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RNA interference (RNAi) is mediated by an ∼21-nt double-stranded small interfering RNA (siRNA) and shows great promise in delineating gene functions and in developing therapeutics for human diseases. However, effective gene silencing usually requires the delivery of multiple siRNAs for a given gene, which is often technically challenging and time-consuming. In this study, by exploiting the type IIS restriction endonuclease-based synthetic biology methodology, we developed the fast assembly of multiplex siRNAs (FAMSi) system. In our proof-of-concept experiments, we demonstrated that multiple fragments containing three, four, or five siRNA sites targeting common Smad4 and/or BMPR-specific Smad1, Smad5, and Smad8 required for BMP9 signaling could be assembled efficiently. The constructed multiplex siRNAs effectively knocked down the expression of Smad4 and/or Smad1, Smad5, and Smad8 in mesenchymal stem cells (MSCs), and they inhibited all aspects of BMP9-induced osteogenic differentiation in bone marrow MSCs (BMSCs), including decreased expression of osteogenic regulators/markers, reduced osteogenic marker alkaline phosphatase (ALP) activity, and diminished in vitro matrix mineralization and in vivo ectopic bone formation. Collectively, we demonstrate that the engineered FAMSi system provides a fast-track platform for assembling multiplexed siRNAs in a single vector, and thus it may be a valuable tool to study gene functions or to develop novel siRNA-based therapeutics., Graphical Abstract, RNA interference shows great promise in delineating gene functions and in developing therapeutics for human diseases. He et al. exploited the type IIS restriction endonuclease-based synthetic biology and developed the fast assembly of multiplex siRNAs (FAMSi) system, which streamlines RNAi-based gene function studies and the development of siRNA-based therapeutics.

The oxide scales of hafnium carbide (HfC) typically exhibit a porous structure after oxidation/ablation due to the release of gas oxidation products, which allows oxygen penetration to promote the rapid oxidation of the HfC matrices. Here, we report that the oxidation/ablation resistance of HfC was enhanced by the incorporation of amorphous silicon carbonitride (SiCN). HfC-SiCN ceramics with 10 vol. % SiCN showed a significant improvement in the oxidation/ablation resistance compared with pure HfC. The HfC-10 vol. % SiCN ceramic has a higher density with good mechanical properties. After being oxidized at 1500 °C for 2 h, a dense and homogeneous HfO2-HfSiO4 layer with low oxygen permeability is formed. The ablation resistance of the HfC-10 vol. % SiCN ceramic is improved due to the formation of the triple-layer structure oxide with good thermal stability and mechanical scouring resistance. After ablation under an oxyacetylene flame for 60 s, the mass and linear ablation rates of HfC-10 vol. % SiCN ceramic are -0.019 mg cm−2 s−1 and -0.156 μm s−1, respectively.

Background At present, minimally invasive endoscopic treatment is mostly used for patients with actively bleeding Dieulafoy's lesions, , as it has the advantages of minimal trauma, short operation time and good hemostatic effect, although bleeding can easily recur postoperatively. Recently, extensive gastric cuneiform resection has been advocated for use in these patients because the constant-diameter artery follows a long path to the gastric mucosa. Case summary A 47-year-old man was admitted to the hospital for repeated hematemesis and black stool, and he was diagnosed with Dieulafoy's disease. We chose a method that not only simulates surgical gastric cuneiform resection but also reduces trauma. We performed enlarged local endoscopic full-thickness resection of the gastric wall and abdominal constant-diameter artery and sutured the gastric wall. Postoperative follow-up showed that the constant-diameter artery had been resected from the gastric wall, which was confirmed to have no blood flow signals by endoscopic ultrasonography. Conclusion Endoscopic full-thickness resection of the gastric wall and abdominal constant-diameter artery with suturing of the gastric wall has demonstrated potential as a new treatment for Dieulafoy's disease.

