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BackgroundNOS1 expression predicts poor prognosis in patients with melanoma. However, the molecular function of NOS1 in the type I IFN response and immune escape of melanoma is still unknown.MethodsThe CRISPR/Cas9 system was used to generate NOS1-knockout melanoma cells and the biological characteristics of NOS1-knockout cells were evaluated by MTT assay, clonogenic assay, EdU assay, and flow cytometric assay. The effect on tumor growth was tested in BALB/c-nu and C57BL/6 mouse models. The gene expression profiles were detected with Affymetrix microarray and RNA-seq and KEGG (Kyoto Encyclopedia of Genes and Genomes) and CLUE GO analysis was done. The clinical data and transcriptional profiles of melanoma patients from the public database TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus, GSE32611) were analyzed by Qlucore Omics Explorer.ResultsNOS1 deletion suppressed the proliferation of melanoma A375 cells in culture, blocked cell cycling at the G0/G1 phase, and decreased the tumor growth in lung metastasis nodes in a B16 melanoma xenograft mouse model. Moreover, NOS1 knockout increased the infiltration of CD3+ immune cells in tumors. The transcriptomics analysis identified 2203 differential expression genes (DEGs) after NOS1 deletion. These DEGs indicated that NOS1 deletion downregulated mostly metabolic functions but upregulated immune response pathways. After inhibiting with NOS1 inhibitor N-PLA, melanoma cells significantly increased the response to IFN[Formula: see text] by upregulation expression of IFN[Formula: see text] simulation genes (ISGs), especially the components in innate immune signaling, JAK-STAT, and TOLL-LIKE pathway. Furthermore, these NOS1-regulating immune genes (NOS1-ISGs) worked as a signature to predict poor overall survival and lower response to chemotherapy in melanoma patients.ConclusionThese findings provided a transcriptional evidence of NOS1 promotion on tumor growth, which is correlated with metabolic regulation and immune escape in melanoma cells.

One of the malignant transformation hallmarks is metabolism reprogramming, which plays a critical role in the biosynthetic needs of unchecked proliferation, abrogating cell death programs, and immunologic escape. However, the mechanism of the metabolic switch is not fully understood. Here, we found that the S-nitrosoproteomic profile of endogenous nitrogen oxide in ovarian cancer cells targeted multiple components in metabolism processes. Phosphofructokinase (PFKM), one of the most important regulatory enzymes of glycolysis, was S-nitrosylated by nitric oxide synthase NOS1 at Cys351. S-nitrosylation at Cys351 stabilized the tetramer of PFKM, leading to resist negative feedback of downstream metabolic intermediates. The PFKM-C351S mutation decreased the proliferation rate of cultured cancer cells, and reduced tumor growth and metastasis in the mouse xenograft model. These findings indicated that S-nitrosylation at Cys351 of PFKM by NOS1 contributes to the metabolic reprogramming of ovarian cancer cells, highlighting a critical role of endogenous nitrogen oxide on metabolism regulations in tumor progression.

Aiming at the problem of target allocation in operations of special-shaped anti-ship missile swarms, a target allocation model based on time coordination is established. Firstly, according to the anti-ship combat situation information, the influence of missile flight time, missile-to-target distance and flight velocity on the target allocation of cluster coordination operations is analyzed, and a time coordination advantage function based on the standard deviation of missile flight time is established, and the comprehensive advantage function is formed integrated the distance advantage function with velocity advantage function. Finally, the optimal solution of model is deduced by genetic algorithm, and the allocation results are gotten by simulation. The results of comparative analysis show that the standard deviation of average time of operation scheme with time coordination is lower than that without time coordination. The standard deviation of average time for two cases descends about 49.18% and 63.49%. The simulation results verify the validity of the model.

As the penetration of renewable energy sources (RESs) in power systems continues to increase, their volatility and unpredictability have exacerbated the burden of frequency regulation (FR) on conventional generator units (CGUs). Therefore, to reduce frequency deviations caused by comprehensive disturbances and improve system frequency stability, this paper proposes an integrated strategy for hybrid energy storage systems (HESSs) to participate in primary frequency regulation (PFR) of the regional power grid. Once the power grid frequency exceeds the deadband (DB) of the HESS, the high-frequency signs of the power grid frequency are managed by the battery energy storage system (BESS) through a division strategy, while the remaining parts are allocated to pumped hydroelectric energy storage (PHES). By incorporating positive and negative virtual inertia control and adaptive droop control, the BESS effectively maintains its state of charge (SOC), reduces the steady-state frequency deviation of the system, and provides rapid frequency support. When the system frequency lies within the DB of the HESS, an SOC self-recovery strategy restores the BESS SOC to an ideal range, further enhancing its long-term frequency regulation (FR) capability. Finally, a regional power grid FR model is established in the RT-1000 real-time simulation system. Simulation validation is conducted under three scenarios: step disturbances, short-term continuous disturbances, and long-term RES disturbances. The results show that the proposed integrated strategy for HESS participation in PFR not only significantly improves system frequency stability but also enhances the FR capability of the BESS. [ABSTRACT FROM AUTHOR]

