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Neural differentiation of embryonic stem cells (ESCs) requires precisely orchestrated gene regulation, a process governed in part by changes in 3D chromatin structure. How these changes regulate gene expression in this context remains unclear. In this study, we observed enrichment of the transcription factor KLF4 at some poised or closed enhancers at TSS-linked regions of genes associated with neural differentiation. Combination analysis of ChIP, HiChIP and RNA-seq data indicated that KLF4 loss in ESCs induced changes in 3D chromatin structure, including increased chromatin interaction loops between neural differentiation-associated genes and active enhancers, leading to upregulated expression of neural differentiation-associated genes and therefore early neural differentiation. This study suggests KLF4 inhibits early neural differentiation by regulation of 3D chromatin structure, which is a new mechanism of early neural differentiation.

Nowadays, vaccines are broadly used to prevent porcine circovirus type 2 (PCV2) infection-induced expenditures, but the virus is still spreading among pigs. The current PCV2 vaccines all rely on the immunogenicity of Cap, yet our previous studies found that Cap is also the major component mediating the PCV2 infection-induced immune suppression through its interaction with host gC1qR. Thereby, new vaccines are still necessary for PCV2 prevention and control. In this study, we constructed a new PCV2 DNA vaccine expressing the gC1qR binding site mutant Cap. We introduced the Intron A and WPRE elements into the vector to improve the Cap expression level, and fused the IL-2 secretory signal peptides to the N-terminal of Cap to mediate the secretion of Cap. We also screened and selected chemokines CXCL12, CCL22, and CCL25 to migrate dendritic cells. In addition, we contained the vectors with PEI and then ultrasonic them into nano size to enhance the entrance of the vectors. Finally, the animal experiments showed that the new PCV2 DNA vaccine expressing the gC1qR binding site mutant Cap could induce stronger humoral and cellular immune responses than the PCV2 DNA vaccine expressing the wild-type Cap and the non-ultrasonic treated PCV2 DNA vaccine in mice, and protect the mice from PCV2 infection and lung lesions. The results indicate the new PCV2 DNA vaccine expressing the gC1qR binding site mutant Cap has a certain development value, and provide new insight into the development of novel PCV2 vaccines.

Salmonella is composed of a wide variety of serovars that cause human self-limited gastrointestinal illnesses or invasive infections. Most of the Salmonella strains of clinical isolates belong to the A - F group. In December 2012, a case of invasive infection was caused by a rare Salmonella, Salmonella enterica serovar Moualine (S. Moualine), identified as 047 outside of groups A - F, which was easily missed or misreported. The goal is to ex-plore clinical symptoms and therapies of blood infection caused by S. Moualine and to provide theoretical basis and molecular level date for Salmonella research by analyzing pathogenic characteristics and genome information of S. Moualine.The S. Moualine genome was sequenced using a PacBio RS II platform and Illumina HiSeq 4000 platform and analysis for serotyping serovars, ST types, the characterization of antibiotic resistance, virulence and phylogeny.The clinical symptoms were mainly irregular recurrent fever, lasting 1 - 3 weeks, with mild gastrointestinal symptoms. The genome size of S. Moualine was 4,611,151 bp, the serotype was 047 (+), Hy (+), H1,6 (+), and multilocus sequence typing analysis was ST3038. S. Moualine contains the majority of virulence genes. Interestingly, S. Moualine also harbors the rck and Typhi colonization factor (tcf) genes, which may play a role in invasive infection. S. Moualine encodes 17 Salmonella pathogenicity islands and is potentially dangerous to human health. Both phenotypic and genomic characterizations have demonstrated that S. Moualine generally showed low antimicrobial resistance potential.There were few reports on S. Moualine. According to clinical symptoms and genetic analysis, S. Moualine was predicted to be a highly virulent bacteria and was also potentially dangerous to health of humans. This study highlights that the transparency of global surveillance genomic data could accelerate the understanding of the virulence and antimicrobial resistance makeup of a previously unknown threat.

ZIF-8 and ZIF-67 are the most investigated zeolitic imidazolate frameworks (ZIFs) materials that have aroused enormous scientific interests in numerous areas of application including electrochemistry, gas storage, separation, and sensors by reason of their fascinating structural properties. Recently, there is a rapidly growing demand for chemical gas sensors for the detection of various analytes in widespread applications including environmental pollution monitoring, clinical analysis, wastewater analysis, industrial applications, food quality, consumer products, and automobiles. In general, the key to the development of superior gas sensors is exploring innovative sensing materials. ZIF-X (8, 67) based nanostructures have demonstrated great potential as ideal sensing materials for high-performance sensing applications. In this review, the general properties and applications of ZIF-X (8, 67) including gas storage and gas adsorption are first summarized, and then the recent progress of ZIF-X (8, 67) based nanostructures for gas-sensing applications and the structure-property correlations are summarized and analyzed.

