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Abstract Background Bladder cancer (BC) is the most common urinary tract malignancy. Aurora kinase B (AURKB), a component of the chromosomal passenger protein complex, affects chromosomal segregation during cell division. Mitotic arrest-deficient 2-like protein 2 (MAD2L2) interacts with various proteins and contributes to genomic integrity. Both AURKB and MAD2L2 are overexpressed in various human cancers and have synergistic oncogenic effects; therefore, they are regarded as emerging therapeutic targets for cancer. However, the relationship between these factors and the mechanisms underlying their oncogenic activity in BC remains largely unknown. The present study aimed to explore the interactions between AURKB and MAD2L2 and how they affect BC progression via the DNA damage response (DDR) pathway. Methods Bioinformatics was used to analyze the expression, prognostic value, and pro-tumoral function of AURKB in patients with BC. CCK-8 assay, colony-forming assay, flow cytometry, SA-β-gal staining, wound healing assay, and transwell chamber experiments were performed to test the viability, cell cycle progression, senescence, and migration and invasion abilities of BC cells in vitro. A nude mouse xenograft assay was performed to test the tumorigenesis ability of BC cells in vivo. The expression and interaction of proteins and the occurrence of the senescence-associated secretory phenotype were detected using western blot analysis, co-immunoprecipitation assay, and RT-qPCR. Results AURKB was highly expressed and associated with prognosis in patients with BC. AURKB expression was positively correlated with MAD2L2 expression. We confirmed that AURKB interacts with, and modulates the expression of, MAD2L2 in BC cells. AURKB knockdown suppressed the proliferation, migration, and invasion abilities of, and cell cycle progression in, BC cells, inducing senescence in these cells. The effects of AURKB knockdown were rescued by MAD2L2 overexpression in vitro and in vivo. The effects of MAD2L2 knockdown were similar to those of AURKB knockdown. Furthermore, p53 ablation rescued the MAD2L2 knockdown-induced suppression of BC cell proliferation and cell cycle arrest and senescence in BC cells. Conclusions AURKB activates MAD2L2 expression to downregulate the p53 DDR pathway, thereby promoting BC progression. Thus, AURKB may serve as a potential molecular marker and a novel anticancer therapeutic target for BC.

IntroductionNitrogen (N) and phosphorus (P) enrichment due to anthropogenic activities can significantly affect soil N transformations in forest ecosystems. However, the effects of N and P additions on nitrification and denitrification processes in Metasequoia glyptostroboides plantations, and economically important forest type in China, remain poorly understood.MethodsThis study investigated the responses of soil nitrification and denitrification rates, as well as the abundances of nitrifiers and denitrifiers, to different levels of N and P additions in a 6-year nutrient addition experiment in a M. glyptostroboides plantation.ResultsStepwise multiple regression analysis was used to identify the main predictors of nitrification and denitrification rates. The results showed that moderate N addition (N2 treatment, 2.4 mol·m-2) stimulated nitrification rates and abundances of ammonia-oxidizing archaea (AOA) and bacteria (AOB), while excessive N and P additions inhibited denitrification rates and reduced the abundance of nirS-type denitrifiers. AOB abundance was the main predictor of nitrification rates under N additions, whereas microbial biomass carbon and nirS gene abundance were the key factors controlling denitrification rates. Under P additions, tree growth parameters (diameter at breast height and crown base height) and AOB abundance were the primary predictors of nitrification and denitrification rates.DiscussionOur study reveals complex interactions among nutrient inputs, plant growth, soil properties, and microbial communities in regulating soil N transformations in plantation forests. This study also offers valuable insights for formulating effective nutrient management strategies to enhance the growth and health of M. glyptostroboides plantations under scenarios of increasing elevated nutrient deposition.

Summary: p53 regulates multiple signaling pathways and maintains cell homeostasis under conditions of DNA damage and oxidative stress. Although USP7 has been shown to promote p53 stability via deubiquitination, the USP7-p53 activation mechanism has remained unclear. Here, we propose that DNA damage induces reactive oxygen species (ROS) production and activates ATM-CHK2, and CHK2 then phosphorylates USP7 at S168 and T231. USP7 phosphorylation is essential for its deubiquitination activity toward p53. USP7 also deubiquitinates CHK2 at K119 and K131, increasing CHK2 stability and creating a positive feedback loop between CHK2 and USP7. Compared to peri-tumor tissues, thyroid cancer and colon cancer tissues show higher CHK2 and phosphorylated USP7 (S168, T231) levels, and these levels are positively correlated. Collectively, our results uncover a phosphorylation-deubiquitination positive feedback loop involving the CHK2-USP7 axis that supports the stabilization of p53 and the maintenance of cell homeostasis.