The notions of os{o}_{s}-convergence and S∗{S}^{\ast }-doubly quasicontinuous posets are introduced, which can be viewed as common generalizations of Birkhoff’s order-convergence and S∗{S}^{\ast }-doubly continuous posets, respectively. We first consider the relationship between os{o}_{s}-convergence and B-topology and show that the topology induced by os{o}_{s}-convergence according to the standard topological approach is the B-topology precisely. Then, the topological characterization for the S∗{S}^{\ast }-doubly quasicontinuity is presented. It is proved that a poset is S∗{S}^{\ast }-doubly quasicontinuous iff the poset equipped with the B-topology is locally hyperclosed iff the lattice of all B-open subsets of the poset is hypercontinuous. Finally, the order theoretical condition for the os{o}_{s}-convergence being topological is given and the complete regularity of B-topology on S∗{S}^{\ast }-doubly quasicontinuous posets is explored.

In this paper, the α waybelow relation, which is determined by O2-convergence, is characterized by the order on a poset, and a sufficient and necessary condition for O2-convergence to be topological is obtained.

Background: Differentiated thyroid cancer involves thyroid follicular carcinoma (FTC) and papillary thyroid carcinoma (PTC). Patients with FTC have a worse prognosis than those with PTC for early metastasis through blood of FTC. However, the mechanism of poor prognosis of FTC is still unclear. Here, we aim to evaluate the role of DUSP5 in the prognostic evaluation of FTC. Method: We searched the Gene Expression Omnibus (GEO) database for the differentially expressed genes (DEGs) between FTC and PTC, and then combined with survival analysis of cBioPortal database to locate the gene significantly related to prognosis. Tissue microarrays and clinical tissues were used to examine DUSP5 expression by immunohistochemical (IHC) staining between FTC and PTC tissues. In vitro experiment, proliferation, migration and invasion of FTC were observed after regulation of DUSP5 by transfection of siRNA and plasmids, respectively. Results: After searching the GEO database, 26 DEGs were found. DUSP5 was significantly associated with prognosis of FTC in combination with survival analysis. Data of IHC staining showed lower expression of DUSP5 in FTC compared to PTC tissues. Furthermore, overexpression of DUSP5 inhibited the proliferation, migration and invasion accompanied with low level of MMP9 and Vimentin and high level of E‐cadherin. Nevertheless, inhibition of DUSP5 ameliorated above damaging effect on the proliferation, migration and invasion. Conclusion: DUSP5 was differentially expressed in FTC and PTC tissues. Low level of DUSP5 in FTC participates in the high frequency of metastasis, and further contributes to poor prognosis of FTC. DUSP5 could be served as a novel therapeutic target for FTC. [ABSTRACT FROM AUTHOR]

Nitric oxide synthase 1 (NOS1) has been reported to promote various cancer processes including chemoresistance. However, the role of NOS1 in chemoresistance has remained unclear. ATP-binding cassette, subfamily G, member 2 (ABCG2) has been identified as a molecular cause of multidrug resistance in a number of cancer types, including ovarian cancer. The present study observed that in ovarian cancer cells, the expression of ABCG2 was significantly upregulated in response to cis-diamminedichloroplatinum (cisplatin/DDP) treatment, in addition the expression of NOS1 exhibited an increasing trend. Additionally, the levels of NOS1 and ABCG2 in chemoresistant ovarian cancer profiles in Gene Expression Omnibus datasets (GSE26712 and GSE51373) were higher than in chemosensitive profiles. Furthermore, overexpression of NOS1 could upregulate ABCG2 expression, and expression of ABCG2 was inhibited by NOS1 selective inhibitor (N-PLA). In assays of cell survival, NOS1 appeared to increase the potential for DDP resistance, and this effect was reversed by addition of ABCG2 inhibitor (verapamil). The present study indicated that NOS1-induced chemoresistance was partly mediated by the upregulation of ABCG2 expression. This result suggests a link between the expression of NOS1 and the ABCG2-associated chemoresistance in ovarian cancer. [ABSTRACT FROM AUTHOR]