The long noncoding RNA HOTAIRM1 reportedly plays important roles in acute myeloid leukemia, gastric cancer and colorectal cancer. Here, we analyzed potential function of HOTAIRM1 in glioma and asked whether it participates in long-range chromatin interactions. We monitored expression of HOTAIRM1 in glioma tissues and correlated levels with patient survival using the TCGA dataset. HOTAIRM1 was highly expressed in glioma tissue, with high levels associated with shortened patient survival time. We then suppressed HOTAIRM1 activity in the human glioblastoma U251 line using CRISPR-cas9 to knock in a truncating polyA fragment. Reporter analysis of these and control cells confirmed that the HOTAIRM1 locus serves as an active enhancer. We then performed Capture-C analysis to identify target genes of that locus and applied RNA antisense purification to assess chromatin interactions between the HOTAIRM1 locus and HOXA cluster genes. HOTAIRM1 knockdown in glioma cells decreased proliferation and reduced expression of HOXA cluster genes. HOTAIRM1 regulates long-range interactions between the HOTAIRM1 locus and HOXA genes. Our work suggests a new mechanism by which HOTAIRM1 regulates glioma progression by regulating high-order chromatin structure and could suggest novel therapeutic targets to treat an intractable cancer.

Privacy and information protection are important issues in the era of big data. At present, China’s elderly care industry is gradually adopting the supply model of smart elderly care to alleviate the contradiction between supply and demand. However, the low level of regulation of smart aging platforms may lead to a low level of privacy protection on the platforms. Therefore, in this paper, based on the evolutionary game and Lyapunov theory, we discuss the willingness of elderly people to participate in regulation, the privacy protection status of platform service providers, and the degree of government regulation, as well as the key factors affecting the equilibrium of the three-party game system, and conduct simulation analysis and game system optimization using MATLAB. The simulation results show that A1(0,0,1) and A5(0,0,0) can be transformed to A8(1,1,0) by adjusting the parameters, i.e., the optimal ESS is participation, high-quality protection, and low investment supervision; the service income of the elderly, the loss of privacy leakage, the investment cost of service providers, and the amount of government rewards and punishments are the key factors affecting the tripartite game system. By analyzing the impact of factors, such as benefits and costs, on privacy protection and the regulation of smart senior care platforms, the level of privacy protection of smart senior care platforms can be improved and the process of the comprehensive regulation of domestic senior care services can be promoted.

Nowadays, colony collapse disorder extensively affects honeybees. Insecticides, including acetamiprid, are considered as critical factors. As prevalent probiotics, we speculated that supplementation with lactic acid bacteria (LAB) could alleviate acetamiprid-induced health injuries in honeybees. Apilactobacillus kunkeei was isolated from beebread; it significantly increased the survival of honeybees under acetamiprid exportation (from 84% to 92%). Based on 16S rRNA pyrosequencing, information on the intestinal bacteria of honeybees was acquired. The results showed that supplementation with A. kunkeei significantly increased survival and decreased pollen consumption by honeybees under acetamiprid exportation. Under acetamiprid exportation, some opportunistic and pathogenic bacteria invaded the intestinal regions. Subsequently, the community richness and diversity of symbiotic microbiota were decreased. The community structure of intestinal bacteria was changed and differentiated. However, with the supplementation of A. kunkeei, the community richness and community diversity of symbiotic microbiota showed an upward trend, and the community structure was stabilized. Our results showed that A. kunkeei alleviated acetamiprid-induced symbiotic microbiota dysregulation and mortality in honeybees. This demonstrates the importance of symbiotic microbiota in honeybees and supports the application of Apilactobacillus kunkeei as probiotics in beekeeping.

Temozolomide (TMZ) is a frequently used chemotherapy for glioma; however, chemoresistance is a major problem limiting its effectiveness. Thus, knowledge of mechanisms underlying this outcome could improve patient prognosis. Here, we report that deletion of a regulatory element in the HOTAIR locus increases glioma cell sensitivity to TMZ and alters transcription of multiple genes. Analysis of a combination of RNA-seq, Capture Hi-C, and patient survival data suggests that CALCOCO1 and ZC3H10 are target genes repressed by the HOTAIR regulatory element and that both function in regulating glioma cell sensitivity to TMZ. Rescue experiments and 3C data confirmed this hypothesis. We propose a new regulatory mechanism governing glioma cell TMZ sensitivity.