Herbaceous plants contribute greatly to plant diversity and play an important role in regulating the structure and functioning of forest ecosystems. Comparing with woody species, herbs exhibit higher sensitivity to seasonal changes from spring-growth to autumn-mortality. Despite extensive research on understory herb diversity (e.g., abundance and richness) in forests, how the underlying mechanisms change across seasons remain unclear, especially in temperate forests. We explored the seasonal dynamics of herb diversity (here abundance and richness) by surveying herbs of 174 quadrats (1 m × 1 m) in a 25-ha (500 m × 500 m) temperate forest in spring, summer, and autumn of 2022, respectively. We examined the effects of overstory trees (diversity, composition, and three-dimensional (3D) structural complexity detected by LiDAR), topography (elevation, slope, and aspect), and microsite conditions (light availability, soil nutrients, and soil water content) on herb diversity in different seasons. We found a similar seasonal pattern for herb abundance and richness, i.e., both decreased from spring to summer and then to autumn, but the driving mechanisms differed remarkably across seasons. Specifically, the importance of overstory trees, topography, and microsite conditions on herb abundance vs. richness varied inversely across seasons. For herb abundance, the importance of overstory trees (primarily 3D structural complexity) increased from spring to autumn, while the importance of topography decreased. Conversely, for herb richness, the importance of overstory trees decreased from spring to autumn, while the importance of topography increased. Microsite conditions governed spatial variations of herb abundance in all seasons but only in autumn for herb richness, with importance of soil nutrients remaining relatively constant while that of soil water content and light availability changed greatly across seasons. Our results demonstrate substantial seasonal variations in driving mechanisms of herb diversity in the temperate forest. These differentiated responses of herb abundance and richness to different drivers across seasons further highlight the significance of considering seasonal variations of the mechanisms underlying understory plant diversity in forest biodiversity conservation.

Phenolic resin pyrolytic carbons were obtained by catalytic pyrolysis of phenolic resin at 500 °C, 600 °C, 700 °C, and 800 °C for 3 h in an argon atmosphere using copper nitrate as a catalyst precursor. The effects of copper salts on the pyrolysis process of phenolic resin as well as the structural evolution and oxidation resistance of phenolic resin pyrolytic carbons were studied. The results showed that copper oxide (CuO) generated from the thermal decomposition of copper nitrate was reduced to copper (Cu) by the gas generated from the thermal decomposition of the phenolic resin. Carbon nanofibers with tapered structures were synthesized by Cu catalysis of pyrolysis gas at 500–800 °C. The catalytic pyrolysis of phenolic resin with Cu increased the graphitization degree and reduced the pore volume of the phenolic resin pyrolytic carbons. The combined action improved the oxidation resistance of phenolic resin pyrolytic carbons.

A novel method is introduced in this study for producing ceramisite coarse aggregates that are both lightweight and possess high strength. The process involves utilizing fly ash as the primary material, along with coal ash floating beads (CAFBs) that have high softening temperature and a spherical hollow structure serving as the template for forming pores. This study examined the impact of varying particle size and quantity of floating beads on the composition and characteristics of ceramisite aggregates. Results showed that the high softening temperature of floating beads provided stability to the spherical cavity structure throughout the sintering process. Furthermore, the pore structure could be effectively tailored by manipulating the size and quantity of the floating beads in the manufacturing procedure. The obtained ceramisite aggregates feature a compact outer shell and a cellular inner core with uniformly distributed pores that are isolated from each other and mostly spherical in form. They achieve a low density ranging from 723 to 855 kg/m3, a high cylinder compressive strength between 8.7 and 13.5 MPa, and minimal water absorption rates of 3.00 to 4.09%. The performance metrics of these coarse aggregates significantly exceeded the parameters specified in GB/T 17431.1-2010 standards.

Nickel-based coatings were prepared by laser cladding assisted with rotating magnetic field on mild steel substrates. The effects of rotating magnetic field on the defects, microstructure, residual stress, microhardness, and wear resistance of the coatings were studied. Results revealed that the rotating magnetic field reduced pores and cracks of the nickel-based coatings. The nickel-based coatings are main composed of γ-(Ni, M), CrB, M23C6, and NbC phases. The average grain size of the coating decreased from 0.67 μm2 to 0.49 μm2 with rotating magnetic field assistance. The number of large-angle grain boundaries was increased too. At the same time, the residual stress in the coating was significantly reduced by the rotating magnetic field. Therefore, the cracking tendency of the coating was reduced. The average microhardness of the nickel-based coating increased from 422.5 HV0.2 to 515.5 HV0.2 due to fine-grain strengthening. The wear mechanisms of the coatings were mix of abrasive wear and adhesive wear. With rotating magnetic field assistance, the wear resistance of the coating was greatly enhanced. The wear rate of the coating reduced 83.7% from 85.2 μm3/(N∗m) to 13.9 μm3/(N∗m). The wear weight loss reduced 87% from 13.8 mg to 1.8 mg.

