Porcine reproductive and respiratory syndrome virus (PRRSV) remains a major economic threat to the global swine industry. The viral 3C-like serine main protease (non-structural protein 4, nsp4) is essential for replication and represents a promising drug target for antiviral intervention. Here, we report that shikonin, a natural naphthoquinone derived from Lithospermum erythrorhizon, covalently modifies C111 and C194 of PRRSV-2 nsp4 in vitro, leading to loss of its proteolytic activity (IC50 = 4.9 μM). This site-specific covalent modification provides a biochemical basis for its inhibitory mechanism. Structural analysis of apo-nsp4 revealed a previously unobserved solvent-exposed conformation of C111, which defines a novel druggable pocket. In cellular assays, shikonin exhibited broad-spectrum antiviral activity against multiple PRRSV-2 strains, with EC50 values ranging from 25.5 to 235.5 nM, achieving >99% reduction in viral RNA at sub‑micromolar concentrations, and showed a high safety margin (CC50 = 10.0 μM). Collectively, these findings elucidate the covalent inhibition mechanism of shikonin against PRRSV-2 nsp4 and support its potential as an agent or lead compound for developing anti-PRRSV therapeutics.

In this work, the growth environment for the SCDs and the diamond film are improved by refine the arrangement of the substrate holder in our self-developed MPCVD apparatus. The arrangement of the substrate holder is controlled by the triangle h which is kept less than 3.0 mm. The plasma around the substrate holder is systematically researched with multi-physical simulation and OES. The triangle h is finally selected at 1.5 mm and 0.5 mm to prepare SCDs and diamond film. Using the arrangement of the substrate holder, the cracks in the SCDs put at the edge of the Mo substrate and the fragmentation of the freestanding diamond film are effective avoided. The results turn out that the uniformity of the plasma can be enhanced by reasonable selecting the triangle h, and in this way the edge effect of the substrate can be effectively utilized. The obtained results provide a guidance for the scalable production of diamond material.

With the rapid development of synthetic biology, lots of synthetic biology technology achievements in various application fields have been commercialized, generating broad market prospects. The commercialization of products employing synthetic biology technology (hereinafter referred as synthetic biology products) has brought benefits to human beings, but it has also produced potential safety risks. At present, relevant laws and standards for regulation of biotechnology or genetically modified organisms have been adopted to regulate the safety risks of commercialization of synthetic biology products (CSBP). However, due to the complexity and uncertainty of synthetic biology, the safety risks of CSBP cannot be comprehensively regulated by these laws and standards. Therefore, it is of great significance to formulate specific supervision and management measures for regulating the safety risks of CSBP. This paper summarized the situation of CSBP in the fields of food, medical care, agriculture, environment, energy and materials, analyzed the safety risks existing in the CSBP, and sorted out current supervision situation of its safety risks in European countries, United States, as well as in China. We further proposed suggestions on the safety supervision and management measures on the safety risks of CSBP, including classified examination and approval, classified identification of products, and strict screening and approval of market entities before entering the market, and strengthening safety supervision and emergency treatment as well as accident responsibility investigation after entering the market. This whole-process safety regulation might provide support for the safety of CSBP and promote the healthy and long-term development of synthetic biology industry.

Treatment failure is one of the main lethal causes of human triple negative breast cancer (TNBC) patients due to inefficient drug administration. The present study demonstrated the development of functional microporous organic polymers (MOPs) as a potential drug carrier and its controlled release. Due to the existence of abundant pores and high surface area, MOPs have promoted the high drug payloads, facilitating prolonged retention time and improved drug release. Herein, porous organic polymer has been fabricated via knitting strategy using the carbonyl bridged external crosslinker. Utilizing the imine chemistry, post-functionalization at the bridging carbon with the diamine resulted in the functional porous framework which had been further modified with single stranded DNA (ssDNA). Due to the conjugated structure, the designed material incorporates the strong blue fluorescence that assists in bio-imaging. In short, the inherent features of hypercrosslinked microporous polymers nanospheres (HMPNs) enabled the high encapsulation of Epirubicin (EPI) and its controlled release in TNBC cell lines (SUM-159 and MDA-MB-231) to inhibit cancer cells proliferation. We anticipate that the further development in functionalization of hypercrosslinked polymers may lead to a breakthrough in biomedical applications.

