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Objective: We employed two‐sample Mendelian randomization (MR) to assess the genetic causal relationship between educational attainment (EA) and risk of five common connective tissue diseases (CTDs). Methods: Educational attainment (self‐reported at age ≥30 years) was obtained from a meta‐analysis of years of schooling in 766 345 participants of European ancestry from genome‐wide association studies (GWAS). A total of 1265 signals associated with EA were identified. Genetic data for five CTDs [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM), and dermatomyositis (DM)] were obtained from the FinnGen consortium. Two‐sample MR analyses were performed separately for EA and the five CTDs. Results: We found a negative causal relationship between EA and RA (ORIVW = 0.627, 95% CI = 0.537–0.732, p <.001), and SLE (ORIVW = 0.341, 95% CI = 0.123–0.944, p =.038). There were no genetic causal association between EA and SSc (ORIVW = 0.647, 95% CI = 0.351–1.195, p =.164), PM (ORIVW = 0.938, 95% CI = 0.320–2.746, p =.907), or DM (ORIVW = 0.754, 95% CI = 0.351–1.619, p =.468). None of the analyses revealed any horizontal pleiotropy or heterogeneity. Conclusion: Our findings indicated a potential causal association between EA and RA, SLE, emphasizing the need for further investigation and potential integration of EA into clinical practice to enhance treatment strategies. [ABSTRACT FROM AUTHOR]

Monodispersed gas/liquid/liquid (G/L/L) double emulsions generated in microfluidic devices have attracted much attention from academic communities to industry fields. In this paper, a numerical simulation method, volume of fluid (VOF) technique, was adopted to study the hydrodynamics of G/L/L double emulsions generated in a circular flow-focusing microchannel. The generation process of double emulsions was presented in detail. The velocity fields inside and outside double emulsions were described. The effects of different phase fluid flow rates, the ratio of outer to middle flow rates, and the ratio of middle to inner flow rates on the size and generation frequency of double emulsions were studied, respectively. The eccentricities and the deformation indices of double emulsions were all explored as well. This work is helpful to understand the physical mechanism of the hydrodynamics of G/L/L double emulsions, and useful to produce and control G/L/L double emulsions in practical applications. [Display omitted] • Processes and models of G/L/L double emulsion generation were presented in detail. • Velocity fields, sizes and flow regimes of G/L/L double emulsions were studied numerically. • Eccentricities and deformation indices of G/L/L double emulsions were investigated deeply. [ABSTRACT FROM AUTHOR]

Microglial hyperactivation mediated by sphingosine kinase 1/sphingosine‐1‐phosphate (SphK1/S1P) signalling and the consequent inflammatory mediator production serve as the key drivers of cerebral ischaemia–reperfusion injury (CIRI). Although SphK1 reportedly controls autophagy and microglial activation, it remains uncertain as to whether SphK1 is similarly capable of regulating damage mediated by CIRI‐activated microglia. In the current study, we adopted both in vitro oxygen–glucose deprivation reperfusion (OGDR) models and in vivo rat models of focal CIRI to ascertain this possibility. It was found that CIRI upregulated SphK1 and induced autophagy in microglia, while inhibiting these changes significantly impaired to prevented neuronal apoptosis. Results of mechanistic investigation revealed that SphK1 promoted autophagy via the tumour necrosis factor receptor associated factor 2 (TRAF2) pathway. Altogether, our findings unfolded to reveal a novel mechanism, whereby SphK1‐induced autophagy in microglia contributed to the pathogenesis of CIRI, potentially highlighting novel avenues for future therapeutic intervention in ischaemic stroke patients. [ABSTRACT FROM AUTHOR]

With the widespread application of electronic devices, multifunctional electromagnetic wave (EMW) absorbing materials suitable for complex high-temperature and high-pressure environments, have attracted tremendous research attention. Herein, multifunctional polyimide (PI) composites doped with fluffy Nb 2 O 5 /CNTs microspheres (NBCP) were prepared by combining the ultrasonic spraying process and freeze-drying technique. Introduction of fillers results in the formation of diverse conduction paths and heterogeneous interfaces, which enhance the dielectric loss. Furthermore, the multi-porous structure of the PI matrix induces multiple reflection scattering events and improves the impedance matching. Such a multi-loss mechanism endows NBCP with an excellent EMW absorption performance. At 15 vol% filling, the minimum reflection loss is −41.66 dB, the effective absorption bandwidth is 2.63 GHz, and the radar cross-section is reduced by 85%. Furthermore, NBCP exhibits outstanding mechanical properties and a thermal insulation of over 100 °C in thermal environment at 150 °C. The proposed multifunctional NBCP is thus an efficient EMW absorber that offers significant potential for applications in harsh environments. [Display omitted] • Lightweight Nb 2 O 5 /CNTs/PI (NBCP) polymer-based materials were fabricated by spray and freeze-drying techniques. • NBCP-15 exhibits minimal reflection loss of −41.66 dB, an effective absorption bandwidth of 2.63 GHz, and radar cross section reduction of 85%. • NBCP has integrative properties of microwave absorption, thermal management, and compression resistance. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a common clinical bacterial pathogen that can cause a diverse range of infections. The establishment of a rapid and reliable assay for the early diagnosis and detection of S. aureus is of great significance. In this study, we developed a closed-tube loop-mediated isothermal amplification (LAMP) assay for the visual detection of S. aureus using the colorimetric indicator hydroxy naphthol blue (HNB). The LAMP reaction was optimized by adjusting the amplification temperature, the concentrations of Mg2+, dNTP, and HNB, and the incubation time. In the optimized reaction system, the specificity of LAMP for S. aureus was 100%. The results established that this method accurately identified S. aureus, with no cross-reactivity with 14 non-S. aureus strains. The limit of detection (LOD) of LAMP was 8 copies/reaction of purified plasmid DNA or 400 colony-forming units/reaction of S. aureus. Compared with conventional PCR, LAMP lowered the LOD by tenfold. Finally, 220 clinically isolated strains of S. aureus and 149 non-S. aureus strains were used to evaluate the diagnostic efficacy of LAMP (test accuracy, 99.46%). The findings indicated that LAMP is a reliable test for S. aureus and could be a promising tool for the rapid diagnosis of S. aureus infections. [ABSTRACT FROM AUTHOR]

Clinical studies have shown that persistent hyperglycemia following oxidative stress is associated with the apoptosis of osteocytes in diabetics. Adiponectin (APN) can ameliorate oxidative stress, and its receptors have been identified in bone‐forming cells. However, the relationship between APN and osteocyte apoptosis has not been fully elucidated. This study aimed to investigate whether APN could prevent osteocyte apoptosis and regulate reactive oxygen species (ROS) generation in a high‐glucose environment. Hoechst staining and fluorescence microscopy were used to observe the apoptosis of osteocytic MLO‐Y4 cells. Real‐time quantitative polymerase chain reaction and Western blot analysis were used to detect the expression of Caspase 3, Caspase 8, and Bcl‐2. ROS generation was investigated with an active oxygen kit and fluorescence microscopy. Furthermore, the expression of proteins in the AMPK/FoxO3A signaling pathway was also studied by Western blot analysis. In a high‐glucose environment, APN promoted the proliferation of MLO‐Y4 osteocytes and the expression of Bcl‐2 but inhibited the expression of Caspase 3, Caspase 8, and ROS in a dose‐dependent manner. APN promoted the activation of p‐AMPK and p‐AMPK/AMPK, which reached their highest levels at 10 min and returned to baseline at 30 min. The expression of p‐FoxO3A/FoxO3A in both the cytoplasm and nucleus peaked at 15 min, and this expression was returned to baseline at 60 min. In summary, APN has an antiapoptotic effect and regulates ROS generation in MLO‐Y4 osteocytes in a high‐glucose environment. The AMPK/FoxO3A signaling pathway might be a key signaling pathway that participates in the effect of APN on regulating osteocyte apoptosis in diabetics. [ABSTRACT FROM AUTHOR]