The non-uniformity of temperature field distribution of long-span steel structure is proportional to the intensity of solar radiation. Based on the background of Guangzhou Baiyun Station large-span complex steel roof structure, this paper studies the non-uniformtemperature field distribution of large-span steel structure under the Summer Solstice daily radiation-thermal-fluid coupling action based on Star-ccm¸ finite element software, and uses Spa2000 software to analyze the stress and deformation of steel roof under temperature action. Combined with the on-site temperature monitoring, the maximum difference with the measured value is 2.5˚C compared with the numerical simulation results, which verifies the validity of the finite element simulation. The results show that: from 8:00, with the increase of solar altitude angle, the intensity of solar radiation increases, the temperature rises, and the temperature distribution of large-span steel structure becomes more and more non-uniform. From14:00 to18:00, the solar radiation weakens, and the temperature distribution tends to be uniform. Finally, reasonable construction suggestions and measures are proposed to reduce the adverse effects of temperature effects, which can provide theoretical references for the safe construction and normal operation of large-span steel structures located in the subtropics.

Bio-degradation of poly(butylene adipate-co-terephthalate) is an attractive tactic but requires an effective hydrolytic enzyme. Here, the authors demonstrate that cutinases are highly potent PBAT-decomposing enzymes and their mechanism is proposed based on substrate-binding mode.

With the rapid development of civil aviation, carbon emissions have brought severe environmental problems. Realizing efficient and sustainable carbon emission reduction is of great significance for achieving green development in civil aviation sector. Therefore, in the process of pursuing civil aviation carbon emission reduction goals, it is necessary to further consider how to achieve emission reduction at the lowest cost. Based on the accurate carbon emission performance evaluation, the carbon abatement cost among different representative airlines have been systematically compared. The main work and findings of this study can be summarized in the following three aspects. Firstly, a new nonparametric shadow price measurement method was constructed based on the Slacks-Based Measurement Data Envelopment Analysis (SBM-DEA). This can better reflect the essence of efficiency evaluation and the calculated shadow price results are more consistent with the real market. Secondly, the average value of carbon emission efficiency has experienced a fluctuating downward trend from 2011 to 2017, indicating that the carbon emission efficiency of global airlines has decreased. Thirdly, the average value of the shadow price is generally between 313.4 and 398.4 dollars/ton, showing an “up-down-up” trend, and reaching a peak of 398.4 dollars/ton in 2014. This can provide a basis for low-carbon policy makers in the civil aviation sector, and also provide reference for different types of airlines to achieve low-cost emission reduction.

Abstract tRNA-derived fragments (tRFs) are an emerging category of small non-coding RNAs that are generated from cleavage of mature tRNAs or tRNA precursors. The advance in high-throughput sequencing has contributed to the identification of increasing number of tRFs with critical functions in distinct physiological and pathophysiological processes. tRFs can regulate cell viability, differentiation, and homeostasis through multiple mechanisms and are thus considered as critical regulators of human diseases including cancer. In addition, increasing evidence suggest the extracellular tRFs may be utilized as promising diagnostic and prognostic biomarkers for cancer liquid biopsy. In this review, we focus on the biogenesis, classification and modification of tRFs, and summarize the multifaceted functions of tRFs with an emphasis on the current research status and perspectives of tRFs in cancer.

WTaNbMo refractory high entropy alloy (RHEA) coatings were prepared by laser cladding assisted with reciprocating dynamic magnetic field on Inconel 718 substrates. The effects of dynamic magnetic field on the microstructure, defects and residual stress were discussed. The results show that the reciprocating magnetic field improves the microstructure homogeneity of the laser cladded WTaNbMo coating. The coatings are composed of WTaNbMo solid solution (BCC) and γ-(Ni, M). With reciprocating magnetic field assistance, the flow in the molten pool is accelerated, porosity is reduced. The residual stress inside the coating is depressed, thereby cracks in the coating are inhibited. The flow behavior in the molten pools was also discussed.

With the rapid development of the underwater Internet of Things (IoT), the number of underwater communication nodes is rapidly increasing. The access capacity of a traditional multi-antenna communication system is limited by the number of transmitting antennas, and multi-beam communication systems using non-orthogonal multiple access (NOMA) technology can enhance the access capacity of the system. However, this can lead to serious inter-beam and intra-beam interference. To address the severe issues of inter-beam and intra-beam interference in underwater multi-beam NOMA systems, we propose an adaptive transmit diversity strategy. We design an algorithm for adaptive selection and merging beams based on the degree of interference between beams in space, which merges LED beams with high interference. Diversity technology is used to reduce interference between beams, and spatial multiplexing is still performed between LED groups with low interference. Within the same beam, we use an OFDM-NOMA scheme to match and group the users. Signals from different user groups are sent through different subcarriers to improve resource utilization. This enhances access capacity while reducing NOMA inter-user interference. Simulation results show that the bit error rate (BER) of users with the adaptive transmit diversity strategy satisfies the forward error correction (FEC) limits in the presence of high inter-beam interference and has a better reachable rate and BER performance compared to the multi-beam access system without interference management. We also analyze the system BER performance of the proposed strategy in the multi-user case, and the BER of all 32 access nodes are lower than the FEC threshold at a communication distance of 5 m. This demonstrates that the strategy can effectively reduce the interference of the multi-beam NOMA system.