International audience; AbstractAs one of the most widely used insecticides, thiamethoxam (Th) plays an important role in agriculture pest control but is hazardous to the health of honeybees (Apis mellifera ligustica). In agricultural practice, several types of insecticides are often applied simultaneously, but their synergistic effects on honeybees remain elusive. Here, we treated honeybees with various binary mixtures of insecticides in which a sublethal dose of Th was mixed with three other common insecticides: λ-cyhalothrin (λ-cy), β-cypermethrin (β-cy), and abamectin (Ab). The mortality rates of the groups treated with the insecticide mixtures were higher than that obtained with the pesticides alone. Specifically, the Th + λ-cy and Th + Ab combinations exerted a synergistic effect (P < 0.05) on bees and resulted in significantly higher mortality than that obtained with the single treatments. However, the Th + β-cy mixture had no synergistic effect (P > 0.05) on bees, and the mortality rate of this group was almost identical to those of the groups administered these pesticides alone. Furthermore, the Th + λ-cy and Th + Ab mixtures significantly suppressed the activity and expression of glutathione S-transferases (GSTs), which are key detoxification enzymes in insects. This result suggests that the Th + λ-cy and Th + Ab combinations at a given concentration adversely affect the survival of honeybees. Our study provides novel information for the selection of pesticide combinations based on protecting honeybee populations.

This paper studies the toppling dynamics of a mass-varying domino system for which the mass of the domino changes at an exponential rate of its sequence number. By introducing geometrical constraints representing the interactions between the dominoes and the ground, we propose a simplified model which can describe their toppling dynamics as a one-degree-of-freedom structural-varying system. Principles of energy and generalized momentum conservation are used to investigate the free falling and the colliding phases of the system, and our proposed model is validated through a comprehensive numerical study. Furthermore, we develop an impact mapping for studying the evolution of the system by using the mathematical properties of their geometrical constraints and establish the occurrence conditions for solitary wave. According to these conditions, the system can exhibit four different propagation modes: non-solitary mode, uniform solitary mode, accelerating solitary mode and stopped mode. Based on the studies in this paper, we can reveal the dynamic characteristics of domino phenomenon and provide an insight into its energy evolution.

Honeybee is an important pollinator for maintaining ecological balance. However, scientist found the bizarre mass death of bees in winter. Meanwhile, some reported that the differences composed of intestinal bacteria between healthy honeybees and CCD honeybees. It is essential that explored dynamic changes to the intestinal bacteria in overwintering honeybees. We collected bee samples before overwintering, during prophase of overwintering, metaphase of overwintering, anaphase of overwintering, telophase of overwintering, and after overwintering. By using high-throughput sequencing targeting the V3 − V4 regions of the 16S rDNA, the abundance of the intestinal bacteria were analyzed in overwintering honeybees. A total of 1,373,886 high-quality sequences were acquired and Proteobacteria (85.69%), Firmicutes (10.40%), Actinobacteria (3.66%), and Cyanobacteria (1.87%) were identified as major components of the intestinal bacteria. All core honeybee intestinal bacteria genera, such as Gilliamella, Bartonella, Snodgrassella, Lactobacillus, Frischella, Commensalibacter, and Bifidobacterium were detected. The abundance of Actinobacteria, Bartonella, and Bifidobacterium increased initially and then decreased in winter honeybees. There were no significant differences in the richness and evenness of the microbiota in overwintering honeybees; however, there was a statistically significant difference in the beta diversity of the intestinal bacteria after overwintering compared with that in other groups. Our results suggested that honeybees maintained their intestinal ecosystem balance, and increased the abundance of gut probiotics in response to environmental and nutrition pressures in winter.

The rapid increases in environmental hazardous gases have laid dangerous effects on human health. The detection of such pollutants gases is mandatory using various optimal techniques. In this paper, porous multifaceted Co

To explore the genetic basis for a pedigree affected with hereditary multiple osteochondroma (HMO).Peripheral blood samples were collected from the proband and members of his pedigree with informed consent. Following extraction of genomic DNA, all coding exons and flanking intronic sequences (-10 bp) of the EXT1 and EXT2 genes were subjected to targeted capture and next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing.A heterozygous nonsense variant (c.1911CA) was found in exon 10 of the EXT1 gene in the proband and his affected father but not in a healthy sister and normal controls. The variant was classified as a pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (PVS1+PM2+PP1). Bioinformatic analysis predicted that the c.1911CA variant may be disease-causing via nonsense-mediated mRNA decay and anomalous splicing.The c.1911CA variant probably underlay the disease in this pedigree. Discovery of this variant enriched the variant spectrum of HMO.