Increased dependence on aerobic glycolysis is characteristic of most cancer cells, whereas the mechanism underlying the promotion of aerobic glycolysis in metastatic breast cancer cells under ambient oxygen has not been well understood. Here, we demonstrated that aberrant expression of signal-induced proliferation-associated 1 (SIPA1) enhanced aerobic glycolysis and altered the main source of ATP production from oxidative phosphorylation to glycolysis in breast cancer cells. We revealed that SIPA1 promoted the transcription of EPAS1, which is known as the gene encoding hypoxia-inducible factor-2α (HIF-2α) and up-regulated the expression of multiple glycolysis-related genes to increase aerobic glycolysis. We also found that blocking aerobic glycolysis by either knocking down SIPA1 expression or oxamate treatment led to the suppression of tumor metastasis of breast cancer cells both in vitro and in vivo. Taken together, aberrant expression of SIPA1 resulted in the alteration of glucose metabolism from oxidative phosphorylation to aerobic glycolysis even at ambient oxygen levels, which might aggravate the malignancy of breast cancer cells. The present findings indicate a potential target for the development of therapeutics against breast cancers with dysregulated SIPA1 expression.

Nuclear-encoded Atp23 was previously shown to have dual functions, including processing the yeast Atp6 precursor and assisting the assembly of yeast mitochondrial ATP synthase. However, it remains unknown whether there are genes functionally complementary to ATP23 to rescue atp23 null mutant. In the present paper, we screen and characterize three revertants of atp23 null mutant and reveal a T1121G point mutation in the mitochondrial gene COX1 coding sequence, which leads to Val374Gly mutation in Cox1, the suppressor in the revertants. This was verified further by the partial restoration of mitochondrial ATP synthase assembly in atp23 null mutant transformed with exogenous hybrid COX1 T1121G mutant plasmid. The predicted tertiary structure of the Cox1 p.Val374Gly mutation showed no obvious difference from wild-type Cox1. By further chase labeling with isotope [35S]-methionine, we found that the stability of Atp6 of ATP synthase increased in the revertants compared with the atp23 null mutant. Taking all the data together, we revealed that the T1121G point mutation of mitochondrial gene COX1 could partially restore the unassembly of mitochondrial ATP synthase in atp23 null mutant by increasing the stability of Atp6. Therefore, this study uncovers a gene that is partially functionally complementary to ATP23 to rescue ATP23 deficiency, broadening our understanding of the relationship between yeast the cytochrome c oxidase complex and mitochondrial ATP synthase complex.

As a Ku70-binding protein of the KUB family, Kub3 has previously been reported to play a role in DNA double-strand break repair in human glioblastoma cells in glioblastoma patients. However, the physiological roles of Kub3 in normal mammalian cells remain unknown. In the present study, we generated Kub3 gene knockout mice and revealed that knockout (KO) mice died as embryos after E18.5 or as newborns immediately after birth. Compared with the lungs of wild-type (WT) mice, Kub3 KO lungs displayed abnormal lung morphogenesis and pulmonary atelectasis at E18.5. No difference in cell proliferation or cell apoptosis was detected between KO lungs and WT lungs. However, the differentiation of alveolar epithelial cells and the maturation of type II epithelial cells were impaired in KO lungs at E18.5. Further characterization displayed that Kub3 deficiency caused an abnormal FGF signaling pathway at E18.5. Taking all the data together, we revealed that Kub3 deletion leads to abnormal late lung development in mice, resulting from the aberrant differentiation of alveolar epithelial cells and the immaturation of type II epithelial cells due to the disturbed FGF signaling pathway. Therefore, this study has uncovered an essential role of Kub3 in the prenatal lung development of mice which advances our knowledge of regulatory factors in embryonic lung development and provides new concepts for exploring the mechanisms of disease related to perinatal lung development.