Abstract The long noncoding RNA (lncRNA) DLGAP1-AS2 has recently been characterized as an oncogenic lncRNA in several cancers. However, its biological roles and clinical significance in gastric cancer (GC) remains barely understood. In this study, we performed a systematic analysis of DLGAP1-AS2 expression with data from the TCGA and GEO database as well as our clinic GC samples. In agreement with previous studies, our findings demonstrated that DLGAP1-AS2 was significantly up-regulated in GC and its high expression was associated with poor prognosis, suggesting that DLGAP1-AS2 might be a putative oncogenic lncRNA of GC. Loss of DLGAP1-AS2 restricted cell proliferation, migration, and invasion in GC cell lines. Mechanically, Wnt1 was identified as the downstream target of DLGAP1-AS2 by using bioinformatics analysis coupled with qPCR and Western blot assays. Furthermore, DLGAP1-AS2 was found to directly interact with the transcriptional repressor Six3, and this interaction hampered Six3 binding to the promoter regions of the Wnt1 gene, thereby leading to transcriptional activation of Wnt1. Consequently, GC cells lacking DLGAP1-AS2 showed a decreased Wnt1 expression and weakened Wnt/β-catenin signaling. Further, Six3 silencing could reverse the above effects, highlighting a pivotal role of Six3 in the DLGAP1-AS2-mediated activation of Wnt/β-catenin signaling. Either genetic (Wnt1 knockdown) or pharmacological (LF3) inhibition of Wnt/β-catenin signaling could effectively abolish the activation of Wnt/β-catenin signaling by Six3 depletion, thereby preventing GC cell malignant transformation. Taken together, our results suggest that DLGAP1-AS2 functions as an oncogenic factor by directly interacting with Six3 to relieve its suppression on Wnt1 expression, thereby driving the malignancy of GC. DLGAP1-AS2/Six3/Wnt1/β-catenin signaling axis might serve as a promising diagnostic and therapeutic target for GC.

Mycoplasma hyopneumoniae is a highly contagious pathogen causing porcine enzootic pneumonia, which elicits prolonged inflammatory response modulated by pattern recognition receptors (PRRs). Although significant advances have been achieved in understanding the Toll-Like receptors that recognize M. hyopneumoniae, the role of nucleotide-binding oligomerization domain 1 (NOD1) in M. hyopneumoniae infected cells remains poorly understood. This study revealed that M. hyopneumoniae activates the NOD1-RIP2 pathway and is co-localized with host NOD1 during infection. siRNA knockdown of NOD1 significantly impaired the TRIF and MYD88 pathway and blocked the activation of TNF-α. In contrast, NOD1 overexpression significantly suppressed M. hyopneumoniae proliferation. Furthermore, we for the first time investigated the interaction between M. hyopneumoniae mhp390 and NOD1 receptor, and the results suggested that mhp390 and NOD1 are possibly involved in the recognition of M. hyopneumoniae. These findings may improve our understanding of the interaction between PRRs and M. hyopneumoniae and the function of NOD1 in host defense against M. hyopneumoniae infection.

Growing evidence has shown the oncogenic function of matrix metallopeptidase 7 (MMP7) in various tumors. However, no systemic pan-cancer analysis on the association between MMP7 and different cancers based on big clinical data is available. TIMER2, GEPIA2, UALCAN, cBioPortal, String, Metascape, and other web databases were searched in the present study. Generally, MMP7 expression is significantly upregulated in most The Cancer Genome Atlas (TCGA) cancer types compared to the paired normal controls, yet is downregulated in tumor tissues of invasive breast carcinoma (BRCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and skin cutaneous melanoma (SKCM). MMP7 protein expression is notably higher in the primary tumor tissues of colon cancer, lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC) than in normal tissues and is significantly lower in the primary tumor tissues of breast cancer, clear cell renal carcinoma, and ovarian cancer. Furthermore, MMP7 expression is strongly associated with pathological stages, clinical outcomes, tumor mutational burden (TMB), and microsatellite instability (TSI). Gene amplification was detected in most TCGA cancer types. In addition, the missense mutation is the primary type of MMP7 genetic alteration in tumors. Significant positive correlations between MMP7 expression and cancer-associated fibroblasts (CAFs) have been demonstrated in most TCGA cancers. MMP7 expression was also found to be positively correlated with infiltration of dendritic cells and macrophages in some specific tumor types. Functional enrichment analysis by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO) methods revealed that RNA processing and DNA damage checkpoints might reveal the pathogenetic mechanisms of MMP7. This pan-cancer analysis provides a clear panorama for the tumorigenic roles of MMP7 across different cancer types. Moreover, MMP7 could be a potential drug therapeutic target in such cancers.