We present JueWu-SL, the first supervised-learning-based artificial intelligence (AI) program that achieves human-level performance in playing multiplayer online battle arena (MOBA) games. Unlike prior attempts, we integrate the macro-strategy and the micromanagement of MOBA-game-playing into neural networks in a supervised and end-to-end manner. Tested on Honor of Kings, the most popular MOBA at present, our AI performs competitively at the level of High King players in standard 5v5 games., IEEE Transactions on Neural Networks and Learning Systems (TNNLS)

Acquired resistance to temozolomide (TMZ) is a major obstacle in glioblastoma treatment. MGMT, a DNA repair protein, and the methylation at its gene promoter, plays an important role in TMZ resistance. However, some evidences have suggested a MGMT-independent mechanisms underlying TMZ resistance. Here, we used MGMT enhancer as a model and discovered that its deletion in glioma cells of low MGMT expression induced increased sensitivity to temozolomide. Analysis of a combination of RNA-seq and Capture Hi-C further suggested multiple long-range target genes regulated by the MGMT enhancer and that interactions may play important roles in glioma cell sensitivity to TMZ. This study reveals a novel mechanism of regulation of TMZ sensitivity in glioma cells.

The adversarial example generation algorithm is currently a very popular algorithm for deceiving machine learning. The main method is to change the original sample in a way that is almost imperceptible to the user, and cause an obvious error in the result returned by the model. At present, there are many adversarial algorithms for computer vision, but there are few for NLP models, and there is almost no algorithm for Question & Answer task. This paper designs a framework of adversarial example generation algorithm KBAA(Knowledge-based Adversarial Attack), which is a black box attack, and is against KBQA (Knowledge-based Question & Answer). By extracting the knowledge graph of the original sample (attribute value is null, Entity-Attribute-(null)), the algorithm chooses the more important one of Entity and Attribute in the original sample and generates an adversarial example in order to deceive the KBQA model.

Synpolydactyly is a congenital limb malformation characterized by incomplete separation and duplication in fingers and/or toes, which is mainly caused by mutations in the homeobox D13 (HOXD13) gene. Here, a four-generation family with variant phenotypes of synpolydactyly was analyzed, in which the proband had bilateral preaxial synpolydactyly in toes with normal fingers, the father had clinodactyly in the fifth fingers, while the mother and grandma was normal. Trio whole-exome sequencing (trio-WES) is a high throughput sequencing targeting whole genome for detecting exonic variants from the proband and the parents in a family. Through trio-WES followed by Sanger sequencing and enzyme digestion, a heterozygous nonsense mutation (c.859 C>T/p.Gln287Ter) was newly identified in the homeodomain of the HOXD13 gene from the proband and the affected father, but not from the unaffected mother, the unaffected grandma, or the normal control. Mutation Taster, Human Splicing Finder and EX-SKIP predicted that the heterozygous mutation (c.859 C>T) would result in haploinsufficiency of HOXD13 protein through nonsense-mediated mRNA decay (NMD) and splicing abnormality, which might disrupt the integrity and reduce the expression level of the HOXD13 protein (loss-of-function). In short, a heterozygous nonsense mutation in the HOXD13 gene was newly identified in two patients with mild phenotypes of synpolydactyly, which extends the mutation spectrum in HOXD13 gene. Moreover, the findings we presented here deepen our understanding of the clinical consequences of non-syndromic synpolydactyly and may provide a new clue for further studies of the pathogenic mechanism of the mutation that causes aberrant splicing of HOXD13 gene.

In a previously published study, to optimize the vibrating and comb-brushing harvesting, the main factors and their parameter values were obtained based on the FEM and RSM. However, the study was based on the extensive cultivation mode which need to be improve. To realize the mechanization of the harvesting of Lycium barbarum L., as well as to face the standardized hedge cultivation mode, a vibrating and comb-brushing harvester machine was designed, which was primarily composed of an execution system, a motion system, and a control system. The mathematical model between the harvest effect index and the operation parameters was established based on response surface methodology (RSM). The effects of various parameters on the harvest index were analyzed, and the best parameter combination was determined: a vibration frequency of 38.73 Hz, a brush speed of 14.21 mm/s, and an insertion depth of 26.07 mm. The field experiment showed that the harvesting rate of ripe fruit was 83.65%, the harvesting rate of unripe fruit was 7.22%, the damage rate of the ripe fruit was 11.49%, and the comprehensive picking index was 87.85. The findings provided a reference for the development of L. barbarum harvesting mechanization in a standardized hedge cultivation mode.

The rapid increases in environmental hazardous gases have laid dangerous effects on human health. The detection of such pollutants gases is mandatory using various optimal techniques. In this paper, porous multifaceted Co3O4/ZnO nanostructures are synthesized by pyrolyzing sacrificial template of core-shell double zeolitic imidazolate frameworks (ZIFs) for gas sensing applications. The fabricated exhibit superior gas sensor response, high selectivity, fast response/recovery times, and remarkable stability and sensitivity to H2S gas. In particular, the multifaceted Co3O4/ZnO nanostructures show a maximum response of 147 at 100 ppm of H2S under optimum conditions. The remarkable gas sensing performances are mainly ascribed to high porosity, wide surface area multifaceted nanostructures, presence of heterojunctions and catalytic activity of ZnO and Co3O4, which are beneficial for H2S gas sensors industry.