Background and Purpose: Sulfonylureas (SUs) have been suggested to have an insulin-independent blood glucose-decreasing activity due to an extrapancreatic effect. However, a lack of adequate in vivo evidence makes this statement controversial. Here, we aimed to evaluate whether glimepiride has extrapancreatic blood glucose-lowering activity in vivo.Experimental Approach: Sulfonylurea receptor 1 deficient (SUR1-/- ) rats were created by means of transcription activator-like effector nucleases (TALEN)-mediated gene targeting technology. Type 2 diabetic models were established by feeding a high-fat diet and administering a low-dose of streptozotocin. These rats were then randomly divided into four groups: glimepiride, gliclazide, metformin and saline. All rats were treated for 2 weeks.Key Results: Glimepiride decreased blood glucose levels and increased insulin sensitivity without elevating insulin levels. Gliclazide showed similar effects as glimepiride. Both agents were weaker than metformin. Further mechanistic investigations revealed that glimepiride increased hepatic glycogen synthesis and decreased gluconeogenesis, which were accompanied by the activation of Akt in the liver. Moreover, glimepiride increased both total and membrane glucose transporter 4 (GLUT4) levels in muscle and fat, which might be attributed to insulin receptor-independent IRS1/Akt activation.Conclusion and Implications: Glimepiride possesses an extrapancreatic blood glucose-lowering effect in vivo, which might be attributed to its direct effect on insulin-sensitive tissues. Therefore, the combination of glimepiride with multiple insulin injections should not be excluded per se. [ABSTRACT FROM AUTHOR]

Background: Our previous research revealed that the apoptosis of proximal tubular epithelial cells (PTECs) occupied a vital position in the early change of diabetic nephropathy (DN) and Bcl-interacting mediator (Bim) was the key factor to be involved in it. Whereas, Bim could also control T cell activation and play a specific regulatory role in other aspects besides inducing cell apoptosis. Changes of podocytes are classic hallmarks of the lesions of DN. Here, the study aims to investigate the specific influence of PTECs which have been damaged on the podocyte injury. Methods: Bim expression in PTECs was modulated, and subsequently podocyte cytoskeleton was determined at different points of time (24, 48, 72 hours) by building transwell co-culture system under high glucose (40mmol/l HG). Results: HG exposure for 48 hours induced the significant changes in podocyte cytoskeleton accompanied with high expression of Bim in PTECs. When co-cultured with PTECs, exacerbated filamentous actin (F-actin) rearrangement and markedly reduced synaptopodin level in podocytes were found compared with single cultured podocytes under HG. Gene knockdown of Bim in PTECs ameliorated above abnormalities in podocytes. Further screening for NFAT subtypes, the key downstream factors of Bim, found that NFAT2 level in PTECs was obviously decreased when suppressing Bim expression. Upregulating NFAT2 disrupted beneficial effects on podocyte F-actin arrangement which was achieved by inhibiting Bim in PTECs. Conclusion: Our preliminary data have indicated that the apoptosis of PTECs mediates the early lesion of DN. It seemed corroborative that there exists crosstalk between PTECs and podocytes; Bim, the pivotal factor related to apoptosis of PTECs participates in the crosstalk by promoting NFAT2 activation, then contributes to injury of podocyte cytoskeleton, emphasizing the role of Bim/NFAT2 pathway in the control of early DN progression from tubular lesions to glomerular abnormalities. Disclosure: C. Xu: None. X. Zhou: None. X. Shen: None. S. Jiang: None. T. Xie: None. Z. Zou: None. Q. Zhang: None. R. Zhang: None. Y. Xing: None. L. Liao: None. J. Dong: None. Funding: National Natural Science Foundation of China (81570742, 81670757, 81770822, 81800732); Shandong Provincial Natural Science Foundation of China (ZR2017LH025); Shandong Provincial Medicine and Health Science and Technology Development Program (2017WS461) [ABSTRACT FROM AUTHOR]

Background/aims: Diabetes affects the entire vascular system and accelerates atherosclerosis and ischemia. Percutaneous transluminal angioplasty with or without stenting is the main therapeutic strategies; however, the restenosis rate is high in diabetics. Sulfonylureas (SUs) are widely prescribed agents for the treatment of type 2 diabetes (T2DM) and function by interacting with sulfonylurea receptors (SURs), which also exists in vascular smooth muscle cells (VSMCs), give rise to the potential that SUs influence VSMCs. The proliferation and migration of VSMCs play important roles in the formations of primary stenosis and restenosis, especially the latter. However, there are no data about the exact effects of SUs on these processes., Methods: Human aortic smooth muscle cells (HASMCs) were exposed to SUs prior to exposure to 30mM glucose. Cell proliferation was detected by CCK8 assay. Cell migration was detected by wound healing assay and transwell assay. Protein expression was determined by immunofluorescence and western blot. Diazoxide was used to evaluate the role of K ATP channel in these processes., Results: The proliferation and migration of HASMCs were significantly aggravated by glibenclamide and glimepiride, and their effects were reversed by diazoxide. In contrast, above characteristics of HASMCs were apparently inhibited by gliclazide, and this was maintained after opening the K ATP channel., Conclusion: These results imply that K ATP channels play an important part in proliferation and migration of VSMCs induced by glibenclamide and glimepiride. In contrast, the inhibitory effect of gliclazide on VSMCs appeared to have more potential for the prevention of vascular obstructive diseases in T2DM., Competing Interests: The authors declare no conflict of interests., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)