Little is known about the genetic alterations characteristic of ovarian clear cell carcinoma (OCCC). Our aim was to identify targetable genomic alterations in this type of cancer. Forty-two OCCC formalin-fixed, paraffin-embedded (FFPE) tissue samples were analyzed by whole-exome sequencing (WES), and 74 FFPE tissue samples underwent targeted sequencing (TS) to confirm the relevant driver mutations. Cell proliferation was assessed by cell counting kit-8 (CCK8) assays. In the 42 samples, ARID1A (64.3%) and PIK3CA (28.5%) were frequently mutated, as were PPP2R1A (11.9%), PTEN (7.1%) and KRAS (4.8%), which have been reported in previous OCCC studies. We also detected mutations in MUC4 (28.6%), MAGEE1 (19%), and ARID3A (16.7%); associations with these genes have not been previously reported. The functional protein-activated pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 83% of OCCCs and with chromatin remodeling in 71% of OCCCs. Patients with alterations in MAGEE1 (64% in the targeted sequencing cohort) had worse clinical outcomes (log-rank p

A 3D dynamic finite element model is developed to study the response of the existing tunnels’ concrete structure under the influence of different train speeds and undercrossing with fixed shield excavation. The intersection area of Metro Line 3 in Guangzhou and the intercity railway between Foshan and Dongguan is used as the case study. A programming idea simulating oblique moving-axle loads in the numerical model by using function expressions to constrain activity area is proposed. The Hilber–Hughes–Taylor time-integration scheme is used to calculate the dynamic response parameters of the double-channel rectangular cross section tunnels. Considering fixed excavation steps in the process of shield crossing, acceleration and deformation of the existing tunnels were analyzed under the moving-axle loads of trains at different speeds. From the perspective of the vibration and deformation of existing tunnels, shield excavation and moving speed have their own emphasis on the dynamic influence of the existing tunnel. In addition, the calculation results of the numerical simulation are in good agreement with the data obtained from some field tests, which further verifies the reliability of the calculation method of the numerical model. The results of this research can guide the arrangements for reinforcement measures for existing tunnels in the later stage.

The vibration-based analysis is an effective technique for planetary gearbox fault diagnosis, but a difficult task is how to accurately identify fault features from noisy vibration signals. In this paper, a nonconvex wavelet thresholding total variation (WATV) denoising method is proposed for planetary gearbox fault diagnosis, which combines wavelet-domain sparsity and total variation (TV) regularization. The TV regularization algorithm is employed to modify the retained wavelet coefficients so that the occurrence of oscillations caused by wavelet thresholding is suppressed. To overcome the underestimation shortcoming of L1-norm regularization, nonconvex penalty function regularization is used to strongly promote the sparsity of estimation while guaranteeing that the global optimal solutions are obtained even though the objective function is nonconvex. Then, the split augmented Lagrangian shrinkage (SALSA) method is developed to solve the nonconvex WATV denoising problem. Two experimental studies are performed to verify the performance and effectiveness of the proposed method. Comparisons with the soft thresholding and basis pursuit denoising (BPD) methods show that the proposed method can accurately estimate the fault features from vibration signals, which means that the proposed method is an effective and promising tool for planetary gearbox fault diagnosis.

The nonlinear bending of the sandwich plates with graphene nanoplatelets (GPLs) reinforced porous composite (GNRPC) core and two metal skins subjected to different boundary conditions and various loads, such as the concentrated load at the center, linear loads with different slopes passing through the center, linear eccentric loads, uniform loads, and trapezoidal loads, has been presented. The popular four-unknown refined theory accounting for the thickness stretching effects has been employed to model the mechanics of the sandwich plates. The governing equations have been derived from the nonlinear Von Karman strain–displacement relationship and principle of virtual work with subsequent solution by employing the classical finite element method in combination with the Newton downhill method. The convergence of the numerical results has been checked. The accuracy and efficiency of the theory have been confirmed by comparing the obtained results with those available in the literature. Furthermore, a parametric study has been carried out to analyze the effects of load type, boundary conditions, porosity coefficient, GPLs weight fraction, GPLs geometry, and concentrated load radius on the nonlinear central bending deflections of the sandwich plates. In addition, the numerical results reveal that the adopted higher order theory can significantly improve the simulation of the transverse deflection in the thickness direction.

The Exocrine Differentiation and Proliferation Factor (EXDPF) gene could promote exocrine while inhibit endocrine functions. Although it is well known that ovary is an endocrine organ, the functions of EXDPF in ovarian cancer development is still unknown. This study demonstrated that EXDPF gene is significantly higher expressed in ovarian tumors compared to normal ovarian tissue controls. EXDPF DNA amplification was exhibited in lots of human tumors including 7.19% of ovarian tumors. Also, high expression of EXDPF positively correlated with poor overall survival (OS) of ovarian cancer patients. EXDPF expression could be universally detected in most epithelial ovarian cancer cells (SKOV3, IGROV1, MACS, HO8910PM, ES2, COV362 and A2780) tested in this study. Knock-down of EXDPF by siRNA delivered by plasmid or lentivirus largely inhibited ovarian cancer cells, IGROV1 and SKOV3 proliferation, migration and tumorigenesis in vitro and/or in vivo. Knock-down of EXDPF sensitized SKOV3 cells to the treatment of the front-line drug, paclitaxel. Mechanism study showed that EXDPF enhanced DNA replication pathway to promote ovarian cancer tumorigenesis. In conclusion, this study demonstrated that EXDPF could be a potential therapeutic target as a pro-oncogene of ovarian cancer.

