels to further strengthen the anti-tumor effect. Furthermore, we discovered in our in vivo experiments that by reducing the drug dosage three times, we could significantly reduce tumor cell growth while avoiding toxic side effects, providing a treatment method with greater clinical application value for TNBC treatment.

Mycotoxins pollution is a global concern, and can pose a serious threat to human health. People and livestock eating contaminated food will encounter acute and chronic poisoning symptoms, such as carcinogenicity, acute hepatitis, and a weakened immune system. In order to prevent or reduce the exposure of human beings and livestock to mycotoxins, it is necessary to screen mycotoxins in different foods efficiently, sensitively, and selectively. Proper sample preparation is very important for the separation, purification, and enrichment of mycotoxins from complex matrices. This review provides a comprehensive summary of mycotoxins pretreatment methods since 2017, including traditionally used methods, solid-phase extraction (SPE)-based methods, liquid-liquid extraction (LLE)-based methods, matrix solid phase dispersion (MSPD), QuEChERS, and so on. The novel materials and cutting-edge technologies are systematically and comprehensively summarized. Moreover, we discuss and compare the pros and cons of different pretreatment methods and suggest a prospect.

An individual-state training method using multiple battery cycling data and initial state training for individual batteries is proposed in this study. The training method is based on the Broyden-Fletcher-Goldfarb-Shanno quasi-Newton method, and is modified to adapt to different battery samples by training the initial states for individual batteries to improve the modeling precision. This is equivalent to training a different model for each battery with shared model parameters, which improves the generalization of the model while preserving the model's capability to account for individual variation. Based on the relatively small sample size and experimentation, the simple recurrent neural network with softplus activation is used as the model. The full NASA battery degradation dataset containing 34 degradation tests under varied cycling conditions is used to validate the proposed method. Compared to methods without the individual-state training, the proposed method reduces the average prediction error under changing cycling conditions from over 1 Ah to under 0.2 Ah for a nominal capacity of around 2 Ah. This improvement in accuracy is attributed to using multiple cycling data during training and the initial state training for individual batteries.

Abstract Background Liver cancer is one of the most common cancers in the world. The primary aim of this research was to discover the correlation between single nucleotide polymorphisms (SNPs) of the MIR155HG and liver cancer risk. Methods The selected SNPs in MIR155HG were genotyped utilizing the Agena MassARRAY platform. We evaluated the correlation between MIR155HG polymorphisms and Liver cancer by genetic model analysis, stratification analysis and haplotype analysis. Relative risk of Liver cancer was shown based on odds ratios (ORs) and 95% confidence intervals (95% CIs). Results Our results uncovered that rs12482371 and rs1893650 in the MIR155HG were associated with protection against Liver cancer. And the rs928883 was related to increase risk of Liver cancer. Furthermore, apart from rs77218221, other selected SNPs formed two LD blocks, and haplotype “GATAG” in block 2 elevated individual liver cancer risk. Conclusions MIR155HG gene polymorphism may be correlated to Liver cancer susceptibility in Han Chinese population, particularly in males and aged ≤55 years.

For aluminized explosive, the charge performance of explosive grenade is very significant for promoting their application. Firstly, the detonation performance of cyclotrimethylenetrinitramine (RDX) based explosives with different aluminum powder (0%, 20%, 25%, 30%, 35%, and 40%, respectively) content was investigated. Next, the air blast tests of RDX-based aluminized explosives were carried out. Then, RDX-based explosive grenade charges of L-1 and L-2 where the aluminum powder content was 20% and 25% were selected for air blast and static blasting fragments velocity tests. Finally, the energy release mechanism of the air blast was deduced via calculation. The results show that RDX-based aluminized explosives have higher detonation heat, detonation velocity, and detonation volume when the aluminum powder content is 20%, and the shock wave over pressure as well as impulse keep a high level at the same time within 4.5 m. The air blast performance of L-1 is better than L-2 within 2.2 m. As the distance increases, the air blast energy of L-1 is mainly used for shell rupture and fragment acceleration, while the contribution of L-2 is less than that of L-1. This study demonstrated that the explosion power of RDX-based explosive grenade charge is the most powerful where the content of aluminum powder is about 20%.

