Porcine reproductive and respiratory syndrome (PRRS) has been a persistent challenge for the swine industry for over three decades due to the lack of effective treatments and vaccines. Reverse ...genetics systems have been extensively employed to build rapid drug screening platforms and develop genetically engineered vaccines. Herein, we rescued recombinant PRRS virus (rPRRSV) WUH3 using an infectious cDNA clone of PRRSV WUH3 acquired through a BstXI-based one-step-assembly approach. The rPRRSV WUH3 and its parental PRRSV WUH3 share similar plaque sizes and multiple-step growth curves. Previously, gene-editing of viral genomes depends on appropriate restrictive endonucleases, which are arduous to select in some specific viral genes. Thus, we developed a restrictive endonucleases-free method based on CRISPR/Cas9 to edit the PRRSV genome. Using this method, we successfully inserted the exogenous gene (EGFP gene as an example) into the interval between ORF1b and ORF2a of the PRRSV genome to generate rPRRSV WUH3-EGFP, or precisely mutated the lysine (K) at position 150 of PRRSV nsp1α to glutamine (Q) to acquire rPRRSV WUH3 nsp1α-K150Q. Taken together, our study provides a rapid and convenient method for the development of genetically engineered vaccines against PRRSV and the study on the functions of PRRSV genes.
Canada welcomes large numbers of immigrants each year, including children. It is certainly important to understand immigrant children’s educational experience beyond standardized tests in reading and ...math. This paper draws on a sociocultural approach by situating language and literacy learning in social and cultural contexts and by emphasizing the active role of learners in different contexts. Specifically, the multiliteracies framework (The New London Group, 1996) is used to understand how culturally and linguistically diverse (CLD) children choose to use different literacies and modes to make sense of their surroundings and to create artistic texts to express their understandings of nature, such as water and forests. A qualitative case study was conducted to understand five CLD children’s meaning-making process in a community setting. Data was collected through observations, informal conversations, semi-structured interviews and artifacts. The initial findings of the study indicate that CLD children are active and creative meaning-makers who select different linguistic, cultural and artistic resources as well as various modalities to effectively express their ideas and perspectives according to audience, purpose and context. The presentation discusses two nature projects and shares the artwork of the participating children to highlight a range of multilingual, multicultural and multimodal literacy practices.
Prompt and accurate identification of anomalies in passenger flow within metro systems is crucial for safety, security, and operational efficiency. However, traditional anomaly detection methods ...often struggle to achieve high accuracy and low latency when constrained by limited labeled data for online applications. This study presents a straightforward yet effective online anomaly detection framework, termed multiview online passenger flow anomaly detection (MVOPFAD), to address these difficulties in a data-driven manner. Specifically, to reduce the computational burden and meet online requirements, we particularly propose an elastic extreme studentized deviate (EESD) model accounting for the characteristic of abnormal passenger flow. Concurrently, an improved shifted wavelet tree (ISWT) is employed to effectively capture various passenger flow features. It is joined by the implementation of ensemble learning techniques and EESD to further enhance the accuracy and robustness of our detection model. To evaluate the performance of our proposed framework, we conducted a comprehensive series of experiments utilizing data collected from the automated fare collection (AFC) system integrated into the Beijing Metro network. Our proposed MVOPFAD demonstrates significant superiority over the other three types of methods across all evaluation metrics. In particular, it yields a 15.49% increase in precision and a 9.71% rise in the <inline-formula> <tex-math notation="LaTeX">F2 </tex-math></inline-formula>-score compared to the second-best model for detecting outbound passenger flow anomalies. Additionally, our model incurs lower computational cost than deep learning models and machine learning models. The experimental results strongly suggest the feasibility of online implementation, thereby demonstrating the practicality and effectiveness of our proposed model.
Efficient representations of drugs provide important support for healthcare analytics, such as drug–drug interaction (DDI) prediction and drug–drug similarity (DDS) computation. However, incomplete ...annotated data and drug feature sparseness create substantial barriers for drug representation learning, making it difficult to accurately identify new drug properties prior to public release. To alleviate these deficiencies, we propose KMR, a knowledge-oriented feature-driven method which can learn drug related knowledge with an accurate representation. We conduct series of experiments on real-world medical datasets to demonstrate that KMR is capable of drug representation learning. KMR can support to discover meaningful DDI with an accuracy rate of 92.19%, demonstrating that techniques developed in KMR significantly improve the prediction quality for new drugs not seen at training. Experimental results also indicate that KMR can identify DDS with an accuracy rate of 88.7% by facilitating drug knowledge, outperforming existing state-of-the-art drug similarity measures.
Models of the consensus of the individual state in social systems have been the subject of recent research studies in the physics literature. We investigate how network structures coevolve with the ...individual state under the framework of social identity theory. Also, we propose an adaptive network model to achieve state consensus or local structural adjustment of individuals by evaluating the homogeneity among them. Specifically, the similarity threshold significantly affects the evolution of the network with different initial conditions, and thus there emerges obvious community structure and polarization. More importantly, there exists a critical point of phase transition, at which the network may evolve into a significant community structure and state-consistent group.