Abstract Exosomes are nanosized extracellular vesicles that can be released by almost all types of cells. Initially considered as the garbage bins acting to discard unwanted products of cells, exosomes are now recognized as an important way for cellular communication by transmitting bioactive molecules including proteins, DNA, mRNAs, and non-coding RNAs. The recent studies have shown that exosomes are critically involved in human health and diseases including cancer. Exosomes have been suggested to participate in the promotion of tumorigenesis, tumor growth and metastasis, tumor angiogenesis, tumor immune escape, and tumor therapy resistance. Increasing evidence indicate that exosomes play important roles in gastric cancer development and progression. In this review, we summarized the current understanding of exosomes in gastric cancer with an emphasis on the biological roles of exosomes in gastric cancer and their potential as biomarkers for gastric cancer diagnosis as well as potential targets for gastric cancer therapy.

Abstract Background Exosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function of tumor-derived exosomes in neutrophil regulation remains unclear. Methods We investigated the effects of gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils and elucidated the underlying mechanisms. Results GC-Ex prolonged neutrophil survival and induced expression of inflammatory factors in neutrophils. GC-Ex-activated neutrophils, in turn, promoted gastric cancer cell migration. GC-Ex transported high mobility group box-1 (HMGB1) that activated NF-κB pathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils. Blocking HMGB1/TLR4 interaction, NF-κB pathway, and autophagy reversed GC-Ex-induced neutrophil activation. Silencing HMGB1 in gastric cancer cells confirmed HMGB1 as a key factor for GC-Ex-mediated neutrophil activation. Furthermore, HMGB1 expression was upregulated in gastric cancer tissues. Increased HMGB1 expression was associated with poor prognosis in patients with gastric cancer. Finally, gastric cancer tissue-derived exosomes acted similarly as exosomes derived from gastric cancer cell lines in neutrophil activation. Conclusion We demonstrate that gastric cancer cell-derived exosomes induce autophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-κB signaling, which provides new insights into mechanisms for neutrophil regulation in cancer and sheds lights on the multifaceted role of exosomes in reshaping tumor microenvironment.

Hypothesis: The role of non-cardiomyocytes in cardiac remodeling and fibrosis has not been totally understood until now. This study investigated if endothelial cell (EC)-specific calpain participates in myocardial endothelial injury via the endothelial- mesenchymal transition (EndMT) and in cardiac fibroblasts during cell proliferation, thereby contributing to cardiac fibrosis eventually. Methods: in vitro cultured mouse cardiac ECs were induced with transforming growth factor (TGF)-β1 (10 ng/ml) and calpain inhibitor III (20 μM) or Akt inhibitor (LY294002, 20 μM). Isolated cardiac fibroblasts were induced by TGF-β1 and an HSP90 inhibitor (17AAG, 20 μM), and EndMT were analysed. Capn4-knockout (KO) specific to ECs of mice was generated. We induced the pathological process mimicking cardiac hypertrophy and fibrosis in both Capn4-KO mice and their wild-type littermates. The histological analysis was used to measure cardiomyocyte size and collagen contained in the heart. The immunofluorescence analysis was performed to demonstrate that the ECs went through the EndMT, transforming mesenchymal cells into fibroblasts and myofibroblasts. Results: Capn4 deletion specific to ECs abrogated activity of both calpain 1 and calpain 2 in ECs, lowered the volume of cardiac collagen and cardiomyocytes size, and ameliorated myocardial dysfunction in the isoproterenol-treated cardiac fibrosis model. An ex vivo analysis of cardiomyocytes by Evans Blue staining revealed that isoproterenol increased cell death compared with the control, and Capn4-KO alleviated this result. Inhibiting calpain in cultured cardiac microvascular endothelial cells (MCECs) reversed the EndMT process, which was induced by TGF-β1. Overexpression of calpastatin decreased the pathological EndMT process, showing that the cultured MCECs have more mesenchymal markers, such as α-smooth muscle actin (SMA), and fewer endothelial markers, such as VE-cadherin. Activating calpain elevated phosphorylated Akt in mice cultured ECs, and inhibiting calpain decreased phosphorylated Akt. Upregulation of phosphorylated Akt by calpain promoted the EndMT, whereas inhibiting calpain switched on the protective mechanism during the EndMT via the heat shock protein (HSP)90/Akt signaling way in cultured ECs. Conclusions: This study demonstrated a vital role of calpain in ECs for inducing myocardiocyte hypertrophy, cell death and the EndMT via the HSP90/Akt signaling pathway, thereby promoting cardiac fibrosis. The results indicate that inhibiting ECs calpain is a novel therapeutic target to retard cardiac fibrosis and has positive effects on heart failure.