To find out the role of hsa‐miR‐570‐3p targeting CD274 in triple negative breast cancer (TNBC) via PI3K/AKT/mTOR signaling pathway. Hsa‐miR‐570‐3p and CD274 expressions in 175 TNBC patients were detected by qRT‐PCR and immunohistochemistry respectively. The human TNBC cell lines (MDA‐MB‐468 and MDA‐MB‐231) were used to verify the targeting relationship between hsa‐miR‐570‐3p and CD274 via dual‐luciferase reporter gene assay. Then, MDA‐MB‐468 and MDA‐MB‐231 cells were divided into Blank, miR‐NC, miR‐570‐3p mimics, NC siRNA, CD274 siRNA, and miR‐570‐3p inhibitors + CD274 siRNA groups. Next, the biological activities of cells were detected by MTT, Cell‐Light EdU, Annexin‐V‐FITC/PI, wound healing and Transwell invasion assays. Western blotting was conducted to detect protein expressions.MiR‐570‐3p expression was lower in tumor tissues than that in adjacent normal tissues, which was more obvious in CD274‐positive TNBC patients, which targeted CD274 in TNBC cell lines. MiR‐570‐3p inhibited cell proliferation, invasion and migration, but induced cell apoptosis accompanying the upregulation of apoptotic proteins and downregulation of anti‐apoptotic protein. CD274 siRNA had the similar results of miR‐570‐3p mimics, which could be reversed by miR‐570‐3p inhibitors. Besides, both miR‐570‐3p mimics and CD274 siRNA blocked PI3K/AKT/mTOR signaling pathway in TNBC cell lines. Hsa‐miR‐570‐3p was downregulated and CD274 was upregulated in TNBC patients. Besides, hsa‐miR‐570‐3p targeted CD274 to inhibit cell proliferation, invasion, migration, and induce cell apoptosis, which may be related to the suppression of PI3K/AKT/mTOR pathway.

HfC-HfB2 composite ceramics were successfully reactively spark plasma sintered with a unique SiB6 additive. The incorporation of the SiB6 not only promotes the densification of HfC (up to ~99%), but also significantly enhances the toughness from 4.3 ± 0.5 MPa m1/2 to 14.2 ± 1.4 MPa m1/2. The flexural strength of the HfC-HfB2 composite ceramics was simultaneously improved to 529 ± 48 MPa, which is about 1.4 times higher than that of HfC. This improvement is attributed to the dense composite microstructure comprising an in-situ formed HfB2 and a solid solution of Si and O in HfC and HfB2 grains.

Scheelite coating was deposited on SiC fiber tows from various liquid-phase precursors at 1100℃. Strength degradation of SiC fiber was found after fiber coating which was found to be caused by the stress corrosion as a result of gases generated from the decomposition of by-products remaining in the coating. A new and simple method of low temperature pre-heat treatment was adopted to eliminate the stress corrosion in the fiber coating process and to isolate the effect of different types of gases on the stress corrosion cracking of fibers. The tensile strength and fractography of samples with and without pre-heat treatment were compared. Furthermore, the effect of gas composition on the strength degradation of SiC fiber was also investigated through the control experiments.

A flexible and robust YAG-Al2O3 composite nanofibrous membrane was fabricated by a combination of sol-gel and electrospinning methods, then a sintering at 900 °C. The effects of Al2O3 on the microstructure and mechanical performance of YAG nanofibrous membranes were investigated. The YAG nanofibrous membrane is brittle but the composite membranes exhibit a brittle-to-flexible transformation as the Al2O3 content reaches 30 wt.%, which can be attributed to an optimized dense hybrid microstructure consisting of finer YAG grain size surrounded by amorphous Al2O3. The YAG-30 wt.% Al2O3 nanofibrous membrane sintered at 900 °C shows a tensile strength of 3.52±0.31 MPa, three times of that of pure Al2O3 sintered at the same temperature. The membrane still presents a decent flexibility with a tensile strength of 0.75±0.25 MPa after sintering at 1000 °C, which is at least 100 °C higher than the sintering temperature of most reported ceramic nanofibrous membranes.