In order to study the anti-inflammatory activity of novel 6-substituted and 6,9-disubstituted purine derivatives, 20 compounds, L1–10 and W1–10, derived from purine and lacking a gold complex were ...designed, synthesized and their anti-inflammatory activity was screened. LPS-induced TNF-α, IL-1β, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-κB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-α, IL-1β, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L3)(PPh3), a known anti-inflammatory agent, at 2–5 h, and W4 was the most effective at 3–5 h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents.
A series of non-Gold complexed 6-substituted and 6,9-disubstituted purine derivatives were synthesized and their anti-inflammatory effect and anti-inflammation mechanism were verified. Display omitted
•Au(L3)(PPh3) lacking gold complex still remains anti-inflammation activity.•The active compounds of purine derivatives have promising anti-inflammatory activity.•The application of 6- and 6,9-substituted purines was expanded for anti-inflammation.
Sustained activation of STAT3 is closely related to the cancer development, but the inhibitors for STAT3 overexpression are still in the clinical research stage. In this study, a series of ...2,6-disubstituted purine derivatives were designed and synthesized, and their biological activities, as small molecule inhibitors of STAT3, were assessed. Compound PD26-TL07 exhibited remarkable antiproliferative activity against three cancer cell lines (IC50 values for HCT-116, SW480 and MDA-MB-231 were 1.77 ± 0.35, 1.51 ± 0.19, and 1.25 ± 0.38 μM, respectively). Moreover, detailed biological assays revealed that PD26-TL07 could effectively inhibited STAT3 phosphorylation, and had little inhibition to others’. The newly discovered PD26-TL07 displayed an expecting anticancer effect both in vitro and in vivo. The molecular docking models revealed that PD26-TL07 could bind to the SH2 domain of STAT3. Three additional compounds (PD26-BZ01, PD26-TL03 and PD26-AS06) were also able to inhibit this phosphorylation. This study described novel 2,6-disubstituted purine derivatives as potent anticancer agents targeting STAT3.
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•A series of 2,6-disubstituted purine derivatives were discovered as STAT3 small molecular inhibitors.•PD26-TL07 could selectively inhibit STAT3 phosphorylation with IC50 value of 2.28 μM.•PD26-TL07 exhibited potent antitumor activity in vitro and in vivo.
Signal transducer and activator of transcription 3 (STAT3) has been confirmed as an attractive therapeutic target for cancer therapy. Herein, we designed and synthesized a series of N-substituted ...Sulfamoylbenzamide STAT3 inhibitors based on small-molecule STAT3 inhibitor Niclosamide. Compound B12, the best active compound of this series, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 0.61–1.11 μM in MDA-MB-231, HCT-116 and SW480 tumor cell lines with STAT3 overexpression, by inhibiting the phosphorylation of STAT3 of Tyr705 residue and the expression of STAT3 downstream genes, inducing apoptosis and inhibiting the migration of cancer cells. Furthermore, in vivo study revealed that compound B12 suppressed the MDA-MB-231 xenograft tumor growth in nude mice at the dose of 30 mg/kg (i.g.), which has better antitumor activity than the positive control Niclosamide. More importantly, B12 is an orally bioavailable anticancer agent as a promising candidate for further development.
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FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR ...with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity 1and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC50 values for H226 and HCC827 GR were 2.11 μM, and 0.93 μM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
Two series of 4,6-pyrimidinediamine derivatives were synthesized as dual EGFR and FGFR inhibitors and their anti-tumor effect was verified. Display omitted
•33 novel dual EGFR and FGFR compounds were synthesized and evaluated for antitumor activities.•Compound BZF 2 exhibited excellent selectivity and high activity.•Compound BZF 2 cound be potent lead compounds as an antitumor agent.
Exosomes are small membrane vesicles that are secreted by most cell types. Circular RNAs (circRNAs) have recently been identified in exosomes, and exosomal circRNAs exert important biological ...activities in human cancers, including oral squamous cell carcinoma (OSCC). The purpose of this study was to investigate whether circRNA GDP dissociation inhibitor 2 (circGDI2) was transferred by exosomes and how exosomal circGDI2 regulated OSCC cell malignant behaviors.
The levels of circGDI2, miR-424-5p and suppressor of cancer cell invasion (SCAI) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Transwell assays were performed to detect cell migration and invasion. Measurement of glucose consumption and lactate production were conducted using a corresponding assay kit. Targeted correlations among circGDI2, miR-424-5p and SCAI were confirmed by dual-luciferase reporter assays. Xenograft assays were used to observe the role of circGDI2 in tumor growth in vivo.
Our data indicated that circGDI2 was down-regulated in OSCC, and it could be transferred by the exosomes in OSCC cells. The up-regulation of exosomal circGDI2 weakened OSCC cell proliferation, migration, invasion and glycolysis. CircGDI2 functioned as a molecular sponge of miR-424-5p, and SCAI was a direct target of miR-424-5p. MiR-424-5p mediated the repression of exosomal circGDI2 overexpression on OSCC cell malignant behaviors, and miR-424-5p silencing mitigated OSCC cell progression by up-regulating SCAI. Moreover, exosomal circGDI2 regulated SCAI expression through sponging miR-424-5p. Additionally, the overexpression of exosomal circGDI2 inhibited tumor growth in vivo.
The present study had led to the identification of exosomal circGDI2 that regulated OSCC cell malignant behaviors through targeting the miR-424-5p/SCAI axis, highlighting circGDI2 as a novel exosome-based cancer biomarker and therapeutic agent for OSCC treatment.
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