Boron powder is an additive for metalized explosives with great application potential. To improve the energy release ability of boron powder, the composites of RDX and nano-boron (RDX@Nano-B) were prepared by the spray-drying process, and the metalized explosives based on it were designed (named PBX-B1). The detonation heat and explosion pressure of boron-containing explosives PBX-B1 under vacuum and air conditions were measured and analyzed by an internal explosion test. On the other hand, the equilibrium pressure and energy release of the PBX-B1 explosive system after detonation were analyzed and compared with that of an explosive formulation of the same composition (named PBX-B2). Results showed that the detonation heat of PBX-B1 was 7456 J/g in a vacuum environment, which was 34.8% higher than that of RDX (5530 J/g). However, in the air environment, the detonation heat of PBX-B1 increased by 19.2% compared with that in the vacuum environment, and the explosive gas products mainly included N2, NOx, CO, H2O, CH4, HCN, and CO2. The peak pressure and equilibrium pressures of PBX-B1 were 11.2 and 0.42 MPa, which were increased by 155% and 75% compared with the vacuum environment, respectively. It is worth noting that, compared with that of PBX-B2, the released energy in the aerobic combustion stage and equilibrium pressure of PBX-B1 were increased by 49.8% and 10.5%. This study demonstrated the strategy of improving the energy release of boron-containing metalized explosives through the design of an explosive microstructure, which provides important clues for the design of higher-energy metalized explosives.

“High-risk” autopsies are those in which the anatomical examination of a corpse entails a substantial risk of contracting a serious infectious disease. Herein, we discuss the risks of infection associated with high-risk autopsies and factors pertaining to risk identification in high-risk autopsies, and we suggest potentially preventative measures focused on anatomy room protection and virtual imaging.

In order to improve the transfers inside an Urban Rail Transit (URT) station between different rail transit lines, this research newly develops two Ordinal Logistic Regression (OLR) models to explore effective ways for saving the Perceived Transfer Time (PTT) of URT passengers, taking into account the difficulty of improving the transfer infrastructure. It is validated that the new OLR models are able to rationally explain probabilistically the correlations between PTT and its determinants. Moreover, the modelling analyses in this work have found that PTT will be effectively decreased if the severe transfer walking congestion is released to be acceptable. Furthermore, the congestion on the platform should be completely eliminated for the evident reduction of PTT. In addition, decreasing the actual transfer waiting time of the URT passengers to less than 5 minutes will obviously decrease PTT.

Layouts of bus networks in cities are always irrational currently, transport service frequencies also need to be optimized according to the real network layouts, operation conditions and travel experience of passengers, so it is essential to optimize bus transit network layouts and transport service frequencies systematically. Different stakeholders are involved in the optimization of urban bus transit network layouts like the government, operators and passengers, whose interests are always contradictory. In order to optimize transit network layout and service frequencies from the view point of operators and utilizers, this research constructs a multi-objective model and proposes a solution algorithm. The proposed multi-objective model is established from the perspective of operators with the goal of minimizing total operating costs for one day, and from the perspective of the utilizers to minimize the total travel time, respectively. Also with the application of electric bus in cities, buses in this research are electric buses all for green travel. Moreover, a solution algorithm is proposed in this research to solve the proposed multi-objective model with simulated annealing algorithm and genetic algorithm. Simulated annealing algorithm is used as the main framework of the solution algorithm from the perspective of operators to minimize operating costs, while genetic algorithm is used as the subroutine of simulated annealing algorithm to optimize total travel time. Verification of the proposed model and the solution algorithm is based on an intuitive network. The application results of a numerical experiment verified that the proposed optimization model and the solution algorithm are able to optimize the network layout and service frequencies at the same time.

Reed marshes are vital habitats for many species of birds, some of which are wholly or largely dependent on this habitat. Reed harvesting in winter is a common practice for increasing economic benefits, but it also promotes reed growth and maintains reed marsh landscapes by removing dry reed stalks. Different reed cutting intervals create different habitat conditions and thus lead to differences in habitat use by marsh birds. Although many studies have reported birds and their habitat conditions in reed marshes with different cutting schemes in Europe, few studies have been conducted in Asia, where reed marshes are widely distributed. Here, we conducted a one-year survey (from March 2019 to February 2020) on birds and their habitat conditions (vegetation and food) in reed marshes with three cutting intervals: age 1 (cutting every year), age 2 (cutting with one-year interval), and uncut (uncut for four years), at Chongming Dongtan, an estuarine wetland on China’s coast. As the cutting interval increased, the growing reed density decreased, the dry reed and total reed density increased, and the food density (in terms of reed seeds, arthropods, and arthropod eggs) decreased. A total of 4627 birds of 23 species were captured by mist nets. In general, species capture rates were similar among the three habitats in the same season, and individual capture rates in uncut reed marshes were lower than those in age 1 and age 2 marshes. This was probably because the relatively low density of reed stems promoted the movement of birds to age 1 and age 2 marshes, where birds could find abundant food. In contrast to previous studies, we found that age 1 marshes provide suitable habitats for birds soon after vegetation is restored in summer. However, reed parrotbills (Paradoxornis heudei), a common reed marsh specialist, had high capture rates in uncut reed marshes in winter. This is probably because they live in dense vegetation, and dense vegetation can reduce threats from aerial predators. This study emphasizes that habitat use should be considered in reed cutting practices and that a mixture of reed marshes with different cutting intervals benefits different birds and also different requirements of the same birds over the course of the year.

