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Abstract Tumor‐associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor‐suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

Summary Two phenazine compounds, diastaphenazine and izumiphenazine C, with complex structures and promising antitumour activity have been isolated from the plant endophytic actinomycete Streptomyces diastaticus W2. Their putative biosynthetic gene cluster (dap) was identified by heterologous expression and gene knockout. There are twenty genes in the dap cluster. dap14‐19 related to shikimic pathway were potentially involved in the precursor chorismic acid biosynthesis, and dapBCDEFG were confirmed to be responsible for the biosynthesis of the dibenzopyrazine ring, the nuclear structure of phenazines. Two transcriptional regulatory genes dapR and dap4 played the positive regulatory roles on the phenazine biosynthetic pathway. Most notably, the dimerization of the dibenzopyrazine ring in diastaphenazine and the loading of the complex side chain in izumiphenazine C could be catalysed by the cyclase homologous gene dap5, suggesting an unusual modification strategy tailoring complex phenazine biosynthesis. Moreover, metabolite analysis of the gene deletion mutant strain S. albus::23C5Δdap2 and substrate assay of the methyltransferase Dap2 clearly revealed the biosynthetic route of the complex side chain in izumiphenazine C.

Bleeding is an effective method to improve the starting performance of the inlet, and the conventional method often adopts the bleeding to longitudinal direction. This article proposes the use of transversal bleeding method to explore the influence on starting capacity by changing the bleeding direction. The paper designs 6 bleeding inlets. By calculating the starting performance, it is found that the projected bleeding rate of the inlet, which is the direct factor influencing the starting performance, would change due to the direction change of bleeding, although designed with the same entrance. For the inlet designed with longitudinal slots and bleeding, it could reach the starting state at Mach 3.6, but it showed the unstart state when they are transversal direction. The same entrance, when inlet is designed by transversal bleeding with longitudinal slots, the starting Mach number would decrease to 3.8. For the changes of aerodynamic capabilities, there would be the “point jump” tendency when reaching starting state, but the same inlets would keep the similar performance when they get the starting state.

Abstract As novel mediators of cell‐to‐cell signalling, small extracellular vesicles (sEVs) play a critical role in physiological and pathophysiological processes. To date, the molecular mechanisms that support sEV generation are incompletely understood. Many kinases are reported for their roles in sEV generation or composition, whereas the involvement of phosphatases remains largely unexplored. Here we reveal that pharmacological inhibition and shRNA‐mediated down‐regulation of tyrosine phosphatase Shp2 significantly increases the formation of sEVs. By Co‐immunoprecipitation (Co‐IP) and in vitro dephosphorylation assays, we identified that Shp2 negatively controlled sEV biogenesis by directly dephosphorylating tyrosine 46 of Syntenin, which has been reported as a molecular switch in sEV biogenesis. More importantly, Shp2 dysfunction led to enhanced epithelial sEV generation in vitro and in vivo. The increase of epithelial sEVs caused by shRNA‐mediated down‐regulation of Shp2 promoted macrophage activation, resulting in strengthened inflammation. Our findings highlight the role of Shp2 in regulating sEV‐mediated epithelial‐macrophage crosstalk by controlling sEV biogenesis through dephosphorylation of Syntenin Y46. The present study determines the strengthened inflammatory characteristics of alveolar macrophages elicited by epithelial sEVs transferred intercellularly. These findings provide a basis for understanding the mechanism of sEV formation and relevant function in epithelial‐macrophage crosstalk.

Background Women have decreased hemodialysis arteriovenous fistula (AVF) maturation and patency rates. We determined the mechanisms responsible for the sex‐specific differences in AVF maturation and stenosis formation by performing whole transcriptome RNA sequencing with differential gene expression and pathway analysis, histopathological changes, and in vitro cell culture experiments from male and female smooth muscle cells. Methods and Results Mice with chronic kidney disease and AVF were used. Outflow veins were evaluated for gene expression, histomorphometric analysis, Doppler ultrasound, immunohistologic analysis, and fibrosis. Primary vascular smooth muscle cells were collected from female and male aorta vessels. In female AVFs, RNA sequencing with real‐time polymerase chain reaction analysis demonstrated a significant decrease in the average gene expression of BMP7 (bone morphogenetic protein 7) and downstream IL17Rb (interleukin 17 receptor b), with increased transforming growth factor‐β1 (Tgf‐β1) and transforming growth factor‐β receptor 1 (Tgfβ‐r1). There was decreased peak velocity, negative vascular remodeling with higher venous fibrosis and an increase in synthetic vascular smooth muscle cell phenotype, decrease in proliferation, and increase in apoptosis in female outflow veins at day 28. In vitro primary vascular smooth muscle cell experiments performed under hypoxic conditions demonstrated, in female compared with male cells, that there was increased gene expression of Tgf‐β1, Tgfβ‐r1, and Col1 with increased migration. Conclusions In female AVFs, there is decreased gene expression of BMP7 and IL17Rb with increased Tgf‐β1 and Tgfβ‐r1, and the cellular and vascular differences result in venous fibrosis with negative vascular remodeling.

Taking Liangxiang Pagoda built in Liao Dynasty in Beijing as the research object, the vibration responses of the pagoda in the east-west direction and south-north direction under the action of trains on the Beijing–Guangzhou Railway Line and microseism were tested. On this basis, a numerical model was established by using ANSYS to further calculate the dynamic response of the pagoda, and the safety and integrity of the pagoda were evaluated based on existing standards. Cumulative fatigue damage theory was introduced to predict the remaining fatigue life of Liangxiang Pagoda. The following conclusions have been drawn: in the two directions mentioned above, the natural vibration frequencies of the pagoda of the first three orders are similar; the 1st-order vibration modes in the plane are bending, and the vibration modes of the 2nd and 3rd orders are shear-bending; under the action of trains, the peak vibration value of Liangxiang Pagoda at the position that bears the maximum load is 0.053 mm/s, which has a little impact on the safety and integrity of the pagoda; under the combined action of gravity and trains, the remaining fatigue life of Liangxiang Pagoda is 5.26×107 times. The research method used in this paper can provide data and scientific support for the protection of historical buildings, as well as the basis for the follow-up research of the studied ancient pagoda.