To find out the role of hsa-miR-570-3p targeting CD274 in triple negative breast cancer (TNBC) via PI3K/AKT/mTOR signaling pathway. Hsa-miR-570-3p and CD274 expressions in 175 TNBC patients were detected by qRT-PCR and immunohistochemistry respectively. The human TNBC cell lines (MDA-MB-468 and MDA-MB-231) were used to verify the targeting relationship between hsa-miR-570-3p and CD274 via dual-luciferase reporter gene assay. Then, MDA-MB-468 and MDA-MB-231 cells were divided into Blank, miR-NC, miR-570-3p mimics, NC siRNA, CD274 siRNA, and miR-570-3p inhibitors + CD274 siRNA groups. Next, the biological activities of cells were detected by MTT, Cell-Light EdU, Annexin-V-FITC/PI, wound healing and Transwell invasion assays. Western blotting was conducted to detect protein expressions.MiR-570-3p expression was lower in tumor tissues than that in adjacent normal tissues, which was more obvious in CD274-positive TNBC patients, which targeted CD274 in TNBC cell lines. MiR-570-3p inhibited cell proliferation, invasion and migration, but induced cell apoptosis accompanying the upregulation of apoptotic proteins and downregulation of anti-apoptotic protein. CD274 siRNA had the similar results of miR-570-3p mimics, which could be reversed by miR-570-3p inhibitors. Besides, both miR-570-3p mimics and CD274 siRNA blocked PI3K/AKT/mTOR signaling pathway in TNBC cell lines. Hsa-miR-570-3p was downregulated and CD274 was upregulated in TNBC patients. Besides, hsa-miR-570-3p targeted CD274 to inhibit cell proliferation, invasion, migration, and induce cell apoptosis, which may be related to the suppression of PI3K/AKT/mTOR pathway.

Mesenchymal stem cells (MSCs) are multipotent progenitors that have the ability to differentiate into multiple lineages, including bone, cartilage, and fat. We previously demonstrated that the least known bone morphogenetic protein (BMP)9 (also known as growth differentiation factor 2) is one of the potent osteogenic factors that can induce both osteogenic and adipogenic differentiation of MSCs. Nonetheless, the molecular mechanism underlying BMP9 action remains to be fully understood. Leptin is an adipocyte-derived hormone in direct proportion to the amount of body fat, and exerts pleiotropic functions, such as regulating energy metabolism, bone mass, and mineral density. In this study, we investigate the potential effect of leptin signaling on BMP9-induced osteogenic differentiation of MSCs. We found that exogenous leptin potentiated BMP9-induced osteogenic differentiation of MSCs both in vitro and in vivo, while inhibiting BMP9-induced adipogenic differentiation. BMP9 was shown to induce the expression of leptin and leptin receptor in MSCs, while exogenous leptin upregulated BMP9 expression in less differentiated MSCs. Mechanistically, we demonstrated that a blockade of JAK signaling effectively blunted leptin-potentiated osteogenic differentiation induced by BMP9. Taken together, our results strongly suggest that leptin may potentiate BMP9-induced osteogenesis by cross-regulating BMP9 signaling through the JAK/STAT signaling pathway in MSCs. Thus, it is conceivable that a combined use of BMP9 and leptin may be explored as a novel approach to enhancing efficacious bone regeneration and fracture healing.

Continuous alumina fiber-reinforced yttria-stabilized zirconia (YSZ) composites with a LaPO4 fiber coating were fabricated by slurry infiltration and spark plasma sintering (SPS). The LaPO4 coating was deposited on the reinforcement alumina fabrics by a modified sol-gel method. The YSZ slurry with good dispersion and stability was prepared by optimizing the pH value, dispersant addition and ball milling time. The fabricated composite with a high density of ∼ 92 % has a good flexural strength of 277 ± 43 MPa, and a superior fracture toughness of 15.93 ± 0.75 MPa·m1/2 exhibiting a non-brittle failure behavior. It was found that the LaPO4 coating reduced the residual stress near the fiber/matrix interface to 131 ± 41 MPa, which was 369 ± 63 MPa in the composite without the fiber coating. The LaPO4 coating renders a weak interphase to improve the composite toughness by activating several toughening mechanisms including crack deflection, fiber debonding and pullout, and delamination behavior.