N-myristoylation is a crucial signaling and pathogenic modification process that confers hydrophobicity to cytosolic proteins. Although different large-scale approaches have been applied, a large proportion of myristoylated proteins remain to be identified. EZH2 is overexpressed in lung cancer cells and exerts oncogenic effects via its intrinsic methyltransferase activity. Using a well-established click chemistry approach, we found that EZH2 can be modified by myristoylation at its N-terminal glycine in lung cancer cells. Hydrophobic interaction is one of the main forces driving or stabilizing liquid-liquid phase separation (LLPS), raising the possibility that myristoylation can modulate LLPS by mediating hydrophobic interactions. Indeed, myristoylation facilitates EZH2 to form phase-separated liquid droplets in lung cancer cells and in vitro. Furthermore, we provide evidence that myristoylation-mediated LLPS of EZH2 compartmentalizes its non-canonical substrate, STAT3, and activates STAT3 signaling, ultimately resulting in accelerated lung cancer cell growth. Thus, targeting EZH2 myristoylation may have significant therapeutic efficacy in the treatment of lung cancer. Altogether, these observations not only extend the list of myristoylated proteins, but also indicate that hydrophobic lipidation may serve as a novel incentive to induce or maintain LLPS. [ABSTRACT FROM AUTHOR]

Background: Allelic imbalance (AI) in tumors is caused by chromosomal and sub-chromosomal gains and losses. Results: We evaluated AI at 109,086 germline exonic SNP loci in four cancer types, and identified a set of SNPs that demonstrate strong tumor allele specificity in AI events. Further analyses demonstrated that these alleles show consistently different frequencies in the cancer population compared to the healthy population and are significantly enriched for predicted protein-damaging variants. Moreover, genes harboring SNPs that demonstrate allele specificity are enriched for cancer-related biological processes and are more likely to be essential in cancer cells. Conclusions: In summary, our study provides a unique and complementary method to identify genes and variants that are relevant to carcinogenesis. [ABSTRACT FROM AUTHOR]

A comparative study between the microwave and conventional sintering of Li 2 TiO 3 –Li 4 SiO 4 biphasic ceramic pebbles was systematically performed. Comparing to samples sintered by conventional method, the microwave sintered samples exhibited homogeneous microstructure with uniform grain size distribution. In addition, the microwave sintered samples showed higher relative density (86.0% T.D.) and crush load (22.7 N). The results indicated that the microwave sintering process is a prospective method for fabricating Li 2 TiO 3 –Li 4 SiO 4 biphasic ceramic pebbles with excellent mechanical performance as tritium breeder materials. [ABSTRACT FROM AUTHOR]

Background: Interferon-γ (IFN-γ) is conventionally regarded as an inflammatory cytokine that has a pivotal role in anti-infection and tumor immune surveillance. It has been used clinically to treat a variety of malignancies. However, increased evidence has suggested IFN-γ can act to induce tumor progression. The role of IFN-γ in regulating antitumor immunity appears to be complex and paradoxical. The mechanism underlying the dual aspects of IFN-γ function in antitumor immunity is not clear. Methods: (1) Lung cancer cells (A549 cells) were cultured with pleural effusion or supernatant of tumor-associated macrophages (TAMs supernatant), and the expression levels of PD-L1 were detected by flow cytometer. The invasion capacity was measured in vitro using trans-well migration assays. (2) Pleural effusion mononuclear cells (PEMC) were separated by Ficoll Hypaque gradient. The expression of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and INF-γ in the tumor-associated macrophages was analyzed by flow cytometry. (3) A549 cells were stimulated with IL-6, IL-10, TNF-α, or IFN-γ and then the expression levels were detected by flow cytometry. (4) The expression levels of phospho-ERK ( p-ERK), phospho-AKT ( p-AKT), and phospho-Sat3 ( p-Stat3) were analyzed with Western blot after stimulation with IFN-γ. (5) Cotreatment of the A549 cells with MAPK/ERK-specific inhibitor PD98059, PI3K/AKT-specific inhibitor LY294002, or JAK/STAT3-specific inhibitor AG490, respectively, blocked IFN-γ-induced PD-L1 expression, and then PD-L1 expression was detected by flow cytometry. Results: We demonstrated that TAMs could induce the expression of PD-L1 by the secretion of IFN-γ through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in A549 cells. Furthermore, the signal pathway blockers LY294002 or AG490 could block the induced expression of PD-L1 by IFN-γ. Conclusions: IFN-γ was not always successful as an antitumor agent. It also can promote tumor cells to evade immune surveillance. Researchers should be cautious in using IFN-γ as a therapeutic agent for cancer treatment. [ABSTRACT FROM AUTHOR]

The emerging pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) critically challenges early and accurate virus diagnoses. However, the current gold standard for SARS-CoV-2 detection, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), has reportedly failed to detect low-viral loads. One compound, graphene oxide (GO), which adsorbs single-stranded DNA (ssDNA), has been widely applied in molecular pathogen detection. This study presents a highly sensitive GO-multiplex qPCR method for simultaneous detection of two SARS-CoV-2 genes (RdRP and E) and one reference gene (RNase P). In a GO-multiplex qPCR system, GO pre-absorbs each forward primer to form specific GO-forward primer composites before entering the amplification system. Target gene amplification is confined within the primer-enriched composites, thus, improving the sensitivity of the assay. Compared to conventional multiplex qPCR, GO-multiplex qPCR reduces the limit of detection by 10-fold to 10 copies/reaction. Hence, the GO-multiplex qPCR assay can be effectively used for SARS-CoV-2 detection. [Display omitted] • A highly sensitive GO-multiplex qPCR method for SARS-CoV-2 detection. • Adjust the GO oxidative degree to an appropriate sp2 to sp3 ratio. • Construct the GO-forward primer composites to enhance assay sensitivity. • GO-multiplex qPCR reduces the limit of detection to 10 copies/reaction. [ABSTRACT FROM AUTHOR]

High mobility and variable road surface condition brings big challenges for road event detection by using vehicular sensor networks (VSNs). VSNs are data-centric networks, so that the efficient collaborations among opportunistic topology structure in the network can help to improve the performance. In this paper, we present the behavior-aware fleet construction schemes to form and maintain the opportunistic fleet topology, and then to make fleet based data collaboration. The fleet formation scheme is to group vehicles according to behavior similarities and stability. The fleet maintenance scheme includes the periodic update and deputy selection to adapt the fleet topology. The collaboration within the fleet is executed in the way of 'follower-to-leader' with data aggregation among behavior-aware vehicles. Our analysis show the schemes are with low overhead and in an on-line and decentralized way, which is well suited for VSNs. We made simulations to testify the scheme performance for road event detection applications. The results show that our schemes achieve better accuracy for road event detection when compared with the other related work . [ABSTRACT FROM AUTHOR]

