As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the ...regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure.
qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay.
Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the "reader" protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis.
Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Postoperative abdominal infectious complication (AIC) is associated with metastasis in locally advanced gastric cancer (GC) patients after radical gastrectomy. However, the underlying mechanism ...remains unclear. Herein, we report that neutrophil extracellular traps (NETs), the DNA meshes released by neutrophils in response to infection, could promote GC cells proliferation, invasion, migration and epithelial-mesenchymal transition dependent on TGF-β signaling. Then we model nude mice with cecal puncture without ligation to simulate postoperative AIC and find that NETs in peripheral blood and ascites fluid facilitate GC cells extravasation and implantation into liver and peritoneum for proliferation and metastasis. Notably, TGF-β signaling inhibitor LY 2157299 could effectively impede liver and peritoneal metastasis but not concurrently aggravate sepsis in those AIC-bearing nude mice. These findings implicate that targeting downstream effectors of NETs such as TGF-β signaling might provide potential therapeutic prospect to reduce the risk of GC metastasis.
Background
Circular RNAs (circRNAs) as a novel subgroup of non-coding RNAs act a critical role in the pathogenesis of gastric cancer (GC). However, the underlying mechanisms by which hsa_circ_0003855 ...(circDUSP16) contributes to GC are still undocumented.
Materials
The differentially expressed circRNAs were identified by GEO database. The association of circDUSP16 or miR-145-5p expression with clinicopathological features and prognosis in GC patients was analyzed by FISH and TCGA-seq data set. Loss- and gain-of-function experiments as well as a xenograft tumor model were performed to assess the role of circDUSP16 in GC cells. circDUSP16-specific binding with miR-145-5p was confirmed by bioinformatic analysis, luciferase reporter, and RNA immunoprecipitation assays.
Results
The expression levels of circDUSP16 were markedly increased in GC tissue samples and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDUSP16 repressed the cell viability, colony formation, and invasive potential in vitro and in vivo, but ectopic expression of circDUSP16 reversed these effects. Moreover, circDUSP16 possessed a co-localization with miR-145-5p in the cytoplasm, and acted as a sponge of miR-145-5p, which attenuated circDUSP16-induced tumor-promoting effects and IVNS1ABP expression in GC cells. MiR-145-5p had a negative correlation with circDUSP16 expression and its low expression was associated with poor survival in GC patients.
Conclusions
CircDUSP16 facilitates the tumorigenesis and invasion of GC cells by sponging miR-145-5p, and may provide a novel therapeutic target for GC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Acknowledging many effects on humans, which are ignored in deterministic models for COVID-19, in this paper, we consider stochastic mathematical model for COVID-19. Firstly, the formulation of a ...stochastic susceptible–infected–recovered model is presented. Secondly, we devote with full strength our concentrated attention to sufficient conditions for extinction and persistence. Thirdly, we examine the threshold of the proposed stochastic COVID-19 model, when noise is small or large. Finally, we show the numerical simulations graphically using MATLAB.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this paper, we considered a new mathematical model depicting the possibility of spread within a given general population. The model is constructed with five classes including susceptible, exposed, ...infected, recovered and deaths. We presented a detailed analysis of the suggested model including, the derivation of equilibrium points endemic and disease-free, reproductive number using the next generation matrix, the stability analysis of the equilibrium points and finally the positiveness of the model solutions. The model was extended to the concept of fractional differentiation to capture different memories including power law, decay and crossover behaviors. A numerical method based on the Newton was used to provide numerical solutions for different memories.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The multitrip pickup and delivery problem with time windows and manpower planning ( MTPDPTW-MP ) determines a set of ambulance routes and finds staff assignment for a hospital. It ...involves different stakeholders with diverse interests and objectives. This study firstly introduces a multiobjective MTPDPTW-MP ( MO-MTPDPTWMP ) with three objectives to better describe the real-world scenario. A multiobjective iterated local search algorithm with adaptive neighborhood selection ( MOILS-ANS ) is proposed to solve the problem. MOILS-ANS can generate a diverse set of alternative solutions for decision makers to meet their requirements. To better explore the search space, problem-specific neighborhood structures and an adaptive neighborhood selection strategy are carefully designed in MOILS-ANS. Experimental results show that the proposed MOILS-ANS significantly outperforms the other two multiobjective algorithms. Besides, the nature of objective functions and the properties of the problem are analyzed. Finally, the proposed MOILS-ANS is compared with the previous single-objective algorithm and the benefits of multiobjective optimization are discussed.
Claudin6 (CLDN6), a member of the tight junction family, is a molecule involved in intercellular adhesion, acting as a physical barrier that prevents solutes and water from freely passing through the ...extracellular space. CLDN6 has important biological functions, and its abnormal expression is associated with Hepatitis C infection. However, there is limited research regarding its role in gastric cancer. In this study, we found that the expression of CLDN6 mRNA and protein was upregulated in gastric cancer cell lines and tissues, which indicated poor prognosis. Both in vitro and in vivo experiments showed that abnormal CLDN6 expression was associated with enhanced proliferation and invasion abilities of gastric cancer. CLDN6 reduced the phosphorylation of LATS1/2 and YAP1 by interacting with LATS1/2 in the Hippo signaling pathway. Thus, CLDN6 affected the entry of YAP1 into the nucleus, causing changes in downstream target genes. Moreover, YAP1 interacted with snail1 to affect the process of EMT and enhanced the invasive ability of GC cells. Collectively, CLDN6 promoted the proliferation and invasive ability of gastric cancer by affecting YAP1 and YAP1-snail1 axis.
Microfluidics has been considered as an effective platform in the mechanism study and large-scale manufacturing of nanomaterials. In this work, we report the facile synthesis of quantum-confined ...CsPbBr3 nanowires (NWs) by using a continuous-flow microfluidic reactor. The optimized reaction temperature is around 50 °C, and one “synthesis run” by microfluidics requires only ten minutes. This study reveals that the formation of CsPbBr3 NWs takes place by a hybrid growth mechanism of seed-mediated growth and oriented attachment growth. This microfluidic approach benefits the alignment of the short quantum-confined NWs and promotes their oriented attachment to form long NWs, while conventional flask synthesis results in large and irregular nanorods under the same reaction conditions. This work not only provides a new synthetic path for the preparation of CsPbX3 NWs but also sheds some light on the fundamental study of CsPbX3 NWs.
Computer virus has caused terrible damage. Establishing appropriate mathematical model is beneficial for comprehending the propagation regular pattern of computer virus. So, in this paper, we build a ...new Susceptible-Exposed-Infected-Kill signals-Recovered (SEIR-KS) computer virus model with two delays. At first, we obtain the basic regeneration number. Afterwards, we regard time delays as parameters and investigate the local stability and Hopf bifurcation of the endemic equilibrium by discussing the distribution of the eigenvalues of the corresponding characteristic equation. Then, we research direction and stability of Hopf bifurcation. In addition, we take some numerical simulations by Matlab to validate the correctness of theoretical results. At last, we analyze the basic reproductive rate and put forward some scientific advices.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
In this manuscript, we investigate a novel Susceptible–Exposed–Infected–Quarantined–Recovered (SEIQR) COVID-19 propagation model with two delays, and we also consider supply chain transmission and ...hierarchical quarantine rate in this model. Firstly, we analyze the existence of an equilibrium, including a virus-free equilibrium and a virus-existence equilibrium. Then local stability and the occurrence of Hopf bifurcation have been researched by thinking of time delay as the bifurcation parameter. Besides, we calculate direction and stability of the Hopf bifurcation. Finally, we carry out some numerical simulations to prove the validity of theoretical results.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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