Growing evidences have demonstrated that multiple TRIM (tripartite motif) proteins exert critical roles in host defense against different microbial pathogens. Although mammalian TRIM21 has been reported to function as an important regulatory factor in antiviral immune and inflammatory response, the role of fish TRIM21 against virus infection still remains largely unknown. In the present study, we investigated the characteristics of TRIM21 gene (EcTRIM21) from orange spotted grouper (Epinephelus coioides). The full-length EcTRIM21 cDNA encoded a 557 amino acid peptide with 92.1% and 31.14% identity with giant grouper (Epinephelus lanceolatus) and human (Homo sapiens), respectively. EcTRIM21 contained four conserved domains, including RING, B-Box, PRY and SPRY domain. EcTRIM21 expression was significantly up-regulated in response to Singapore grouper iridovirus (SGIV) and red-spotted grouper nervous necrosis virus (RGNNV) infection, suggesting that EcTRIM21 might be involved in host defense against fish virus infections. Subcellular localization showed that EcTRIM21 were distributed in the cytoplasm in a punctate manner. Overexpression of EcTRIM21 in vitro significantly inhibited RGNNV and SGIV replication, as evidenced by the decreased severity of cytopathic effect (CPE) and the reduced expression levels of viral core genes. Consistently, knockdown of EcTRIM21 by small interfering RNA (siRNA) promoted the replication of RGNNV and SGIV in vitro. Furthermore, EcTRIM21 overexpression increased both interferon (IFN) and interferon stimulated response element (ISRE) promoter activities. In addition, the transcription levels of IFN signaling related molecules were positively regulated by EcTRIM21 overexpression. Together, our data demonstrated that fish TRIM21 exerted antiviral activity against fish viruses through positive regulation of host interferon response.

At present, China’s marine energy industry is still in its infancy, but there is no doubt that the development of this industry will help China to achieve sustainable development. Therefore, effective policies are needed to promote the industrialization of the industry as soon as possible. This paper systematically consulted the relevant information on the research and development of marine renewable energy, focusing on China’s marine energy industry policy, including the national energy strategy, the progress of China’s marine energy policy, technology policy, market policy and other related content, emphasizing the importance of marine energy policy in promoting the development of marine energy industry. Finally, in view of the deficiencies in the development of marine energy industry in China, the corresponding improvement strategies are put forward.

High altitude heart disease (HAHD) is a common pediatric disease in high altitude areas. It usually occurs in people who have lived for a long time or have lived for more than 2500m above sea level. Its common inducement is respiratory tract infection. The clinical differential diagnosis is difficult because the symptoms of HAHD are similar to those of congenital heart disease; Due to the limitation of medical conditions, many patients are in the state of losing follow-up or not seeking medical treatment, resulting in poor prognosis of HAHD and becoming a high-altitude disease with high mortality. Clarifying the molecular mechanism of HAHD, developing early molecular screening technology and accurate treatment methods of HAHD are the key to improve the ability of prevention and treatment of HAHD.First, the literature in the PubMed and CNKI databases were screened based on keywords and abstracts. Then, the literature for the study was identified based on the fitness between the content of the literature, the research objectives, and the timeliness of the literature. Finally, a systematic molecular mechanism of HAHD was established by investigating the literature and sorting out the genetic adaptations of Tibetan populations compared with low-altitude populations that migrated to the plateau.With the investigation of the 48 papers screened, it was found that genes capable of enhancing the hypoxic ventilatory response and resistance to pulmonary hypertension were all correlated with the hypoxia-inducible factor (HIF) pathway, consisting mainly of three pathways, HIF-1α, HIF-2α, and NO.The low prevalence of HAHD in Tibetan aboriginal children was mainly due to the genetic adaptation of the Tibetan population to the high altitude environment, which coordinated the cellular response to hypoxia by regulating the downstream hypoxia control genes in the HIF pathway.