A novel biomass carbon (BC) composites derived from dictyostelium loaded with CNTs were successfully fabricated by simple carbonization and ultrasonic oscillation process. The microstructure and electromagnetic wave absorption (EMA) property as well as the related mechanism of as-prepared CNTs/BC composites were investigated. The unique porous structure of BC material provided more transmission paths for charge and enhanced multiple reflection and scattering of electromagnetic wave. With the introduction of highly conductive CNTs, not only the conductance loss and relaxation polarization loss of CNTs/BC composites was enhanced, but also the impedance matching was improved. With the synergistic effect of favorable impedance matching and attenuation ability, the excellent EMA property was achieved that the minimum reflection loss (RL min) is −20.4 dB with the wide effective absorption bandwidth (EAB) of 2.73 GHz at a thickness of 2.35 mm. This study will provide a valuable reference for exploring new biomass-carbon based EMA materials. [Display omitted] • High-performance CNTs/biomass carbon composites derived from dictyostelium • Unique porous structures formed through a carbonization process. • Improved EMA property with an effective absorption bandwidth of 2.73 GHz [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-associated death worldwide and is classified into non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC accounts for approximately 80%–85% of all lung cancer cases. Chenodeoxycholic acid (CDCA), a primary bile acid, has been reported to inhibit carcinoma cell proliferation. Here, we aimed to determine the effects and mechanism of action of CDCA against lung adenocarcinoma (LUAD). Western blotting and quantitative real-time polymerase chain reaction were used to evaluate the protein and mRNA expression levels in LUAD cell lines, respectively. Cell Counting Kit-8 and clone formation assays were performed to evaluate the proliferation ability of different cell types in vitro. Tumor cell motility was evaluated using Transwell assays. The transcriptional profile of A549 cells treated with CDCA was determined through RNA sequencing analysis. A xenograft model was established to evaluate the effects of CDCA on LUAD progression in vivo. CDCA inhibited LUAD cell proliferation, migration, and invasion. Furthermore, it promoted apoptosis in LUAD cells. Mechanistically, CDCA inhibited the integrin α5β1 signaling pathway in LUAD cells by inhibiting the expression of the α5 and β1 subunits of integrin and phosphorylated FAK. Moreover, CDCA induced an increase in the levels of p53, a downstream gene of the integrin α5β1/FAK pathway. In addition, CDCA significantly decreased tumor volume in mice without inducing significant toxicity. Our findings indicate that CDCA attenuates LUAD pathogenesis in vitro and in vivo via the integrin α5β1/FAK/p53 axis. [Display omitted] [ABSTRACT FROM AUTHOR]

The vehicle delay tolerant networks (DTNs) make opportunistic communications by utilizing the mobility of vehicles, where the node makes delay-tolerant based 'carry and forward' mechanism to deliver the packets. The routing schemes for vehicle networks are challenging for varied network environment. Most of the existing DTN routing including routing for vehicular DTNs mainly focus on metrics such as delay, hop count and bandwidth, etc. A new focus in green communications is with the goal of saving energy by optimizing network performance and ultimately protecting the natural climate. The energy-efficient communication schemes designed for vehicular networks are imminent because of the pollution, energy consumption and heat dissipation. In this paper, we present a directional routing and scheduling scheme (DRSS) for green vehicle DTNs by using Nash Q-learning approach that can optimize the energy efficiency with the considerations of congestion, buffer and delay. Our scheme solves the routing and scheduling problem as a learning process by geographic routing and flow control toward the optimal direction. To speed up the learning process, our scheme uses a hybrid method with forwarding and replication according to traffic pattern. The DRSS algorithm explores the possible strategies, and then exploits the knowledge obtained to adapt its strategy and achieve the desired overall objective when considering the stochastic non-cooperative game in on-line multi-commodity routing situations. The simulation results of a vehicular DTN with predetermined mobility model show DRSS achieves good energy efficiency with learning ability, which can guarantee the delivery ratio within the delay bound. [ABSTRACT FROM AUTHOR]

Fire hazard monitoring and evacuation for building environments is a novel application area for the deployment of wireless sensor networks. In this context, adaptive routing is essential in order to ensure safe and timely data delivery in building evacuation and fire fighting resource applications. Existing routing mechanisms for wireless sensor networks are not well suited for building fires, especially as they do not consider critical and dynamic network scenarios. In this paper, an emergency-adaptive, real-time and robust routing protocol is presented for emergency situations such as building fire hazard applications. The protocol adapts to handle dynamic emergency scenarios and works well with the routing hole problem. Theoretical analysis and simulation results indicate that our protocol provides a real-time routing mechanism that is well suited for dynamic emergency scenarios in building fires when compared with other related work. [ABSTRACT FROM AUTHOR]

Hyperbolic embedding can effectively preserve the property of complex networks. Though some state-of-the-art hyperbolic node embedding approaches are proposed, most of them are still not well suited for the dynamic evolution process of temporal complex networks. The complexities of the adaptability and embedding update to the scale of complex networks with moderate variation are still challenging problems. To tackle the challenges, we propose hyperbolic embedding schemes for the temporal complex network within two dynamic evolution processes. First, we propose a low-complexity hyperbolic embedding scheme by using matrix perturbation, which is well-suitable for medium-scale complex networks with evolving temporal characteristics. Next, we construct the geometric initialization by merging nodes within the hyperbolic circular domain. To realize fast initialization for a large-scale network, an R tree is used to search the nodes to narrow down the search range. Our evaluations are implemented for both synthetic networks and realistic networks within different downstream applications. The results show that our hyperbolic embedding schemes have low complexity and are adaptable to networks with different scales for different downstream tasks. [ABSTRACT FROM AUTHOR]

Background: As a result of the one‐child policy of 1979, today there are numerous one‐child families with adolescents in Mainland China. Little is known about the experiences of parents of such adolescents diagnosed with cancer. Objectives: This study explored the experiences of parents whose adolescent child was diagnosed with cancer in one‐child families in China. Methods: A qualitative methodology based on hermeneutic phenomenology was employed. The participants were parents of adolescent cancer patients in one‐child families. Data were collected using in‐depth semi‐structured interviews and analysed using van Manen's hermeneutic phenomenological approach. The COREQ checklist was used for this study. Results: Fourteen parents (eleven mothers, three fathers) participated in the study. One overarching theme emerged: feeling like the sky is falling down. In addition, there were five related themes: self‐condemnation; 'white lies' – that is, difficulty in telling the truth; struggling with a sense of collapse; fear of losing the child and hopelessness. Almost all the participants experienced insomnia after learning about the diagnosis. In a few cases, hopelessness‐induced suicidal ideation or even suicidal behaviour. Conclusions: Parents of adolescents diagnosed with cancer in one‐child families in China experienced extremely painful emotions. The truth about their child's condition not only caused immense psychological trauma but also induced pessimism about their own future. Implications for clinical practice: The experiences of parents in one‐child families where an adolescent child has been diagnosed with cancer should be taken seriously. In addition, support should be provided to help parents maintain a normal life and feel hopeful for their future. [ABSTRACT FROM AUTHOR]

Expression quantitative trait loci (eQTLs) are used to inform the mechanisms of transcriptional regulation in eukaryotic cells. However, the specificity of genome-wide eQTL identification is limited by stringent control for false discoveries. Here, we described a method based on the non-homogeneous Poisson process to identify 125 489 regions with highly frequent, multiple eQTL associations, or 'eQTL-hotspots', from the public database of 59 human tissues or cell types. We stratified the eQTL-hotspots into two classes with their distinct sequence and epigenomic characteristics. Based on these classifications, we developed a machine-learning model, E-SpotFinder, for augmented discovery of tissue- or cell-type-specific eQTL-hotspots. We applied this model to 36 tissues or cell types. Using augmented eQTL-hotspots, we recovered 655 402 eSNPs and reconstructed a comprehensive regulatory network of 2 725 380 cis -interactions among eQTL-hotspots. We further identified 52 012 modules representing transcriptional programs with unique functional backgrounds. In summary, our study provided a framework of epigenome-augmented eQTL analysis and thereby constructed comprehensive genome-wide networks of cis -regulations across diverse human tissues or cell types. [ABSTRACT FROM AUTHOR]