Tumour cell metastasis can be genetically regulated by proteins contained in cancer cell-derived extracellular vesicles (EVs) released to the tumour microenvironment. Here, we found that the number of infiltrated macrophages was positively correlated with the expression of signal-induced proliferation-associated 1 (SIPA1) in invasive breast ductal carcinoma tissues and MDA-MB-231 xenograft tumours. EVs derived from MDA-MB-231 cells (231-EVs) significantly enhanced macrophage migration, compared with that from SIPA1-knockdown MDA-MB-231 cells (231/si-EVs) both in vitro and in vivo. We revealed that SIPA1 promoted the transcription of MYH9, which encodes myosin-9, and up-regulated the expression level of myosin-9 in breast cancer cells and their EVs. We also found that blocking myosin-9 by either down-regulating SIPA1 expression or blebbistatin treatment led to the suppression of macrophage infiltration. Survival analysis showed that breast cancer patients with high expression of SIPA1 and MYH9 molecules had worse relapse-free survival (p = 0.028). In summary, SIPA1high breast cancer can enhance macrophage infiltration through EVs enriched with myosin-9, which might aggravate the malignancy of breast cancer.

Mo 2 C was prepared by microwave plasma chemical vapor deposition（MPCVD）technique with the power of 800 W and pressure of 18 k Pa. Compared with traditional preparation methods,MPCVD has faster growth rate and higher purity of the products. The influence of growth time on the morphology and structure of Mo 2 C was characterized by X-ray diffraction and Scanning Electron Microscopy. The photocatalytic performance of Mo 2 C was tested. It was found that Mo 2 C had good photocatalytic performance and the 6 h sample had the highest photodegradation rate,indicating the great potential of Mo 2 C as photocatalyst.

Signal-induced proliferation-associated protein 1 (SIPA1) is highly expressed and mainly located in the nucleus in some breast cancer cell lines and clinical tumor tissues. Previous study revealed that nuclear localization of SIPA1 is functionally involved in breast cancer metastasis in the lymphatic gland. In the current study, we identified a non-typical region (140-179aa) of SIPA1 as a novel nuclear localization region (NLR) which is crucial for translocating the proteins into the nucleus in HEK293 cells and breast cancer cells. This region contained one basic amino acid, His160, and had no common features of typical nuclear localization signals. In addition, overexpressing SIPA1 without NLR could suppress breast cancer cell proliferation but could not promote cell migration in MCF7 cells. Furthermore, we found that a high expression of SIPA1 upregulated the expression of ABCB1, encoding multi-drug resistance protein MDR1, and promoted the resistance to epirubicin in breast cancer cells, while this effect was largely abolished in the cells with the expression of NLR-deleted SIPA1. This study overall, identified a nuclear localization-dependent region determining the nuclear distribution of SIPA1 and its regulation on epirubicin-sensitivity in breast cancer cells, which could be a potential drug target to facilitate the development of breast cancer chemotherapy.

Two chaperones, Atp23p and Atp10p, were previously shown to regulate the assembly of yeast mitochondrial ATP synthase, and extra expression of ATP23 was found to partially rescue an atp10 deletion mutant, by an unknown mechanism. Here, we identified that the residues 112-115 (LRDK) of Atp23p were required for its function in assisting assembly of the synthase, and demonstrated both functions of Atp23p, processing subunit 6 precursor and assisting assembly of the synthase, were required for the partial rescue of atp10 deletion mutant. By chasing labeling with isotope S-35-methionine, we found the stability of subunit 6 of the synthase increased in atp10 null strain upon overexpression of ATP23. Further co-immunoprecipitation (Co-IP) and blue native PAGE experiments showed that Atp23p and Atp10p were physically associated with each other in wild type. Moreover, we revealed the expression level of Atp23p increased in atp10 null mutant compared with the wild type. Furthermore, we found that, after 72 hours growth, atp10 null mutant showed leaky growth on respiratory substrates, presence of low level of subunit 6 and partial recovery of oligomycin sensitivity of mitochondrial ATPase activity. Further characterization revealed the expression of Atp23p increased after 24 hours growth in the mutant. These results indicated, in atp10 null mutant, ATP10 deficiency could be partially complemented with increased expression of Atp23p by stabilizing some subunit 6 of the synthase. Taken together, this study revealed the two chaperones Atp23p and Atp10p coordinated to regulate the assembly of mitochondrial ATP synthase, which advanced our understanding of mechanism of assembly of yeast mitochondrial ATP synthase.