Xanthohumol, a natural isoflavone from Humulus lupulus L., possesses biological activities. However, the biological fate of xanthohumol in vivo remains unclear. The aim of this study was to investigate the absorption and metabolism of xanthohumol in rats through UPLC-MS/MS. The plasma, urine and fecal samples were collected after oral administration of xanthohumol (25, 50, 100 mg/kg) in SD rats. The contents of xanthohumol and its metabolites were determined by UPLC-MS/MS. A total of 6 metabolites of xanthohumol were identified in rats, including methylated, glucuronidated, acid-catalyzed cyclization and oxidation, indicating xanthohumol underwent phase I and II metabolism. Besides, isoxanthohumol was the major metabolites of xanthohumol. Xanthohumol was rapidly absorbed, metabolized, and eliminated in rats. The pharmacokinetics results showed the T

MicroRNAs (miRNAs or miRs) are single-stranded, ∼22-nucleotide noncoding RNAs that regulate many cellular processes. While numerous miRNA quantification technologies are available, a recent analysis of 12 commercial platforms revealed high variations in reproducibility, sensitivity, accuracy, specificity and concordance within and/or between platforms. Here, we developed a universal hairpin primer (UHP) system that negates the use of miRNA-specific hairpin primers (MsHPs) for quantitative reverse transcription PCR (RT-qPCR)-based miRNA quantification. Specifically, we analyzed four UHPs that share the same hairpin structure but are anchored with two, three, four and six degenerate nucleotides at 3′-ends (namely UHP2, UHP3, UHP4 and UHP6), and found that the four UHPs yielded robust RT products and quantified miRNAs with high efficiency. UHP-based RT-qPCR miRNA quantification was not affected by long transcripts. By analyzing 14 miRNAs, we demonstrated that UHP4 closely mimicked MsHPs in miRNA quantification. Fine-tuning experiments identified an optimized UHP (OUHP) mix with a molar composition of UHP2:UHP4:UHP6 = 8:1:1, which closely recapitulated MsHPs in miRNA quantification. Using synthetic LET7 isomiRs, we demonstrated that the OUHP-based qPCR system exhibited high specificity and sensitivity. Collectively, our results demonstrate that the OUHP system can serve as a reliable and cost-effective surrogate of MsHPs for RT-qPCR-based miRNA quantification for basic research and precision medicine.

Singapore grouper iridovirus (SGIV), belonging to genus Ranavirus, family Iridoviridae, causes great economic losses in the aquaculture industry. Previous studies demonstrated the lipid composition of intracellular unenveloped viruses, but the changes in host-cell glyceophospholipids components and the roles of key enzymes during SGIV infection still remain largely unknown. Here, the whole cell lipidomic profiling during SGIV infection was analyzed using UPLC-Q-TOF-MS/MS. The lipidomic data showed that glycerophospholipids (GPs), including phosphatidylcholine (PC), phosphatidylserine (PS), glycerophosphoinositols (PI) and fatty acids (FAs) were significantly elevated in SGIV-infected cells, indicating that SGIV infection disturbed GPs homeostasis, and then affected the metabolism of FAs, especially arachidonic acid (AA). The roles of key enzymes, such as cytosolic phospholipase A2 (cPLA2), 5-Lipoxygenase (5-LOX), and cyclooxygenase (COX) in SGIV infection were further investigated using the corresponding specific inhibitors. The inhibition of cPLA2 by AACOCF3 decreased SGIV replication, suggesting that cPLA2 might play important roles in the process of SGIV infection. Consistent with this result, the ectopic expression of EccPLA2α or knockdown significantly enhanced or suppressed viral replication in vitro, respectively. In addition, the inhibition of both 5-LOX and COX significantly suppressed SGIV replication, indicating that AA metabolism was essential for SGIV infection. Taken together, our results demonstrated for the first time that SGIV infection in vitro disturbed GPs homeostasis and cPLA2 exerted crucial roles in SGIV replication.