Background: Approximately 30% of patients with epidermal growth factor receptor (EGFR)-activating mutations have no response to EGFR-tyrosine kinase inhibitors (TKIs) (primary resistance). However, little is known about the molecular mechanism involved in primary resistance to EGFR-TKIs in EGFR-mutant non-small cell lung cancer (NSCLC). Programmed death ligand-1 (PD-L1) plays important regulatory roles in intracellular functions and leads to acquired resistance to EGFR-TKIs in NSCLC. Here, we investigated the mechanistic role of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant NSCLC cells.Methods: The expression levels of PD-L1 and the sensitivity to gefitinib in H1975, HCC827 and PC-9 cells were determined by quantitative real-time PCR analysis (qRT-PCR) and Cell Counting Kit-8 (CCK-8) assays, respectively. Molecular manipulations (silencing or overexpression) were performed to assess the effect of PD-L1 on sensitivity to gefitinib, and a mouse xenograft model was used for in vivo confirmation. Western blotting and qRT-PCR were used to analyse the expression of epithelial-mesenchymal transition (EMT) markers. The effect of PD-L1 on migratory and invasive abilities was evaluated using the Transwell assay and mice tail intravenous injection.Results: Higher expression of PD-L1 was related to less sensitivity to gefitinib in EGFR-mutant NSCLC cell lines. The overexpression or knockdown of PD-L1 presented diametrical sensitivity to gefitinib in vitro and in vivo. Furthermore, the overexpression of PD-L1 led to primary resistance to gefitinib through the induction of EMT, which was dependent on the upregulation of Smad3 phosphorylation. Moreover, in the mouse model, the knockdown of PD-L1 inhibited transforming growth factor (TGF)-β1-induced cell metastasis in vivo.Conclusion: PD-L1 contributes to primary resistance to EGFR-TKI in EGFR-mutant NSCLC cells, which may be mediated through the induction of EMT via the activation of the TGF-β/Smad canonical signalling pathway. [ABSTRACT FROM AUTHOR]

Objective: To investigate the status of self-monitoring of blood glucose (SMBG) among patients with type 2 diabetes mellitus in Shanghai and analyze the factors affecting the frequency of SMBG. Methods: A total of 987 Chinese subjects with type 2 diabetes mellitus aged 20 to 80 years old was included in the present study from August 2017 to December 2017. A standard questionnaire was completed. The frequency of SMBG and related factors of hyperglycemia were analyzed. The subjects were divided into two groups according to the frequency of SMBG. The relatively high frequency group (RHF) (more than twice a week) and the relatively low frequency group (RLF) (one and twice a week). Results: Among all the subjects, 337 (34.2%) of them were in the RHF group, and 648 (65.8%) were in the RLF group. The number of patients who monitored blood glucose three times a day and more than three times a day was less (16 and 43, 1.6% and 4.4% respectively). Majority of patients adjusted their blood glucose levels through exercise (38.9%) and diet (38.1%), rather than drug (7.7%) after SMBG. Other methods (15.2%) were also used to alleviate hyperglycemia. Multivariate logistic regression analyses showed that age, duration of diabetic history, glycated hemoglobin, educational levels, insulin usage were factors influencing the frequency of SMBG in patients. Conclusions: The current status of SMBG among diabetic patients in Shanghai is not optimistic, in which the frequency of SMBG is relatively low. It is of great importance to increase the frequency of SMBG in controlling blood glucose levels. Disclosure: L. Wei: None. Y. Zeng: None. Y. Xiao: None. L. Ji: None. M. Liu: None. Funding: National Natural Science Foundation of China (81570778) [ABSTRACT FROM AUTHOR]

In this study, three proteases (papain, neutral protease, bromelain) were employed to hydrolyze crocodile (Crocodylus siamensis) myofibrillar protein (MP), effects of hydrolysis duration on functional and structural properties of MP hydrolysates was investigated. The findings revealed that solubility of all hydrolysates exceeded 60%, with the highest reaching 96.7%. The emulsifying activity of neutral protease hydrolysates exhibited a significant superiority over the other two hydrolysates (P < 0.05). The Fe2+ chelating and DPPH radical scavenging activity of hydrolysates ranged from 20% to 60%, and 60%–90%, respectively. Based on the experiment results, the hydrolysates of papain at 1h, neutral protease at 1h, and bromelain at 2h were used for structural analysis. Compared to MP, the secondary structure of hydrolysates showed a reduction of 9.6%, 15.2%, and 4.7% in α-helix and the increase of 42.4%, 29.6%, and 44.2% in β-fold content of papain, neutral protease and bromelain hydrolysates respectively, suggesting the transition from spiral to folding structure and the exposure of hydrophobic group, which was proved by free amino acid analysis. SEM results confirmed the alterations in MP structure. The molecular weight distributions of three hydrolysates were predominantly below 1000 Da, demonstrating that crocodile MP was effectively hydrolyzed into bioactive peptides. • The functional and structural changes of three different MP hydrolysates were analyzed. • All three proteases treatments enhanced the antioxidant activity of crocodile MP. • All three proteases treatments increased the exposure of protein hydrophobic groups. • The Mws of all three hydrolysates were predominantly lower than 1000 Da. • Relationship between structure and function of crocodile MP hydrolysates were analyzed. [ABSTRACT FROM AUTHOR]

• SC in China was measured using the benefit transfer method and NDVI correction factor. • Spatially non-stationary relationships between LF and SC services were identified. • SC is aggravated by LF, but it exhibits variation in response to spatial heterogeneity. Soil conservation (SC), which supports ecosystems by retaining vegetation, controlling erosion, retaining sediment, cycling nutrients, retaining water, maintaining diversity, and forming soil, is threatened by human-induced soil erosion and landscape fragmentation (LF). Therefore, revealing the spatial relationship between LF and SC can provide a scientific basis for ecosystem conservation policy-making and landscape planning. However, previous studies failed to reveal the spatially non-stationary response of SC to LF, especially at the national scale in China. To compensate for the research gaps, this study first measured the SC at the county scale with the benefit transfer method, then the LF was characterized with landscape pattern indices, and finally the spatial relationships between the SC and LF from global and local perspectives through regression models were analyzed. Results showed that national values of SC services per unit area in 2000, 2010, and 2018 were $134.73/ha, $132.30/ha, and $130.71/ha, respectively, showing a continuous decreasing trend. The high-value areas were distributed in the south of the Qinling-Huaihe River, Greater Khingan Mountains, and Changbai Mountain areas. In contrast, the low-value areas were mainly distributed in northwest China. LF was low in the northwestern region, while Shanxi, Shaanxi, Hebei, and southern Gansu presented highly fragmented landscapes. The spatial regression results showed that the higher the regional LF, the lower the value of SC. Meanwhile, there was significant spatial heterogeneity in the response of SC to LF, which was closely related to population distribution and resource endowment. In the future, landscape planning, land use structure and layout can take the impact mechanism of LF on SC as the essential basis. [ABSTRACT FROM AUTHOR]