The herb Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae family), also known as Tu-Bei-Mu (TBM) in Chinese, has shown curative effects to treat several types of cancer as an adjunctive therapy. Thereby we intend to find its effect on the human hepatocellular carcinoma (HCC) and to understand the pharmacological mechanism behind it. In this study, an integrative serum pharmacology-based approach linking serum pharmacology and bioinformatics prediction was employed. Firstly, we used the serum taken introgastrically from the rats dministered by TBM aqueous bulb extract to culture the HCC cell line BEL-7404 and detect its anti-tumor effects. Secondly, the TBM putative targets were predicted using the ETCM database and known therapeutic targets of NPC were collected from the OMIM database. Then, a TBM-HCC putative targets network was constructed using the DAVID and STRING databases. Thirdly, key gene targets were obtained based on topological analysis and pathway enrichment analysis. The expression of 4 representative key targets were validated by Western blotting. As a result, 36 TBM targets and 26 known therapeutic targets of HCC were identified. These key targets were found to be frequently involved in 13 KEGG pathways and 4 biological processes. The expression of four representative key targets: TP53, CASP3, BCL2 and BAX further supports the suppression of TBM on HCC. In general, our study shows the curative effects of TBM against HCC. By using this integrative approach, we may find novel potential therapeutic targets to suppress HCC using TBM as an adjunctive therapy. And it could also help us understand the mechanism of HCC treatments in response to TBM.

Background: Adenylyl cyclase type 9 (ADCY9) modulates signal transduction by producing the second messenger cyclic AMP. It has been reported that ADCY9 gene polymorphisms were associated with cancer development. The aim of this study was to investigate whether ADCY9 gene polymorphisms could contribute to the susceptibility of hepatocellular carcinoma (HCC) in the Chinese Han population.Methods: In the present study, five single-nucleotide polymorphisms (SNPs) in ADCY9 were genotyped using Agena MassARRAY platform in 876 subjects from China. Logistic regression was used to assess the effects of SNPs on HCC risk. Associations were also evaluated for HCC risk stratified by age and gender. False discovery rate (FDR) was used to correct multiple testing.Results: After adjusting for age and gender, we found a significant relationship between heterozygous genotypes of rs2531995 and HCC risk (OR = 1.34, 95% CI = 1.01–1.77, p = 0.045). ADCY9 rs2230742 had a strong relationship with lower risk of HCC in allele (p = 0.006), co-dominant (p = 0.023), dominant (p = 0.010), and additive (p = 0.006) models. Stratified analysis showed that rs879620 increased HCC risk and rs2230742 was associated with lower risk of HCC in the individuals aged 55 or younger, rs2531992 significantly decreased HCC risk in the elder group (age > 55). For women, rs2230742 and rs2230741 were significantly associated with HCC risk in multiple models (p < 0.05). FDR analysis showed that rs2230742 could protect individuals from HCC risk in the allele model (FDR-p = 0.030). In addition, haplotype analysis indicated that Crs879620Ars2230742Ars2230741 haplotype was a protective factor for HCC (OR = 0.67, 95% CI = 0.50–0.89, p = 0.007, FDR-p = 0.028).Conclusion: Our findings suggest that ADCY9 gene polymorphisms are associated with HCC risk in the Chinese Han population.

The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Inhibiting the cAMP effector protein Epac prevents SRT1720 from activating AMPK or Sirt1 in myotubes. Moreover, SRT1720 does not increase mitochondrial function or improve glucose tolerance in AMPKα2 knockout mice. Interestingly, weight loss induced by SRT1720 is not sufficient to improve glucose tolerance. Therefore, contrary to current belief, the metabolic effects produced by SRT1720 require AMPK, which can be activated independently of Sirt1.