Herein a novel electrochemiluminescence resonance energy transfer (ECL-RET) pair of isoreticular metal organic framework-3 (IRMOF-3) enriched nitrogen-doped graphene quantum dots (N-GQDs) luminescent material (N-GQDs@IRMOF-3@N-GQDs, donor) and Au nanoparticles modified zinc oxide nanorod (ZnO@Au, acceptor) were firstly designed to fabricate a dual-quenching sandwich-type ECL immunosensor for ultrasensitive analysis of procalcitonin (PCT). IRMOF-3 not only acted as a carrier for abundantly enriching luminescent N-GQDs by internal encapsulation and external decoration, but also a coreaction accelerator which could boost the transformation of persulfate ion S2O82− to generate more anion radical SO4 −, so as to promote the ECL emission of N-GQDs. Additionally, Au nanoparticles were loaded onto the ZnO nanorods through in-situ modification to obtain ZnO@Au, which was firstly applied as a dual-quencher of ECL signal. In the best test environment, a wide detection range from 0.0001 to 100 ng mL−1 was obtained and the limit of detection is 12.58 fg mL−1 (S/N = 3). With excellent reproducibility and sensitivity, the practical test consequence of PCT in human serum samples was satisfactory. These results suggested that this sensing system could provide a reference model for effective detection of disease markers in clinical medicine.

Neonicotinoid insecticides are now the most widely used insecticides in the world. Previous studies have indicated that sublethal doses of neonicotinoids impair learning, memory capacity, foraging, and immunocompetence in honey bees (Apis mellifera, Linnaeus) (Hymenoptera: Apidae). Despite these, few studies have been carried out on the molecular effects of neonicotinoids. In this study, we focus on the second-generation neonicotinoid thiamethoxam, which is currently widely used in agriculture to protect crops. Using high-throughput RNA-Seq, we investigated the transcriptome profile of honey bees after subchronic exposure to 10 ppb thiamethoxam over 10 d. In total, 609 differentially expressed genes (DEGs) were identified, of which 225 were upregulated and 384 were downregulated. Several genes, including vitellogenin, CSP3, defensin-1, Mrjp1, and Cyp6as5 were selected and further validated using real-time quantitative polymerase chain reaction assays. The functions of some DEGs were identified, and Gene Ontology-enrichment analysis showed that the enriched DEGs were mainly linked to metabolism, biosynthesis, and translation. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that thiamethoxam affected biological processes including ribosomes, the oxidative phosphorylation pathway, tyrosine metabolism pathway, pentose and glucuronate interconversions, and drug metabolism. Overall, our results provide a basis for understanding the molecular mechanisms of the complex interactions between neonicotinoid insecticides and honey bees.

A new type of sandwich electrochemiluminescence (ECL) immunosensor dependent on ECL resonance energy transfer (ECL-RET) to achieve sensitive detection of procalcitonin (PCT) has been designed. In brief, carbon nanotubes (CNT) and Au-nanoparticles-functionalized graphitic carbon nitride (g-C

How to check and assess the whole process of Test and Evaluation on equipment software is one of the major challenges faced by the development of equipment software at present. In order to solve above problems, this paper proposed the development strategies of Test and Evaluation assessment for equipment software in terms of the overall design, data-driven, assessment system and method construction. Then the process of Test and Evaluation assessment on equipment software was checked to verify the development ability, design and organization ability. Therefore, the assessment loop of quality for equipment software as well as the assessment loop of design, development, and stereotyping for equipment software could be gotten through. In this way, the assessment of Test and Evaluation provides supports and traction for equipment software. Moreover, the development strategy of Test and Evaluation assessment on equipment software were made for the operational and in-service usage, which could finally and greatly improve the quality and operational effectiveness of equipment software.

Temozolomide (TMZ) is a frequently used chemotherapy for glioma; however, chemoresistance is a major problem limiting its effectiveness. Thus, knowledge of mechanisms underlying this outcome could improve patient prognosis. Here, we report that deletion of a regulatory element in the HOTAIR locus increases glioma cell sensitivity to TMZ and alters transcription of multiple genes. Analysis of a combination of RNA-seq, Capture Hi-C, and patient survival data suggests that CALCOCO1 and ZC3H10 are target genes repressed by the HOTAIR regulatory element and that both function in regulating glioma cell sensitivity to TMZ. Rescue experiments and 3C data confirmed this hypothesis. We propose a new regulatory mechanism governing glioma cell TMZ sensitivity.