Background: The Ecotropic viral integration site 5 (EVI5), an important protein in regulating cell cycle, cytokinesis and cellular membrane traffic, functions as a stabilizing factor maintaining anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 in S/G2 phase. However, the mechanism by which EVI5 promotes malignant transformation of non-small cell lung cancer (NSCLC) remains unknown. In the present study, we addressed the role of EVI5 in NSCLC by regulating tumor growth, migration and invasion. Methods: The expression levels of EVI5 and miR-486-5p in NSCLC tissues and cells were measured by real-time PCR. Meanwhile, EVI5 and its associated protein expression were analyzed by western blot and co-immunoprecipitation assay. Flow cytometry was performed to determine cell proliferation and apoptosis. CCK-8 and clonogenic assays were used to analyze cell viability. Wound healing, transwell migration and matrigel invasion assays were utilized to assess the motility of tumor cells. To investigate the role of EVI5 in vivo, lung carcinoma xenograft mouse model was applied.. Results: EVI5 was upregulated in NSCLC tissues and cell lines when compared with that in normal tissues and cell line. Knockdown of EVI5 in vitro inhibited tumor cell proliferation, migration and invasion in NSCLC cells. Further, inoculation of EVI5-deficient tumor cells into nude mice suppressed tumor proliferation and metastasis compared to control mice inoculated with unmanipulated tumor cells. These data indicated that EVI5 promote the proliferation of NSCLC cells which was consistent with our previous results. Additionally, we showed that EVI5 was directly regulated by miR-486-5p, and miR-486-5p-EVI5 axis affected the NSCLC migration and invasion through TGF-β/Smad signaling pathway by interacting with TGF-β receptor II and TGF-β receptor I. Conclusions: Based on these results, we demonstrated a new post-transcriptional mechanism of EVI5 regulation via miR-486-5p and the protumoral function of EVI5 in NSCLC by interacting with Emi1 and/or TGF-β receptors, which provides a new insight into the targeted therapy of NSCLC. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests the critical roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and tumor progression. However, the role of m6A in non-small cell lung cancer (NSCLC) is still unclear. This study aimed to explore the role of the m6A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of NSCLC. Methods: A human m6A epitranscriptomic microarray analysis was used to identify downstream targets of FTO. Quantitative real-time PCR (qRT‒PCR) and western blotting were employed to evaluate the expression levels of FTO and FAP in NSCLC cell lines and tissues. Gain-of-function and loss-of-function assays were conducted in vivo and in vitro to assess the effects of FTO and FAP on NSCLC metastasis. M6A-RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), luciferase reporter assays, and RNA stability assays were used to explore the mechanism of FTO action. Co-immunoprecipitation (co-IP) assays were used to determine the mechanism of FAP in NSCLC metastasis. Results: FTO was upregulated and predicted poor prognosis in patients with NSCLC. FTO promoted cell migration and invasion in NSCLC, and the FAK inhibitor defactinib (VS6063) suppressed NSCLC metastasis induced by overexpression of FTO. Mechanistically, FTO facilitated NSCLC metastasis by modifying the m6A level of FAP in a YTHDF2-dependent manner. Moreover, FTO-mediated metastasis formation depended on the interactions between FAP and integrin family members, which further activated the FAK signaling. Conclusion: Our current findings provided valuable insights into the role of FTO-mediated m6A demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC. EwEnNquqUtx8DT1YGQrFDq Video Abstract Plain English Summary: Emerging evidence suggests the crucial roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and progression. Nonetheless, the role of m6A in NSCLC remains unclear. The purpose of this study was to investigate the role of m6A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of non-small cell lung cancer (NSCLC). Results illustrated that FTO was upregulated and predicted poor prognosis in NSCLC patients. FTO promoted cell migration and invasion in NSCLC, and the FAK inhibitor defactinib (VS6063) suppressed NSCLC metastasis induced by overexpression of FTO. Mechanistically, FTO facilitated NSCLC metastasis by modifying the m6A level of FAP in a YTHDF2-dependent manner. Moreover, FTO-mediated metastasis formation depended on the interactions between FAP and integrin family members, which further activated the FAK signaling. Our current findings provided valuable insights into the role of FTO-mediated m6A demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]

Transportation is a huge problem that curbs development of societies and economy in many countries nowadays. Participatory sensing technologies encourage people to be involved in environment monitoring through smart devices. Vehicle sensor networks (VSNs) are a novel solution for road event detection with advantages. In this paper, we consider runtime road event detection using VSNs to satisfy the application-specific requirements through collaboration among vehicles. A group road detection scheme (GRD) by using dynamic clustering in VSNs is presented to improve detection performance with low time complexity and message complexity. The simulations with testbed of 5 remote controllable vehicles show that GRD scheme provides effectiveness under different road scenarios. [ABSTRACT FROM AUTHOR]

Background: The prognosis and the value of postmastectomy radiotherapy (PMRT) between post‐chemotherapy ypT1‐2ypN1 and de novo pT1‐2N1 breast cancer (BC) remain controversial. We aimed to evaluate the prognostic differences and the effect of PMRT between the two patient subsets. Methods: Patients diagnosed with pT1‐2N1M0 BC were identified between 2010 and 2018. The study endpoints were overall survival (OS), breast cancer‐specific survival (BCSS), locoregional recurrence‐free survival (LRFS), distant metastasis‐free survival (DMFS) and disease‐free survival (DFS). The chi‐square test, Kaplan–Meier method and Cox regression analysis were used for data analysis. Results: Total number of 2103 pT1‐2N1M0 BC patients were included in the study, including 270 post‐chemotherapy (97 without PMRT, 173 with PMRT) and 1833 de novo cases (993 without PMRT, 840 with PMRT). No significant differences were found between post‐chemotherapy ypT1‐2ypN1 and de novo pT1‐2N1 BC patients in 5‐year OS (p = 0.068), BCSS (p = 0.054), LRFS (p = 0.241), DMFS (p = 0.104) or DFS (p = 0.08). PMRT did not improve any survival outcome in patients receiving neoadjuvant chemotherapy; however, the PMRT group had a better 5‐year BCSS (97.0% vs. 95.8%, p = 0.033) in de novo pT1‐2N1 BC. Cox multivariate analysis demonstrated that PMRT was a significant independent predictor of BCSS (HR 0.628; 95% CI, 0.403–0.978; p = 0.04) in de novo pT1‐2N1 patients. Conclusions: There seemed no survival difference in post‐chemotherapy ypT1‐2ypN1 and de novo pT1‐2N1 BC patients with contemporary systemic therapy. In addition, PMRT might be exempted in patients with post‐chemotherapy ypT1‐2ypN1 BC, while not in patients with de novo pT1‐2N1 BC. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most lethal tumour worldwide. Copine 1 (CPNE1) was identified as a novel oncogene in NSCLC in our previous study. However, its specific function and relative mechanisms remain poorly understood. Methods: The biological role of CPNE1 and RACK1 in NSCLC was investigated using gene expression knockdown and overexpression, cell proliferation assays, clonogenic assays, and Transwell assays. The expression levels of CPNE1, RACK1 and other proteins were determined by western blot analysis. The relationship between CPNE1 and RACK1 was predicted and investigated by mass spectrometry analysis, immunofluorescence staining, and coimmunoprecipitation. NSCLC cells were treated with a combination of a MET inhibitor and gefitinib in vitro and in vivo. Results: We found that CPNE1 facilitates tumorigenesis in NSCLC by interacting with RACK1, which further induces activation of MET signaling. CPNE1 overexpression promoted cell proliferation, migration, invasion and MET signaling in NSCLC cells, whereas CPNE1 knockdown produced the opposite effects. In addition, the suppression of the enhancing effect of CPNE1 overexpression on tumorigenesis and MET signaling by knockdown of RACK1 was verified. Moreover, compared to single-agent treatment, dual blockade of MET and EGFR resulted in enhanced reductions in the tumour volume and downstream signaling in vivo. Conclusions: Our findings show that CPNE1 promotes tumorigenesis by interacting with RACK1 and activating MET signaling. The combination of a MET inhibitor with an EGFR-TKI attenuated tumour growth more significantly than either single-drug treatment. These findings may provide new insights into the biological function of CPNE1 and the development of novel therapeutic strategies for NSCLC. 3n8P5VYzQLauDz5o6kqwUE Video Abstract [ABSTRACT FROM AUTHOR]