Based on computer-aided simulation studies, the comprehensive effect of target speed, Passenger Capacity Utilization Rate (PCUR) and formation of a High-Speed Railway (HSR) train on its transport efficiency is analysed in this research. It is found that if the target speed of a HSR train is no lower than approximately 80 % of its designed top speed, the time expense per unit of the passenger-kilometres completed by this train will be relatively very small when the PCUR of the train becomes more than about 60 %. From the perspectives of both efficiency and sustainability, it is suggested that the PCUR of a HSR ought to be over 60 % and, meanwhile, its target speed should be about 80 % of its designed top speed. In addition, the long formation of a HSR train is preferred if its PCUR can be kept over 60 %.

The herb Radix Ophiopogonis (RO) has been used effectively to treat nasopharyngeal carcinoma (NPC) as an adjunctive therapy. Due to the complexity of the traditional Chinese herbs, the pharmacological mechanism of RO’s action on NPC remains unclear. To address this problem, an integrative approach bridging proteome experiments with bioinformatics prediction was employed. First, differentially expressed protein profile from NPC serum samples was established using isobaric tag for relative and absolute quantification (iTRAQ) coupled 2-D liquid chromatography (LC)-MS/MS analysis. Second, the RO putative targets were predicted using Traditional Chinese Medicines Integrated Database and known therapeutic targets of NPC were collected from Drugbank and OMIM databases. Then, a network between RO putative targets and NPC known therapeutic targets was constructed. Third, based on pathways enrichment analysis, an integrative network was constructed using DAVID and STRING database in order to identify potential candidate targets of RO against NPC. As a result, we identified 13 differentially expressed proteins from clinical experiments compared with the healthy control. And by bioinformatics investigation, 12 putative targets of RO were selected. Upon interactions between experimental and predicted candidate targets, we identified three key candidate targets of RO against NPC: VEGFA, TP53, and HSPA8, by calculating the nodes’ topological features. In conclusion, this integrative pharmacology-based analysis revealed the anti-NPC effects of RO might be related to its regulatory impact via the PI3K-AKT signaling pathway, the Wnt signaling pathway, and the cAMP signaling pathway by targeting VEGFA, TP53, and HSPA8. The findings of potential key targets may provide new clues for NPC’s treatments with the RO adjunctive therapy.

Summary: The polycomb repressive complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/H3K27me3) have been interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs. They also reveal that modifying the ratio of H3K27me2 and H3K27me3 is sufficient for the acquisition and repression of defined cell lineage transcriptional programs and phenotypes and influences induction of the ESC ground state. : Juan et al. use genome editing to subtly modify H3K27 methylation states (H3K27me2/H3K27me3) and report that such perturbation influences the ability of ESCs to differentiate into preferential cell lineages and acquire a “ground state.” Keywords: polycomb proteins, H3K27 methylation, embryonic stem cells

An LC-MS/MS assay based on a signature peptide was developed and fully validated for the quantitation of bovine lactoferrin in infant formulas. Three unreported signature peptides were derived and identified from the tryptic peptides of bovine lactoferrin. The peptide ETTVFENLPEK was used for quantification based on assay performance. The blank matrix camel milk powder and bovine lactoferrin protein standards were mixed and spiked with stable isotope-labeled internal standard to establish a calibration curve. The established method was extensively validated by determining the linearity (R2 > 0.999), sensitivity (limit of quantitation, 0.16 mg/100 g), recovery (83.1-91.6%), precision (RSD < 5.4%) and repeatability (RSD < 7.7%). To validate the applicability of the method, four different brands of infant formulas in China were analysed. The acquired contents of bovine lactoferrin were 52.60-150.56 mg/100 g.

Hazardous materials (HAZMAT) are important for daily production in cities, which usually have a high population. To avoid the threat to public safety and security, the routes for HAZMAT transportation should be planned legitimately by mitigating the maximum risk to population centers. For the objective of min-max local risk in urban areas, this study has newly proposed an optimization model where the service of a link for HAZMAT transportation was taken as the key decision variable. Correspondingly, the symmetric problem of min-max optimization takes significant meanings. Moreover, in consideration of the work load of solving the model under a lot of decision variables, a heuristic algorithm was developed to obtain an optimal solution. Thereafter, a case study was made to test the proposed model and algorithm, and the results were compared with those generated by deterministic solving approaches. In addition, this research is able to be an effective reference for authorities on the management of HAZMAT transportation in urban areas.