Large-size single crystals of MAPbI3 were grown using inverse temperature crystallization. The crystalline anisotropy is important for understanding, designing and controlling the growth and properties of MAPbI3 series materials. The optoelectronic performances using MAPbI3 crystals with three different orientations of (100), (112) and (001) were studied, which revealed the anisotropic optoelectronic properties. The responsivity of the (112) facet of MAPbI3 reaches 7.08 mA/W which shows excellent optoelectronic properties.

Bismuth layered structure materials with Aurivillius phase usually show amazing structure and physical properties. The influence of La and Ni doping on the structure, ferroelectricity and photocatalytic performance of Bi7Ti3Fe3O21 (BTF), Bi5.6La1.4Ti3Fe3O21 (La: BTF), Bi7Ti3Fe2.4Ni0.6O21 (Ni: BTF) and Bi5.6La1.4Ti3Fe2.4Ni0.6O21 (La, Ni: BTF) ceramics are explored. The enhancement of La: BTF ferroelectricity is due to the reduction of leakage current and oxygen vacancies. Co-doped La, Ni: BTF has the highest degree of ferroelectric polarization due to the large distortion of the lattice structure. La: BTF has the highest photocatalytic degradation efficiency for methylene blue (MB) dye. The reduction of grain radius, band gap and enhancement of ferroelectric polarization play a vital role in improving photocatalytic efficiency. Ni doping suppresses photocatalysis of BTF to some extent.

目的 在实验室自制的5 kW圆柱形单模微波等离子体化学气相沉积(MPCVD)装置上,系统研究各放电参数对等离子体的影响.方法 采用模拟计算与实验调控相结合的方式,分析微波等离子体、基团的运动和分布与放电参数之间的关系.利用发射光谱诊断等离子体环境,同时,利用SEM和Raman对所沉积的金刚石膜的形貌和质量进行表征,以验证MPCVD装置的调控原则.结果 气压和温度满足Tg=8/3 P关系时,吸收功率密度可达最大.单独提高微波功率和工作气压,能很大程度地增强等离子体的电子密度及改善等离子体球的均匀性,而两者相互之间匹配升高能极大地增加等离子体的电子密度,同时激发更多Hα、Hβ、CH及C2这类适合高质量金刚石膜沉积的活性基团.得到了MPCVD装置长时间稳定运行的等离子体稳定边界,并成功制备出高质量的金刚石膜.结论 功率气压及温度相匹配可以提高吸收功率密度、等离子体密度及均匀性.在圆柱形装置稳定运行的边界条件下,能沉积得到较高质量的金刚石膜.

We reported three hybrid organic–inorganic perovskite single crystals of (CH3NH3)2MnCl4, (CH3NH3)2CuCl4 and (CH3NH3)2CoCl4. Magnetic measurements show that all the single crystals display magnetic ordering at low temperature.

在实验室自主研制的10 kW微波等离子体化学气相沉积装置上,通过改变气体的进出方式,探讨了气体流动方式对金刚石膜均匀性和质量的影响.结果表明:随着Si基片表面气体分子数增多,等离子体中的H原子和CH活性基团强度增强,扩散到基片表面中心的原子H和含碳活性基团增多,基片中心区域的金刚石膜生长速率略微有所提升,由原来的2.5μm/h提高到2.8μm/h,沉积得到的金刚石膜质量和均匀性均得到改善.