Background: Traditional Chinese Medicine (TCM) is distinguished by Syndrome differentiation, which prescribes various formulae for different Syndromes of same disease. This study aims to investigate the underlying mechanism. Methods: Using a strategy which integrated proteomics, metabolomics study for clinic samples and network pharmacology for six classic TCM formulae, we systemically explored the biological basis of TCM Syndrome differentiation for two typical Syndromes of CHD: Cold Congealing and Qi Stagnation (CCQS), and Qi Stagnation and Blood Stasis (QSBS). Results: Our study revealed that CHD patients with CCQS Syndrome were characterized with alteration in pantothenate and CoA biosynthesis, while more extensively altered pathways including D-glutamine and D-glutamate metabolism; alanine, aspartate and glutamate metabolism, and glyoxylate and dicarboxylate metabolism, were present in QSBS patients. Furthermore, our results suggested that the down-expressed PON1 and ADIPOQ might be potential biomarkers for CCQS Syndrome, while the down-expressed APOE and APOA1 for QSBS Syndrome in CHD patients. In addition, network pharmacology and integrated analysis indicated possible comorbidity differences between the two Syndromes, that is, CCQS or QSBS Syndrome was strongly linked to diabetes or ischemic stroke, respectively, which is consistent with the complication disparity between the enrolled patients with two different Syndromes. These results confirmed our assumption that the molecules and biological processes regulated by the Syndrome-specific formulae could be associated with dysfunctional objects caused by the Syndrome of the disease. Conclusion: This study provided evidence-based strategy for exploring the biological basis of Syndrome differentiation in TCM, which sheds light on the translation of TCM theory in the practice of precision medicine. Highlights: 1. Our work was based on clinical samples rather than pure data analysis or animal models. 2. We conducted multiple omics studies. Especially, as for metabolomics study, we performed both untargeted and targeted metabolomics experiments. 3. We performed network pharmacological study to cross-validated the results of multi-omics study. Although the data sources of network pharmacology were completely unrelated with our omics data, they came to the same conclusion about the difference of the two Syndromes. 4. In the network pharmacological study, we made efforts to collect and screen high-quality data. We collected data from multiple TCM databases and conducted drug likeness screening. Especially, we added quality markers of each herb, whose pharmacological relevance had been validated. To enhance the reliability of targets, for each Syndrome, we only studied common targets of 3 different TCM formulae prescribed for this Syndrome. [ABSTRACT FROM AUTHOR]

Background: Tetraspanins CD151, a transmembrane 4 superfamily protein, has been identified participating in the initiation of a variety of cancers. However, the precise function of CD151 in non-small cell lung cancer (NSCLC) remains unclear. Here, we addressed the pro-tumoral role of CD151 in NSCLC by targeting EGFR/ErbB2 which favors tumor proliferation, migration and invasion. Methods: First, the mRNA expression levels of CD151 in NSCLC tissues and cell lines were measured by RT-PCR. Meanwhile, CD151 and its associated proteins were analyzed by western blotting. The expression levels of CD151 in NSCLC samples and its paired adjacent lung tissues were then verified by Immunohistochemistry. The protein interactions are evaluated by co-immunoprecipitation. Flow cytometry was applied to cell cycle analysis. CCK-8, EdU Incorporation, and clonogenic assays were used to analyze cell viability. Wound healing, transwell migration, and matrigel invasion assays were utilized to assess the motility of tumor cells. To investigate the role of CD151 in vivo, lung carcinoma xenograft mouse model was applied. Results: High CD151 expression was identified in NSCLC tissues and cell lines, and its high expression was significantly associated with poor prognosis of NSCLC patients. Further, knockdown of CD151 in vitro inhibited tumor proliferation, migration, and invasion. Besides, inoculation of nude mice with CD151-overexpressing tumor cells exhibited substantial tumor proliferation compared to that in control mice which inoculated with vector-transfected tumor cells. Noteworthy, we found that overexpression of CD151 conferred cell migration and invasion by interacting with integrins. We next sought to demonstrate that CD151 regulated downstream signaling pathways via activation of EGFR/ErbB2 in NSCLC cells. Therefore, we infer that CD151 probably affects the sensitivity of NSCLC in response to anti-cancer drugs. Conclusions: Based on these results, we demonstrated a new mechanism of CD151-mediated tumor progression by targeting EGFR/ErbB2 signaling pathway, by which CD151 promotes NSCLC proliferation, migration, and invasion, which may considered as a potential target of NSCLC treatment. [ABSTRACT FROM AUTHOR]

Hyperbolic graph embedding has garnered significant attention in a wide range of downstream applications. This is because hyperbolic geometry provides a valuable mapping tool, whereby the scale-free or hierarchical properties of complex networks can be naturally reflected as hyperbolic metric properties. Despite this, most advancements have focused on learning hyperbolic representations of static graphs, the potential advantages of hyperbolic metrics in dynamic graphs embedding have not been fully exploited. To fully harness the properties of hyperbolic space, we propose DHGAT 1 1 https://github.com/Lihaogx/DHGAT. , a dynamic hyperbolic graph attention network with a novel architecture that designs a spatiotemporal self-attention mechanism based on hyperbolic distance. DHGAT maps dynamic graphs into the hyperbolic space, generates spatiotemporal self-attention of nodes, and directly aggregates weighted node representations without the tangent space. This is achieved by using the Einstein gyromidpoints, which reduces distortions and preserves manifold properties. The results of experiments on real-world datasets demonstrate that DHGAT performs exceptionally well in multi-step link prediction tasks, particularly in predicting new links compared to the baselines. [ABSTRACT FROM AUTHOR]

Objective: Increased vascular permeability and inflammation are principal hallmark of sepsis. Moesin (MSN) is a membrane-associated cytoskeleton protein and crucial for the vascular endothelial function. This study is aimed at evaluating the role of MSN in endothelial injury during the process of sepsis.Methods: Serum MSN in septic patients was measured by ELISA. BALB/c mice were injected with different doses of lipopolysaccharide (LPS) or underwent cecal ligation and single or double puncture (CLP) to mimic sublethal and lethal sepsis. After treatment, their serum MSN and PCT levels, wet to dry lung weights (W/D ratio), bronchoalveolar lavage fluid (BALF) protein concentrations, and lung injury scores were measured. The impact of MSN silencing on LPS-altered Rock1/myosin light chain (MLC), NF-κB, and inflammatory factors in human microvascular endothelial cells (HMECs), as well as monolayer HMEC permeability, was tested in vitro.Results: Compared with healthy controls, serum MSN increased in septic patients and was positively correlated with SOFA scores and serum PCT levels in septic patients. LPS injection significantly increased serum the MSN and PCT expression, BALF protein levels, and W/D ratio, and the serum MSN levels were positively correlated with serum PCT, lung W/D ratio, and lung injury scores in mice. Similar results were obtained in the way of CLP modelling. LPS enhanced MSN, MLC, NF-κB phosphorylation, increased Rock1 expression, and inflammatory factors release in the cultured HMECs, while MSN silencing significantly mitigated the LPS-induced Rock1 and inflammatory factor expression, NF-κB, and MLC phosphorylation as well as the monolayer hyperpermeability in HMECs.Conclusions: Increased serum MSN contributes to the sepsis-related endothelium damages by activating the Rock1/MLC and NF-κB signaling and may be a potential biomarker for evaluating the severity of sepsis. [ABSTRACT FROM AUTHOR]

Background: Acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance limits the long-term clinical efficacy of tyrosine kinase-targeting drugs. Although most of the mechanisms of acquired EGFR-TKI resistance have been revealed, the mechanism of ~ 15% of cases has not yet been elucidated. Methods: Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Proteome profiler array analysis was performed to find proteins contributing to acquired EGFR-TKI resistance. Secreted OPN was detected by ELISA. Immunohistochemical analysis was conducted to detect expression of integrin αV in NSCLC tissue. The effect of VS-6063 on apoptosis and proliferation of PC9 gefitinib-resistant cells was detected by fluorescence-activated cell sorting (FACS) and clonogenic assays. A mouse xenograft model was used to assess the effect of VS-6063 on the sensitivity of PC9 gefitinib-resistant cells to gefitinib. Results: OPN was overexpressed in acquired EGFR-TKI-resistant NSCLCs. Secreted OPN contributed to acquired EGFR-TKI resistance by activating the integrin αVβ3/FAK pathway. Inhibition of FAK signalling increased sensitivity to EGFR-TKIs in PC9 gefitinib-resistant cells both in vitro and in vivo. Conclusions: OPN contributes to acquired EGFR-TKI resistance by up-regulating expression of integrin αVβ3, which activates the downstream FAK/AKT and ERK signalling pathways to promote cell proliferation in NSCLC. [ABSTRACT FROM AUTHOR]