Taking a representative metro station in Beijing as example, this research has newly developed a random coefficient model to predict the short-term passenger flows with sudden increases sometimes into an urban rail transit station. The hierarchical Bayesian approach is iteratively applied in this work to estimate the new model and the estimation outcomes in each of the iterative calibrations are improved by sequential Bayesian updating. It has been proved that the estimation procedure is able to effectively converge to rational results with satisfying accuracies. In addition, the model application study reveals that besides sufficient preparations in manpower, devices, etc.; the information of the factors affecting the passenger flows into an urban rail transit station should be timely transferred in advance from important buildings, road intersections, squares and so on in neighborhood to this station. In this way, this station is able to cope with the unexpectedly sharp increases of the passenger flows into the station to ensure its operation safety.

Rational traffic flow forecasting is essential to the development of advanced intelligent transportation systems. Most existing research focuses on methodologies to improve prediction accuracy. However, applications of different forecast models have not been adequately studied yet. This research compares the performance of three representative prediction models with real-life data in Beijing. They are autoregressive integrated moving average, neutral network, and nonparametric regression. The results suggest that nonparametric regression significantly outperforms the other models. With Wilcoxon signed-rank test, the root mean square errors and the error distribution reveal that the nonparametric regression model experiences superior accuracy. In addition, the nonparametric regression model exhibits the best spatial-transferred application effect.

It is expected that improvement of transport networks could give rise to the change of spatial distributions of population-related factors and car ownership, which are expected to further influence travel demand. To properly reflect such an interdependence mechanism, an aggregate multinomial logit (A-MNL) model was firstly applied to represent the spatial distributions of these exogenous variables of the travel demand model by reflecting the influence of transport networks. Next, the spatial autocorrelation analysis is introduced into the log-transformed A-MNL model (called SPA-MNL model). Thereafter, the SPA-MNL model is integrated into the four-step travel demand model with feedback (called 4-STEP model). As a result, an integrated travel demand model is newly developed and named as the SPA-STEP model. Using person trip data collected in Beijing, the performance of the SPA-STEP model is empirically compared with the 4-STEP model. It was proven that the SPA-STEP model is superior to the 4-STEP model in accuracy; most of the estimated parameters showed statistical differences in values. Moreover, though the results of the simulations to the same set of assumed scenarios by the 4-STEP model and the SPA-STEP model consistently suggested the same sustainable path for the future development of Beijing, it was found that the environmental sustainability and the traffic congestion for these scenarios were generally overestimated by the 4-STEP model compared with the corresponding analyses by the SPA-STEP model. Such differences were clearly generated by the introduction of the new modeling step with spatial autocorrelation.

Kadsura longipedunculata (KL) has been widely used for the treatment of insomnia in traditional Chinese medicine. The aim of this study was to explore the mechanism of the sedative and hypnotic effects of KL.The content of KL was evaluated by HPLC-TOF-MS, and a potential target was found and used to construct its 3D structure to screen for potential ligands among the compounds in KL by using bioinformatics analysis, including similarity ensemble approach (SEA) docking, homology modeling, molecular docking and ligand-based pharmacophore. The PCPA-induced insomnia rat model was then applied to confirm the potential targets related to the sedative effects of KL by performing the forced swimming test (FST), the tail suspension test (TST) and the measurement of target-related proteins using western blotting and immunofluorescence.Bioinformatics analysis showed that most of lignan compounds in KL were optimal ligands for the 5-HT1A receptor (5-HT1AR), and they were found to be potential targets related to sedative effects; the main lignan content of KL extracts was characterized by HPLC-TOF-MS, with 7 proposed lignans detected. Administration of KL could significantly reduce FST and TST immobility time in the PCPA-induced 5HT-depleted insomnia rat model. The expressions of proteins related to the 5-HT1AR pathway were regulated by extracts of KL in a concentration-dependent manner, indicating that extracts of KL had 5-HT1AR agonist-like effects.In silico analysis and experimental validation together demonstrated that lignan extracts from KL can target 5-HT1AR in insomniac rats, which could shed light on its use as a potential 5-HT1AR agonist drug.

Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation.

The energy cost of a rail transport system is very big especially for the tractions of trains in its daily operation. Continual effort on decreasing the traction energy cost intensities of various rail transport modes has been made by many researchers and practitioners on different aspects for a long time. From the rail transport operation perspective, this study reviews such energy-saving research mainly focusing on the optimizations of train coasting schemes, the rational designs and utilizations of track alignments, the ameliorations of train attributes, and the improvements of system operations. According to the review work, it is confirmed that in sound responses to distinct track alignments, dynamically optimizing control programs of trains with their reasonably improved attributes ought to be further studied in view of the systematic transport operation of a rail line or network in an integrated manner as much as possible in the future research on traction energy saving of rail transport.