SIPA1, a GTPase activating protein that negatively regulates Ras-related protein (Rap), is a potential modulator of tumor metastasis and recurrence. In this study, we first showed that SIPA1 facilitated the stemness features of breast cancer cells, such as of tumorsphere formation capability and the expression of stemness marker CD44. In addition, SIPA1 promoted the expression of four stemness-associated transcription factors through increasing the expression of SMAD2 and SMAD3 in vitro and in vivo. The stemness features were abolished by blocking the phosphorylation of SMAD3 with its specific inhibitor SIS3. Furthermore, SIPA1 decreased the breast cancer cell sensitivity to chemotherapy drugs. This effect was, however, competitively reversed by blocking the SMAD3 phosphorylation by SIS3 treatment in breast cancer cells. Taken together, SIPA1 promotes and sustains the stemness of breast cancer cells and their resistance to chemotherapy by increasing the expression of SMAD2 and SMAD3, and blocking SMAD3 phosphorylation could suppress the cancer cell stemness and increase the sensitivity to chemotherapy in breast cancer cells expressing a high level of SIPA1.

Studies have begun to emerge showing the protumor effects of tumor-associated neutrophils (TANs) in tumorigenesis, which may involve dysfunction of NK cells. However, the mechanism through which these rebellious neutrophils modulate NK cell immunity in tumor-bearing state remains unclear. In the present study, we demonstrate that neutrophils can impair the cytotoxicity and infiltration capability of NK cells, and downregulate CCR1 resulting in the weakened infiltration capability of NK cells. Moreover, neutrophils can decrease the responsiveness of NK-activating receptors, NKp46 and NKG2D. Mechanistically, enhanced PD-L1 on neutrophils and PD-1 on NK cells, and subsequent PD-L1/PD-1 interactions were the main mechanisms determining the suppression of neutrophils in NK cell immunity. G-CSF/STAT3 pathway was responsible for PD-L1 upregulation on neutrophils, while IL-18 was essential for PD-1 enhancement on NK cells. The crosstalk between neutrophils and NK cells was cell-cell interaction-dependent. These findings suggest that neutrophils can suppress the antitumor immunity of NK cells in tumor-bearing status through the PD-L1/PD-1 axis, highlighting the importance of PD-L1/PD-1 in the inhibitory effect of neutrophils on NK cells. Targeting G-CSF/STAT3 and IL-18 signaling pathway may be potential strategies to inhibit residual tumor in tumor therapy.

为了探讨气态污染物NO2对高血压患者血压水平和脉压的短期影响,本文基于前瞻性队列研究,收集甘肃省金昌市2011年1月1日～2015年11月30日逐日NO2监测数据及同期气象观测数据,运用混合效应模型,在控制随机效应及其他混杂因素的基础上,分析NO2与高血压患者血压水平和脉压的关联性.结果表明:(1)NO2在滞后1d(lag1)时平均浓度每升高1个IQR,收缩压升高0.457mmHg(0.131～0.784),滞后7d(lag7)和4d(lag4)时NO2的平均浓度每升高1个IQR,舒张压上升0.276mmHg(0.025～0.527),脉压上升0.402mmHg(0.047～0.758),且结果均具有统计学意义.(2)性别、年龄、BMI、吸烟、饮酒、季节在NO2对高血压患者血压水平和脉压的效应中可能具有修饰作用.多污染物模型及调整沙尘影响后,NO2对高血压患者血压及脉压的影响保持一致.

采用MPCVD技术,研究了CO2-CH4-N2体系中N2对纳米金刚石膜生长状态及晶界处H含量的影响.利用SEM,XRD,Raman,FTIR及TEM对纳米金刚石膜的形貌、结构和质量进行研究,并利用Raman及FTIR对晶界处H的含量进行计算分析.结果 表明,N2流量的增加会在促使纳米金刚石膜的晶粒团聚体从球状逐渐转变为针状的同时减小晶粒尺寸,并使择优取向由<111>转变为<110>.随着N2流量的增加,纳米金刚石膜的质量也随之降低,但晶界处的H含量逐渐上升.具有针状晶粒团聚体的纳米金刚石膜具有明显的金刚石相和晶体石墨相.N2流量的增加不仅可以有效降低纳米金刚石膜的晶粒尺寸,改变晶粒的团聚形态及择优取向,还可以显著增加晶界处H的含量,促进石墨相的生成.