This paper gives an oil‐based granulation approach to realize the efficient preparation of Li2O breeder materials, which solve the problems of long preparation cycle, high manufacturing cost and difficult to be homogenization and densification in the past. Li2O precursor spheres with narrow size distribution and uniform spherical shape can be obtained using paraffin oil as binders. The Li2O feed powder with bimodal size distribution will self‐organize to form a core‐shell structured sphere during granulation, in which the core and shell are composed of small particles and large particles, respectively. Notably, the Li2O ceramic spheres sintered at 900°C can achieve a crush load of 40.69 ± 4.01 N and a theoretical density of 79.66% TD, which was not achievable by the methods reported in the previous literature. The strategy proposed in this work not only can be easily extended to other material systems but also opens up a new avenue for the design and preparation of tritium breeder materials with uniform size distribution and satisfactory mechanical properties. [ABSTRACT FROM AUTHOR]

Lung cancer is the primary cause of death among cancer patients in China, among which nonsmall cell lung cancer (NSCLC) makes up the great majority. Hence, it is imperative to identify the biomarkers and mechanisms involved in NSCLC oncogenesis. Our present research found that KIAA1199 expression was significantly increased in NSCLC and closely related to cell proliferation, motility, and poor prognosis. We demonstrated that knockdown of KIAA1199 reduced NSCLC cell growth and motility in vitro whereas overexpression of KIAA1199 had the opposite effect. Inhibition of KIAA1199 significantly suppressed tumor growth in mouse NSCLC xenograft models. Mechanistically, as an epidermal growth factor receptor (EGFR)‐binding protein, KIAA1199 promotes EGFR signaling and regulates EGFR‐dependent Src, Erk, and Akt phosphorylation, as well as downstream kinases in the EGF‐mediated EMT pathway. We demonstrated that KIAA1199 can function as a direct binding target for miR‐486‐5p and that miR‐486‐5p overexpression can attenuate proliferation and migration of NSCLC cells via regulating the EGFR signaling pathways. To conclude, our results defined KIAA1199 as an oncogenic protein that promotes cancer cell proliferation and migration by regulating EGF‐mediated signaling pathways. This study provided new insight into NSCLC oncogenesis, which could lead to the development of innovative therapeutic plans for NSCLC. [ABSTRACT FROM AUTHOR]

Background: Although many studies have defined mechanisms of resistance to EGFR‐TKIs, acquired resistance remains the major limitation of monotherapy with EGFR‐TKIs. Methods: Cell viability was analyzed using a Cell Counting Kit‐8 (CCK‐8) assay. EGFR T790M mutation was sequenced on a HiSeq 4000 platform. mRNAs from HCC827 and HCC827 gefitinib‐resistant (GR) cells were analyzed by genome analyzer‐based deep sequencing. The effect of anlotinib on apoptosis and cell cycle arrest of HCC827 GR was detected by fluorescence‐activated cell sorting (FACS) analysis. A mouse xenograft model was used to assess the effect of anlotinib on HCC827 GR cells. Results: The T790M mutation was found in the PC‐9 GR cell line but not in the HCC827 GR cell line. Anlotinib could suppress the growth of HCC827 GR cells by inhibiting FGFR1 in vitro and in a mouse xenograft model. Moreover, FGFR1 was overexpressed in HCC827 GR cells, and the knockdown of FGFR1 reversed gefitinib resistance in HCC827 GR cells. Furthermore, anlotinib induced apoptosis and cell cycle arrest in HCC827 GR cells by increasing the activity of Caspase‐3. Conclusions: FGFR1 overexpression could be the mechanism of EGFR‐TKI acquired resistance and anlotinib can suppresse the growth of EGFR‐TKI‐resistant NSCLC cells without T790M mutation. [ABSTRACT FROM AUTHOR]

A novel mass production method of lithium titanite (Li 2 TiO 3) tritium breeder ceramic pebbles using polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) assisted granulation method (APG) was proposed. A binder solution of polyvinyl alcohol (PVA) was used to modify the Li 2 TiO 3 precursor powder. The powders with adhesive properties were prilled to form green pebbles (GPs) by spheronization at a low rotation speed and spraying with polyvinyl pyrrolidone (PVP), in several cycles. Then, the density and the crush load of the GPs were improved by high-speed rolling. Finally, the ceramic pebbles were produced by sintering. The phase, the microstructure, and the crush load of the ceramic pebbles were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and with a universal tester, respectively. [ABSTRACT FROM AUTHOR]

Synthesis of fine Li 2 TiO 3 powders via low-temperature solid-state reaction (LTSSR) was studied. Solid Li 2 CO 3 and H 2 TiO 3 were blended by planetary ball mill with deionized water as medium. Calcination of the milled powder at low temperature of 500 °C resulted in the formation of pure Li 2 TiO 3 nanoparticles. Another Li 2 TiO 3 powder was also prepared by the conventional solid-state reaction (SSR) and a good comparison between different routes was realized. The results show that the particle size of LTSSR powder is significantly decreased to 19.6 nm while the one obtained by SSR is 146.6 nm. Low temperature calcined powders have less agglomeration and higher sinterability, which can be sintered at lower temperature. Pebbles sintered from the LTSSR powders at 750 °C exhibit small grain size (650 nm), high relative density (85.1%) and satisfactory crush load (42.8 N), whereas the SSR pebbles can only be sintered above 950 °C with the relative density close to 80%. Besides, the LTSSR samples also have a higher conductivity at room temperature, indicating the lower tritium diffusion barrier in ceramics. It is confirmed that H 2 TiO 3 rather than TiO 2 is more appropriate for the solid-state reaction to produce Li 2 TiO 3 powders with nano-size particles and favorable properties. [ABSTRACT FROM AUTHOR]

Lithium metatitanate (Li 2 TiO 3) ceramic pebbles were fabricated from the powder synthesised via low-temperature solid-state precursor method. Solid H 2 TiO 3 and LiOH·H 2 O react chemically during ball milling process to form a nano-sized precursor powder. Pure β-Li 2 TiO 3 powder can be obtained by calcining the precursor powder at 500 °C, which is half the temperature of conventional solid-state method. The synthesis process is simple and low-cost, which would be more available to achieve batch production among all feasible techniques. The low-temperature calcination will effectively avoid hard particle aggregates and poor sinterability caused by high-temperature heat treatment, which is conducive to prepare ceramics with good properties. The results show that the powder exhibits high sinterability with small particle size of 19 nm. The Li 2 TiO 3 ceramic pebbles sintered at 800 °C have small grain size (470 nm), high relative density (83%) and good crush load (45 N), which has great potential as tritium breeding materials for fusion reactors. [ABSTRACT FROM AUTHOR]