The use of the convolutional neural network for fault diagnosis has been a common method of research in recent years. Since this method can automatically extract fault features, it has played a good role in some research studies. However, this method has a clear drawback that the signals will be significantly affected by working conditions and sample size, and it is difficult to improve diagnostic accuracy by directly learning faults, regardless of working conditions. It is therefore a research orientation worthy of a diagnosis of high precision defect in various working conditions. In this article, using a fine-grained classification algorithm, the operating conditions of the object system are considered an approximate classification. A specific failure in different working conditions is considered a beautiful classification. Samples of different faults in different working conditions are learned uniformly and the common characteristics are extracted from the convolutional network so that different faults of different working conditions can simultaneously be identified on the basis of the entire sample. Experimental results show that the method effectively uses the set of samples of the working conditions of the variables to obtain the dual recognition of defects and specific working conditions and the accuracy of the recognition is significantly higher than the method of learning regardless of working conditions.

Abstract Background Long non-coding RNAs (lncRNAs) have emerged as important regulators of human cancers. However, the functional roles of lncRNAs and the mechanisms responsible for their aberrant expression in gastric cancer (GC) have not been well characterized. Methods In this study, we examined the expression of lncRNA UFC1 in GC by qRT-PCR and explored its correlation with clinicopathological parameters. In vitro cell functional assays and in vivo animal studies were performed to determine the roles of UFC1 in GC progression. Results UFC1 was elevated and predicted poorer prognosis in GC. UFC1 knockdown inhibited while UFC1 overexpression promoted GC cell proliferation, migration, and invasion. UFC1 bound to miR-498 to antagonize its tumor suppressive effect on Lin28b. Suppression of Lin28b by miR-498 could be rescued by UFC1 overexpression, whereas Lin28b overexpression partially rescued UFC1 knockdown-mediated inhibition of GC cell function. Lin28b expression was increased in GC and suggested a co-expression pattern with UFC1. Conclusions UFC1 has a promoting role in GC progression, at least in part, by acting as a miR-498 sponge and derepressing Lin28b expression, which would provide a novel biomarker for GC diagnosis and prognosis and offer a potential target for GC therapy.

Background/Aims: Emerging evidence points towards an important role of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of gastric cancer (GC). MT1JP has recently been reported to be differentially expressed and act as a tumor suppressor in different tumors, with its mechanisms not fully understood in GC. Methods: RT-qPCR was used to detect the expression of MT1JP, miR-214-3p and RUNX3 in tumor tissues and cell lines of GC. The CCK-8 assay, colony formation, Transwell assay and wound healing assay were used to evaluate the proliferation, invasion and migration of GC cells, respectively. Bioinformatics analysis and luciferase reporter assay were performed to disclose the interaction between MT1JP, miR-214-3p and RUNX3. Western blot and immunofluorescence were applied to assess the downstream signaling of RUNX3. Results: MT1JP was found downregulated in GC tissues and cells. Low expression of MT1JP was significantly correlated with advanced TNM stage and lymphatic metastasis. The expression of plasma MT1JP was also found decreased in GC patients compared to healthy controls, with an area under the ROC curve (AUC) of 0.649 for diagnosis of GC. Gain- and loss-of-function of MT1JP revealed that MT1JP functioned as a ceRNA for miR-214-3p to facilitate RUNX3 expression and then upregulated p21 and Bim levels suppressing GC cell proliferation, invasion and migration, and promoting apoptosis. Furthermore, MT1JP overexpression suppressed tumor growth and inhibited the expression of miR-214-3p and proliferation antigen Ki-67, but increased the expression of RUNX3, p21 and Bim in vivo. Conclusions: Our results suggest a potential ceRNA regulatory network involving MT1JP regulates RUNX3 expression by competitively binding endogenous miR-214-3p in tumorigenesis and progression of GC. This mechanism may contribute to a better understanding of GC pathogenesis and provide potential therapeutic strategy for GC.

Abstract Background The recurrence, metastasis and poor prognosis are important characteristics of ovarian carcinoma (OC), which are associated with exfoliation of cells from the primary tumor and colonization of the cells in pelvic cavity. On the other hand, the life quality of the patients undergoing surgical resection of OC was influenced by postoperative adhesions. Therefore, preventing postoperative implant tumor and adhesion may be effective methods to improve OC treatment. HyaRegen Gel, a cross-linked hyaluronan gel (CHAG), has been widely used as an anti-adhesive agent following pelvic operation in clinic. However, whether it can affect the implantation and growth of OC cells or not is still not clear. Methods Migration and invasion assays were applied to detect the effect of CHAG on migration and invasion of OC cells. Western blotting was performed to detect the phosphorylation/activation of EGFR and ERK, and the expression of PCNA and MMP7. Pull down assay was used to analyze the effect of CHAG on the activation of small G protein Rac1. Nude mice implantation tumor model was applied to observe the effect of CHAG on implantation tumor of OC cells. Results The results of in vitro experiments showed that CHAG suppressed both basic and EGF-induced migration and invasion of OC cells, blocked the activation of EGF-initiated EGFR activation, inhibited downstream signal transduction of EGFR, and decreased expression of proliferation and migration/invasion related proteins. Meanwhile, results of in vivo experiments showed that CHAG not only inhibited the formation of implantation tumor of OC cells but also delayed the of the growth of the tumors. Conclusions CHAG inhibited migration, invasion and proliferation of OC cells in vitro, and suppressed development of implantation tumor of OC in vivo. This made it as both anti-tumor and anti-adhesion agents.