Simple Summary The hypopharyngeal glands (HPGs) are a pair of aciniform glands that are located in the frontal area of the heads of worker bees (Apis mellifera L.) that exhibit age and behavior-dependent development. Little is known about whether/how miRNAs regulate the HPGs development. In this study, small RNA sequencing was employed to analyze the miRNA profiles of HPGs in newly-emerged bees (NEB), nurse bees (NB), and forager bees (FB). We found that there were a total of 31 known miRNAs differentially expressed among the three stages, which might have regulatory roles in the growth and development, protein synthesis, and carbohydrate and energy metabolism in the HPGs. Additionally, the downregulation of ame-miR-184-3p and ame-miR-252a-5p in nurse bees may be involved in royal jelly secretion, while the lower expression of ame-miR-11-3p and ame-miR-281-3p in forager bees are responsible for honey processing. Abstract This study aims to investigate the expression differences of miRNAs in the hypopharyngeal glands (HPGs) of honeybees at three developmental stages and to explore their regulation functions in the HPGs development. Small RNA sequencing was employed to analyze the miRNA profiles of HPGs in newly-emerged bees (NEB), nurse bees (NB), and forager bees (FB). Results showed that a total of 153 known miRNAs were found in the three stages, and ame-miR-276-3p, ame-miR-375-3p, ame-miR-14-3p, ame-miR-275-3p, and ame-miR-3477-5p were the top five most abundant ones. Furthermore, the expression of 11 miRNAs, 17 miRNAs, and 18 miRNAs were significantly different in NB vs. FB comparison, NB vs. NEB comparison, and in FB vs. NEB comparison, respectively, of which ame-miR-184-3p and ame-miR-252a-5p were downregulated in NB compared with that in both the FB and NEB, while ame-miR-11-3p, ame-miR-281-3p, and ame-miR-31a-5p had lower expression levels in FB compared with that in both the NB and NEB. Bioinformatic analysis showed that the potential target genes of the differentially expressed miRNAs (DEMs) were mainly enriched in several key signaling pathways, including mTOR signaling pathway, MAPK signaling pathway-fly, FoxO signaling pathway, Hippo signaling pathway-fly. Overall, our study characterized the miRNA profiles in the HPGs of honeybees at three different developmental stages and provided a basis for further study of the roles of miRNAs in HPGs development.

Multiple osteochondromas (MO) is one of the most common benign bone tumors in humans with an autosomal dominant hereditary mode. MO is a genetic heterogeneity disease with variable number and size of osteochondromas, as well as changeable number and location of diseased bones. Mutations in Exostosin-1/Exostosin-2 (EXT1/EXT2) genes are the main molecular basis of MO. EXT1 and EXT2 genes encode exostosin 1 and exostosin 2, respectively, both of which are transmembrane glycosyltransferases that elongate the chains of heparin sulfate (HS) at HS proteoglycans (HSPGs). HSPGs are considered to be involved in regulating the proliferation and differentiation of chondrocytes. Owing to large size of EXT1/EXT2 genes and lack of mutation hotspots, molecular diagnosis of MO is challenging. Here, we applied targeted next-generation sequencing (t-NGS) in mutation screening of EXT1/EXT2 genes for 10 MO patients. The results were compared and validated with Sanger sequencing. Overall, nine mutations identified by t-NGS were confirmed with Sanger sequencing, excluding two variants of false positive, suggesting the reliability of mutation screening by t-NGS. The nine mutations identified by t-NGS include two missense mutations (EXT1: c.1088G>A and c.2120C>T), one splicing mutation (EXT2: c.744-1G>T), and six nonsense mutations (EXT1: c.351C>G, c.1121G>A, and c.1843_1846dup; EXT2: c.67C>T, c.561delG, and c.575T>A). In summary, our paper provides the primary data of the application of t-NGS in MO molecular diagnosis, including six newly identified mutations (EXT1: c.1843_1846dup, c.1088G>A, c.351C>G, and c.2120C>T and EXT2: c.744-1G>T and c.575T>A), which further enrich the mutation database of MO from the Chinese population.

A new process that could directly prepare α-haloacetal of ketones from various ketones with N-halosuccinimide (NBS/NCS) and ethylene glycol in one step without any other catalysts was reported. The effects of solvents, NBS/NCS and reaction temperature were investigated. Under the optimal condition, most of α-haloacetals of ketones were obtained in 90–100% yield.