We explore the association of hope and quality of life in breast cancer chemotherapy women. Their quality of life is related to treatment effects and disease outcomes. This cross-sectional study was conducted in City, China, in 2017. In a convenience sampling, 450 women who underwent breast cancer chemotherapy were selected from two hospitals. Descriptive statistics, single-factor analysis, Spearman correlation, linear regression, and structural equation modeling were used to analyze data. The mean quality of life score was 65.65. In linear regression analysis, we found patients’ quality of life was significantly related to age, marital status, education level, chemotherapy cycle, and hope. Structural equation results showed the “temporality and future” and “interconnectedness” subscales of the HHI explained 43% of the variance in quality of life. We found hope is an important aspect in quality of life, and further research is needed to determine if nurses can influence this aspect of care.

This study aimed to investigate the impact of air pollution on the development of adolescents and the mediating role of students’ emotional disorders. Participants came from a longitudinal sample group of adolescents (n = 1301) in Southern China from the years 2016 to 2018. They were assessed for the Positive Youth Development and emotional disorders, and air pollution was measured by the Air Quality Index. The results show that students’ higher degree of exposure to air pollution was negatively associated with their positive development. Three out of four emotional disorders (i.e., anxiety, neuroticism, and withdrawal) mediate this association. The results suggest that the physical environment can have a paramount influence on the emotional status and overall development of adolescents, calling for intervention programs by policymakers.

Yttrium aluminum garnet (YAG) fibers were prepared by a sol-gel method, and then sintered in air or nitrogen atmosphere, respectively. The effects of sintering atmosphere on the densification process and microstructure of YAG fibers were investigated. No obvious difference can be found in the fibers sintered below 800 °C. At 1100 °C, the grain size of YAG fibers sintered in nitrogen is much smaller than in air. This difference is much clearer at the higher temperature of 1200 °C. The fine grains are explained by the existence of residual carbon in YAG fibers, which can be trapped at the grain boundaries to hinder the movement of grain boundary. Meanwhile, the densification degree of fibers sintered in nitrogen is higher than in air at 1200 °C, due to the smaller grain size and higher oxygen vacancy concentration generated in the nitrogen atmosphere, which leads to a higher fiber densification rate.

Objectives: Acute myeloid leukemia (AML) is caused by multiple genetic alterations in hematopoietic progenitors, and molecular genetic analyses have provided useful information for AML diagnosis and prognostication. This study aimed to integratively understand the prognostic value of specific copy number variation (CNV) patterns and CNV-modulated gene expression in AML. Methods: We conducted integrative CNV profiling and gene expression analysis using data from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) and The Cancer Genome Atlas (TCGA) AML cohorts. CNV-related genes associated with survival were identified using the TARGET AML cohort and validated using the TCGA AML cohort. Genes whose CNV-modulated expression was associated with survival were also identified using the TARGET AML cohort and validated using the TCGA AML cohort, and patient bone marrow samples were then used to further validate the effects of CNV-modulated gene expression on survival. CNV and mRNA survival analyses were conducted using proportional hazards regression models (Cox regression) and the “survminer” and “survival” packages of the R Project for Statistical Computing. Genes belonging to the Kyoto Encyclopedia of Genes and Genomes (KEGG) cancer panel were extracted from KEGG cancer-related pathways. Results: One hundred two CNV-related genes (located at 7q31-34, 16q24) associated with patient survival were identified using the TARGET cohort and validated with the TCGA AML cohort. Among these 102 validated genes, three miRNA genes (MIR29A, MIR183, and MIR335) were included in the KEGG cancer panel. Five genes (SEMA4D, CBFB, CHAF1B, SAE1, and DNMT1) whose expression was modulated by CNVs and significantly associated with clinical outcomes were identified, and the deletion of SEMA4D and CBFB was found to potentially exert protective effects against AML. The results of these five genes were also validated using patient marrow samples. Additionally, the distribution of CNVs affecting these five CNV-modulated genes was independent of the risk group (favorable-, intermediate-, and adverse-risk groups). Conclusions: Overall, this study identified 102 CNV-related genes associated with patient survival and identified five genes whose expression was modulated by CNVs and associated with patient survival. Our findings are crucial for the development of new modes of prognosis evaluation and targeted therapy for AML.