Novel inhibitors are urgently needed for use as targeted therapies to improve the overall survival (OS) of patients with ovarian cancer. Here, we show that cell division cycle 25B (CDC25B) is over-expressed in ovarian tumors and associated with poor patient prognosis. All previously reported CDC25B inhibitors have been identified by their ability to reversibly inhibit the catalytic dephosphorylation activity of CDC25B in vitro; however, none of these compounds have entered clinical trials for ovarian cancer therapy. In this study, we synthesized a novel small molecule compound, WG-391D, that potently down-regulates CDC25B expression without affecting its catalytic dephosphorylation activity. The inhibition of CDC25B by WG-391D is irreversible, and WG-391D should therefore exhibit potent antitumor activity against ovarian cancer. WG-391D induces cell cycle progression arrest at the G2/M phase. Half maximal inhibitory concentration (IC50) values of WG-391D for inhibition of the proliferation and migration of eight representative ovarian cancer cell lines (SKOV3, ES2, OVCAR8, OVTOKO, A2780, IGROV1, HO8910PM, and MCAS) and five primary ovarian tumor cell lines (GFY004, GFY005, CZ001, CZ006, and CZ008) were lower than 10 and 1 μM, respectively. WG-391D inhibited tumor growth in nude mice inoculated with SKOV3 cells or a patient-derived xenograft (PDX). The underlying mechanisms were associated with the down-regulation of CDC25B and subsequent inactivation of cell division cycle 2 (CDC2) and the serine/threonine kinase, AKT. In conclusion, this study demonstrates that WG-391D exhibits strong antitumor activity against ovarian cancer and indicates that the down-regulation of CDC25B by inhibitors could provide a rationale for ovarian cancer therapy.

Background: microRNAs (miRNAs) are small non-coding RNAs and have been shown to play a crucial role in the colorectal cancer (CRC) tumorigenesis and progression. The aim of this study was to investigate the clinical significance and prognostic value of miR-140-5p in CRC. The exact functions and the underlying molecular mechanisms of miR-140-5p in CRC was further determined. Methods: miR-140-5p expression was detected in CRC samples, their adjacent nontumor tissues as well as CRC cell lines by RT-qPCR. Cell proliferation was detected using CCK-8, and cell invasion and migration were evaluated using Transwell assay. The direct regulation of VEGFA by miR-140-5p was identified using luciferase reporter assay. Results: miR-140-5p was significantly dowregulated in CRC tissues and cell lines. Downregulation of miR-140-5p was significantly correlated with advanced CRC stage and poorer overall survival. Both gain-of-function and loss of function studies demonstrated that miR-140-5p acted as a tumor suppressor by inhibiting cell proliferation, migration and invasion. Integrated analysis identified VEGFA as a direct and functional target gene of miR-140-5p. Silencing VEGFA by small interfering RNA (siRNA) resembled the phenotype resulting from ectopic miR-140-5p expression, while overexpression of VEGFA attenuated the effect of miR-140-5p on CRC cells. Conclusions: Our results suggested a tumor suppressive role of miR-140-5p in CRC tumorigenesis and progression by targeting VEGFA.

The kurtosis-based indexes are usually used to identify the optimal resonant frequency band. However, kurtosis can only describe the strength of transient impulses, which cannot differentiate impulse noises and repetitive transient impulses cyclically generated in bearing vibration signals. As a result, it may lead to inaccurate results in identifying resonant frequency bands, in demodulating fault features and hence in fault diagnosis. In view of those drawbacks, this manuscript redefines the correlated kurtosis based on kurtosis and auto-correlative function, puts forward an improved correlated kurtosis based on squared envelope spectrum of bearing vibration signals. Meanwhile, this manuscript proposes an optimal resonant band demodulation method, which can adaptively determine the optimal resonant frequency band and accurately demodulate transient fault features of rolling bearings, by combining the complex Morlet wavelet filter and the Particle Swarm Optimization algorithm. Analysis of both simulation data and experimental data reveal that the improved correlated kurtosis can effectively remedy the drawbacks of kurtosis-based indexes and the proposed optimal resonant band demodulation is more accurate in identifying the optimal central frequencies and bandwidth of resonant bands. Improved fault diagnosis results in experiment verified the validity and advantage of the proposed method over the traditional kurtosis-based indexes.