Background S. Typhimurium was the dominant serovar in an infant in Fuzhou, China. There have been few comprehensive studies on Salmonella typhimurium in infants in China. Methods We conducted a retrospective study on 30 Salmonella typhimurium from 3,200 fecal samples of infants with acute diarrhea from 2015 to 2017. Thirty S. Typhimurium strains were tested for antimicrobial susceptibility and characterized for virulence genes. Pulsed-field gel electrophoresis (PFGE) was also applied for comparison of genetic relatedness. Results All of the strains harbored misL, orfL, pipD, prgH, sifA, sopB, sitC, spiC, and invA genes. The other three gene distributions in the strains are different. Strains subtyped into 4 virulotypes (VP1-VP4), the most common virulence profile was VP3, accounting for 63.3% of the strains. The resistance to ciprofloxacin and ceftriaxone was 26.7%. The proportion of MDR isolates is approximately 90.0%. Sixteen different antimicrobial resistance patterns were observed and the most frequent resistance type was antibiotype 13 (resistance to streptomycin, tetracycline, amoxicillin), occurring in 43.3% of the isolates. Regarding PFGE, 30 isolates of S. Typhimurium showed genetic diversity, while no predominant PFGE patterns were observed in S. Typhimurium. Moreover, no correlation between virulence profiles or antibiotic patterns and PFGE clusters was observed. With one exception, VP1 which harbors pefA showed more diversity than the other virulence profiles among PFGE profiles. Conclusions Our study provided valuable information on virulence gene content, antibiotic resistance, and genetic diversity of S. Typhimurium isolated from infant with acute diarrhea in Fuzhou, China.

A hierarchical heat map showing the transformed expression values for transcripts (mRNA and lncRNA). Red shows higher expression, and blue shows lower expression. (PPTX 347 kb)

We study the reinforcement learning problem of complex action control in the Multi-player Online Battle Arena (MOBA) 1v1 games. This problem involves far more complicated state and action spaces than those of traditional 1v1 games, such as Go and Atari series, which makes it very difficult to search any policies with human-level performance. In this paper, we present a deep reinforcement learning framework to tackle this problem from the perspectives of both system and algorithm. Our system is of low coupling and high scalability, which enables efficient explorations at large scale. Our algorithm includes several novel strategies, including control dependency decoupling, action mask, target attention, and dual-clip PPO, with which our proposed actor-critic network can be effectively trained in our system. Tested on the MOBA game Honor of Kings, our AI agent, called Tencent Solo, can defeat top professional human players in full 1v1 games., Comment: AAAI 2020

Venn diagram of common differential expression transcripts (lncRNA and mRNA) among two comparison groups (SCC_YF vs. SCC_YN and SCC_OF vs. SCC_ON). (PPTX 175 kb)

Background The behavioural transition from nurses to foragers in honey bees is known to be affected by intrinsic and extrinsic factors, including colony demography, hormone levels, brain chemistry and structure, and gene expression in the brain. However, the molecular mechanism underlying this behavioural transition of honey bees is still obscure. Results Through RNA sequencing, we performed a comprehensive analysis of lncRNAs and mRNAs in honey bee nurses and foragers. Nurses and foragers from both typical colonies and single-cohort colonies were used to prepare six libraries to generate 49 to 100 million clear reads per sample. We obtained 6863 novel lncRNAs, 1480 differentially expressed lncRNAs between nurses and foragers, and 9308 mRNAs. Consistent with previous studies, lncRNAs showed features distinct from mRNAs, such as shorter lengths, lower exon numbers, and lower expression levels compared to mRNAs. Bioinformatic analysis showed that differentially expressed genes were mostly involved in the regulation of sensory-related events, such as olfactory receptor activity and odorant binding, and enriched Wnt and FoxO signaling pathways. Moreover, we found that lncRNAs TCONS_00356023, TCONS_00357367, TCONS_00159909 and mRNAs dop1, Kr-h1 and HR38 may play important roles in behavioural transition in honey bees. Conclusion This study characterized the expression profile of lncRNAs in nurses and foragers and provided a framework for further study of the role of lncRNAs in honey bee behavioural transition. Electronic supplementary material The online version of this article (10.1186/s12864-019-5664-7) contains supplementary material, which is available to authorized users.

The cyano-substituted neonicotinoid insecticide, thiacloprid, is nowadays widely used in agriculture for controlling insect pests. However, it also simultaneously has adverse effects on the health of important pollinators, such as honey bees. Previous studies have reported that sublethal doses of neonicotinoids impaired immunocompetence, learning and memory performance, and homing behaviour in honey bees. In the present study, using LC-MS-based combined with GC–MS-based metabolomic approaches, we profiled the metabolic changes that occur in the head of honey bee after subchronic exposure to 2 mg/L thiacloprid over 3 days. The estimated total dose of thiacloprid fed to each bee was 0.12 μg. The results showed that there were 115 metabolites significantly affected in thiacloprid-treated bees compared to control. The metabolites with high level of abundance enriched to wide range pathways associated with oxidative stress and detoxification suggest that the honey bees have activated their detoxification system to resistant toxicity of thiacloprid. While, the reduction of serotonin suggest thiacloprid may hinder the brain activity implicated in learning and behaviour development. Our study expand the understanding of the molecular basis of the complex interactions between neonicotinoids and honey bees.