In this study, Li 2 O porous ceramic pebbles were synthesized by decomposing the xLi 2 CO 3 -yLiNO 3 precursor pebbles at low temperature. This efficient decomposition reaction was mainly attributed to the two-stage support decomposition of Li 2 CO 3 and LiNO 3. The results indicated that the molar ratio of Li 2 CO 3 and LiNO 3 will directly affect the phase composition, pore structure and crush load of sintered pebbles. The high-purity Li 2 O ceramic pebbles sintered from Li 2 CO 3 –LiNO 3 precursor pebbles at 730 °C exhibits the open porosity of 24.8 ± 0.7%. The crush load of the ceramic reaches 21.18 ± 1.38 N although the structure was porous. The Li 2 O porous ceramics fabricated in this study will have potential application in tritium breeder materials. • High-purity Li 2 O porous ceramic pebbles can be achieved by a novel method. • Two-stage support decomposition can realize the efficient synthesis of Li 2 O. • The effect of Li 2 CO 3 /LiNO 3 molar ratio on the phase composition was clarified. • Li 2 O ceramic pebble shows high open porosity and satisfactory crush load. [ABSTRACT FROM AUTHOR]

An advanced core-shell ceramic pebble with Li 4 TiO 4 pure phase core and Li 2 TiO 3 nanostructured shell was prepared by a physical coating method. The phase compositions, morphology and microstructure of Li 4 TiO 4 –Li 2 TiO 3 core-shell ceramic pebbles were investigated. We discovered that using chitosan solution to assist rolling coating helps to improve the coating uniformity of core-shell green pebbles. In addition, the results show that the obtained Li 4 TiO 4 –Li 2 TiO 3 core-shell ceramic pebbles have a diameter of ∼1.1 mm, the shell thickness of ∼13 μm and density of 2.31 ± 0.03 g/cm3. It is also noted that the Li 2 TiO 3 shell still maintains the nanostructure (∼80 nm) after sintering. This study provides a feasible method for preparing Li 4 TiO 4 –Li 2 TiO 3 core-shell ceramic pebbles which have a great potential application for the test blanket module (TBM) of International Thermonuclear Experimental Reactor (ITER). [ABSTRACT FROM AUTHOR]

It is well‐known that phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor which negatively regulates PI3K/AKT signaling and is activated widely in non‐small cell lung cancers (NSCLC). However, genetic alterations in PTEN genes are rare, suggesting an undefined mechanism(s) for their suppression. Notably, growing evidence indicates that PTEN can be regulated by microRNAs involved in cancer progression. In this study, we discover that the miR‐4286 is overexpressed in NSCLC and negatively regulates the expression of PTEN. Furthermore, we found that miR‐4286 reduces PTEN expression by directly binding to PTEN 3′‐untranslated region (UTR), thereby inhibiting NSCLC cell proliferation and mobility. Moreover, mechanistic investigations revealed that miR‐4286 overexpression was a result of PTEN‐mediated activation of the PI3K/AKT pathway. Taken together, our findings elucidate that miR‐4286 promotes the tumorigenesis of NSCLC by interacting with PTEN. This miR‐4286‐mediated upregulation of PTEN might lead to new therapeutic strategies for NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Effects of cetyl trimethyl ammonium bromide (CTAB) on the formation of Li 2 TiO 3 nanocrystals during ethanol-water solvothermal reactions were investigated. Addition of CTAB changed Li 2 TiO 3 crystalline morphology from large to small aggregate particles due to the steric repulsion and electrostatic interaction of the CTAB ligands. Aggregate particle size of the Li 2 TiO 3 precursor was reduced from 455.2 to 138.7 nm by preventing their agglomeration after CTAB addition. This was followed by sintering the green body prepared with the CTAB-modified precursor powders using an indirect wet method, then the nanostructured Li 2 TiO 3 ceramic pebbles were obtained at relatively low temperatures from 750 to 800 °C for 4 h. Nanostructured Li 2 TiO 3 ceramic pebbles had small grains and a large number of grain boundaries, which might potentially improve the radiation tolerance, tritium release rate, and mechanical properties of Li 2 TiO 3 tritium breeder pebbles. In addition, grain growth mechanisms as function of different sintering temperatures, crush load as well as relative density of fabricated nanostructured Li 2 TiO 3 ceramic pebbles were also investigated. Highlights • The effects of CTAB on dispersibility of Li 2 TiO 3 precursor powders were further researched. • Sintering kinetics of Li 2 TiO 3 ceramic pebble and microstructure changes with variations in temperature were investigated. • A lower sintering temperature of nanostructured Li 2 TiO 3 ceramic pebble was obtained. • Relatively ideal sintering temperature was determined through synthetically evaluating grain size, crush load and relative density. [ABSTRACT FROM AUTHOR]

Abstract Using Nd and Ce with the ratio of 1:5 as simultaneous substitutions of trivalent and tetravalent actinides in gadolinium zirconate, a series of Gd 2-x Nd x Zr 2-5x Ce 5x O 7 (0 ≤ x ≤ 0.4) ceramics were prepared by rapid microwave sintering with a co-precipitation assisted solvothermal synthesized nanocrystalline powders. The simulated proportional nuclear waste disposal behaviours were identified by various characterization methods. XRD results show that when x is less than 0.4, all samples only have the single defect fluorite structure, while Gd 1.2 Ce 0.8 O 3.2 is formed in Gd 1.6 Nd 0.4 Ce 2 O 7 as x raise to 0.4. The relative density and average grain size both increase with the elevation of sintered temperature and x value. Sintering maps show that the obvious grain growth happens when x ≥ 0.3 and the densification processes can occur at different sintering temperatures with different x values. Highlights • Microwave sintering was employed to prepare Gd 2 Zr 2 O 7 -based ceramic waste forms. • Nd and Ce with ratio of 1:5 was firstly used to simulate nuclear waste. • Simulated nuclear waste has a solubility as high as 37.38 wt% in Gd 2 Zr 2 O 7 matrix. • The sintering map of Gd 2-x Nd x Zr 2-5x Ce 5x O 7 (0 ≤ x ≤ 0.4) ceramics has been plotted. [ABSTRACT FROM AUTHOR]

Abstract In this paper, a method combining hydrolysis of tetrabutyl orthotitanate (TBOT) and solvothermal reaction was first used to fabricate nanostructured Li 2 TiO 3 tritium breeder ceramic pebbles. Initially, superfine nanostructured Li 2 TiO 3 powders were synthesized with average particle size of about 10 nm, according to TEM. The surface area of precursor particles synthesized via this method was found to be 115.85 m2/g by BET analysis, which is much larger than that of the product obtained using traditional methods. The results showed that precursor particles had high sintering activity. XRD pattern revealed that the phase transition temperature for monoclinic phase Li 2 TiO 3 prepared by this method was nearly 450 °C, which was the lowest phase transition temperature reported among all wet chemical methods to date. Subsequently, investigation of ceramic sintering demonstrated that Li 2 TiO 3 ceramic pebbles with desired nano-crystalline sizes (27.98 ~ 55.03 nm) were obtained by sintering at 500 ~ 600 °C for 4 h. The possible mechanisms were proposed based on the reaction processes of TBOT hydrolysis, solvothermal reaction and sintering. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes. Results: We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR = 0.00188). In addition, we report ZNF750 and CDC27 , of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 × 10− 4). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR < 0.1). Conclusions: We report multiple factors that influence the mutational processes in ESCC including: the subpopulations of Chinese; the germline and somatic statuses of ZNF750 and CDC27 and exposure to alcohol and tobacco. Our findings based on the evidences from both germline and somatic levels reveal potential genetic regulators of the somatic mutational processes and provide insights into the biology of esophageal carcinogenesis. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of β2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders. [Display omitted] • Elevation of plasma B2M levels impairs cognitive and synaptic function • Peripheral depletion of B2M ameliorates synaptic deficits in DS mice • B2M antagonizes NMDAR function in an MHC-I- and TCR-independent manner • Blocking the B2M-NMDAR interaction corrects synaptic deficits in DS and aged mice β2-microglobulin dissociates from MHC-I complex, crosses the blood-brain barrier, antagonizes NMDA receptors, and impairs synaptic function under pathological conditions such as Down syndrome and aging. [ABSTRACT FROM AUTHOR]