This paper studies a new comprehensive model for toppling dynamics of regularly spaced dominoes in an array. The model has unlocked the hypotheses introduced by Stronge and Shu (Stronge, W. J., and Shu, D., 1988, “The Domino Effect: Successive Destabilization by Cooperative Neighbours,” Proc. R. Soc. A, 418(1854), pp. 155–163), which can provide us some essential insights into the mechanism of domino wave. Extensive comparisons are made between the proposed model and the experimental results studied in the existing literature. Our numerical studies show that the existing theoretical models are special cases of the proposed model, and the fluctuation in the waveform of propagation speed observed from experiments was caused by the irregular multiple impacts between colliding dominoes. The influence of physical parameters of domino on the natural speed of toppling dominoes is also considered, and it is found that the coefficients of friction and restitution between colliding dominoes have more effects due to the energy dissipation during impact.

Multiple osteochondromas (MO) is one of the most common benign bone tumors in humans with an autosomal dominant hereditary mode. MO is a genetic heterogeneity disease with variable number and size of osteochondromas, as well as changeable number and location of diseased bones. Mutations in Exostosin-1/Exostosin-2 (EXT1/EXT2) genes are the main molecular basis of MO. EXT1 and EXT2 genes encode exostosin 1 and exostosin 2, respectively, both of which are transmembrane glycosyltransferases that elongate the chains of heparin sulfate (HS) at HS proteoglycans (HSPGs). HSPGs are considered to be involved in regulating the proliferation and differentiation of chondrocytes. Owing to large size of EXT1/EXT2 genes and lack of mutation hotspots, molecular diagnosis of MO is challenging. Here, we applied targeted next-generation sequencing (t-NGS) in mutation screening of EXT1/EXT2 genes for 10 MO patients. The results were compared and validated with Sanger sequencing. Overall, nine mutations identified by t-NGS were confirmed with Sanger sequencing, excluding two variants of false positive, suggesting the reliability of mutation screening by t-NGS. The nine mutations identified by t-NGS include two missense mutations (EXT1: c.1088GA and c.2120CT), one splicing mutation (EXT2: c.744-1GT), and six nonsense mutations (EXT1: c.351CG, c.1121GA, and c.1843_1846dup; EXT2: c.67CT, c.561delG, and c.575TA). In summary, our paper provides the primary data of the application of t-NGS in MO molecular diagnosis, including six newly identified mutations (EXT1: c.1843_1846dup, c.1088GA, c.351CG, and c.2120CT and EXT2: c.744-1GT and c.575TA), which further enrich the mutation database of MO from the Chinese population.

To detect potential mutation of EXT1 gene in a pedigree affected with multiple osteochondroma and explore its pathogenic mechanism.The coding regions and their flanking sequences of the EXT1/EXT2 genes were subjected to PCR amplification and Sanger sequencing. Suspected mutations were verified by excluding possible single nucleotide polymorphisms and bioinformatics analysis. Transcripts of the EXT1 gene in the proband were analyzed by TA clone-sequencing, with its abundance compared with that of healthy controls.DNA sequencing has identified in the proband a novel heterozygous point mutation (c.1164+1G to A) at the 5'splice sites of intron 3 of the EXT1 gene. The same mutation was not found in the healthy controls. Bioinformatics analysis indicated that the mutation is highly conserved and can lead to skipping of exon 3 or aberrant splicing. TA clone-sequencing indicated that the numbers of transcripts with skipping of exon 3 has significantly increased in the proband (0.05) compared with the controls.The c.1164+1G to A mutation has resulted in skipping of exon 3 in a proportion of EXT1 gene transcripts. As the result, the number of transcripts with tumor suppressing function is relatively reduced and has ultimately led to the tumors.

MicroRNAs (miRNAs) are small endogenous noncoding single-stranded RNAs regulating gene expression in eukaryotes. They play important roles in regulating caste differentiation, behavior development, and immune defences in the honey bee, Apis mellifera (Linnaeus) (Hymenoptera: Apidae). In this study, we explored the effect of the neonicotinoid insecticide, thiamethoxam, on miRNA expression in this species using deep small RNA sequencing. The results showed that seven miRNAs were significantly differentially expressed (q-value 1) upon exposure to 10 ppb thiamethoxam over 10 d. Some candidate target genes were related to behavior, immunity, and neural function. Several miRNAs, including ame-miR-124, ame-miR-981, ame-miR-3791, and ame-miR-6038, were selected and further validated using real-time quantitative PCR analysis. The findings expand our understanding of the effects of neonicotinoid insecticides on honey bees at the molecular level.