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Abstract Organs-on-chips are microphysiological systems that allow to replicate the key functions of human organs and accelerate the innovation in life sciences including disease modeling, drug development, and precision medicine. However, due to the lack of standards in their definition, structural design, cell source, model construction, and functional validation, a wide range of translational application of organs-on-chips remains a challenging. “Organs-on-chips: Intestine” is the first group standard on human intestine-on-a-chip in China, jointly agreed and released by the experts from the Chinese Society of Biotechnology on 29th April 2024. This standard specifies the scope, terminology, definitions, technical requirements, detection methods, and quality control in building the human intestinal model on a chip. The publication of this group standard will guide the institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of intestine-on-a-chip for translational applications.

There are a large number of overlapping coal and natural gas resources in China, and due to the requirement of resource extraction efficiency, a large number of overlapping coal and natural gas resources need to be extracted synchronously in the same time and space, and the traditional coal and natural gas extraction theories and technologies are difficult to meet the technical problems arising from coordinated extraction, and the process of coordinated extraction of coal and natural gas has been seriously constrained. Based on this, a scientific definition of coal and natural gas synergistic mining is made based on the overlapping coal and natural gas resources in China, and the existing coal and natural gas mining technologies and related theories are summarised. We have established the near-field rock mechanics theory of natural gas wells, the coupled damage theory of natural gas near-field surrounding rock, the coupled damage theory of “surrounding rock-cement ring-casing”, and the coupled damage theory of vertical surrounding rock of coal and natural gas synergistic mining, which reveal the coupled damage mechanism of surrounding rock of coal and natural gas synergistic mining, and provide a theoretical basis for the construction of the technology system of coal and natural gas. It provides a theoretical basis for the construction of coal and natural gas technology system. The three technologies of “Coal and Natural Gas Cooperative Mining Technology”, “Coal Mining through Abandoned Wells Technology” and “Natural Gas Near-Field Small Coal Pillar Retention Technology” are proposed, as well as the “Coal and Natural Gas Cooperative Mining Zoning Planning Technology”. Three major systems, namely, “Coal and Natural Gas Cooperative Mining Zoning Planning System”, “Transparent Geological and Production Information Dynamic Monitoring System” and “Coal and Natural Gas Cooperative Zone Safety Monitoring and Evaluation System”, provide technical support for coal and natural gas cooperative mining, and improve the safety of coal and natural gas production. This system provides technical support for the synergistic mining of coal and natural gas and improves the mining efficiency of coal and natural gas resources. On this basis, the theoretical and technological system of coal and natural gas synergistic mining is constructed, the future research focus of coal and natural gas synergistic mining is clarified, and the technological path and research direction for the safe, green and high-efficiency synergistic mining of coal and natural gas resources in China are proposed.

ABSTRACTIdentifying tumor-relevant T cell subsets in the peripheral blood (PB) has become a potential strategy for cancer treatment. However, the subset of PB that could be used to treat cancer remains poorly defined. Here, we found that the CX3CR1+ T cell subset in the blood of patients with lung cancer exhibited effector properties and had a higher TCR matching ratio with tumor-infiltrating lymphocytes (TILs) compared to CX3CR1− T cells, as determined by paired single-cell RNA and TCR sequencing. Meanwhile, the anti-tumor activities, effector cytokine production, and mitochondrial function were enhanced in CX3CR1+ T cells both in vitro and in vivo. However, in the co-culture system of H322 cells with T cells, the percentages of apoptotic cells and Fas were substantially higher in CX3CR1+ T cells than those in CX3CR1− T cells. Fas-mediated apoptosis was rescued by treatment with an anti-PD-1 antibody. Accordingly, the combination of adoptive transfer of CX3CR1+ T cells and anti-PD-1 treatment considerably decreased Fas expression and improved the survival of lung xenograft mice. Moreover, an increased frequency of CX3CR1+ T cells in the PB correlated with a better response and prolonged survival of patients with lung cancer who received anti-PD-1 therapy. These findings indicate the promising potential of adoptive transfer of peripheral CX3CR1+ T cells as an individual cancer immunotherapy.

BackgroundThyroid hormones significantly influence cardiovascular pathophysiology, yet their prognostic role in acute aortic dissection (AAD) remains inadequately explored. This study assesses the prognostic value of thyroid hormone levels in AAD, focusing on the mediating roles of renal function and coagulation.MethodsWe included 964 AAD patients in this retrospective cohort study. Utilizing logistic regression, restricted cubic splines, and causal mediation analysis, we investigated the association between thyroid hormones and in-hospital mortality and major adverse cardiovascular events (MACEs).ResultsIn AAD patients overall, an increase of one standard deviation in FT4 levels was associated with a 31.9% increased risk of MACEs (OR 1.319; 95% CI 1.098–1.584) and a 36.1% increase in in-hospital mortality (OR 1.361; 95% CI 1.095–1.690). Conversely, a higher FT3/FT4 ratio was correlated with a 20.2% reduction in risk of MACEs (OR 0.798; 95% CI 0.637–0.999). This correlation was statistically significant predominantly in Type A AAD, while it did not hold statistical significance in Type B AAD. Key renal and coagulation biomarkers, including blood urea nitrogen, creatinine, cystatin C, prothrombin time ratio, prothrombin time, and prothrombin time international normalized ratio, were identified as significant mediators in the interplay between thyroid hormones and MACEs. The FT3/FT4 ratio exerted its prognostic influence primarily through the mediation of renal functions and coagulation, while FT4 levels predominantly impacted outcomes via a partial mediation effect on coagulation.ConclusionFT4 levels and the FT3/FT4 ratio are crucial prognostic biomarkers in AAD patients. Renal function and coagulation mediate the association between the thyroid hormones and MACEs.

Background: Angiogenesis plays a critical protective role in myocardial ischemia-reperfusion injury (MIRI); however, therapeutic targeting of associated genes remains constrained. To bridge this gap, we conducted bioinformatics analysis to identify pivotal angiogenesis-related genes in MIRI, potentially applicable for preventive and therapeutic interventions. Methods: We collected two mouse heart I/R expression datasets (GSE61592 and GSE83472) from Gene Expression Omnibus, utilizing the Limma package to identify differentially expressed genes (DEGs). Angiogenesis-related genes (ARGs) were extracted from GeneCards, and their overlap with DEGs produced differentially expressed ARGs (ARDEGs). Further analyses included Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and disease ontology to explore biological functions. Weighted gene correlation network analysis (WGCNA) was used to investigate molecular modules linked to MIRI. Additionally, a protein–protein interaction (PPI) network was constructed to pinpoint hub genes relevant to MIRI. Receiver operating characteristic curves were used to assess the diagnostic efficacy of these hub genes for MIRI. An ischemia-reperfusion injury model was established using human cardiac microvascular endothelial cells (HCMECs), with the expression of hub genes validated within this experimental framework. Results: We identified 47 ARDEGs, 41 upregulated and 6 downregulated. PPI network analysis revealed suppressor of cytokine signaling 3 (Socs3), C-X-C motif chemokine ligand 1 (Cxcl1), interleukin 1 beta (Il1b), and matrix metallopeptidase 9 (Mmp9) as hub genes. Receiver operating characteristic (ROC) curve analysis demonstrated strong diagnostic potential for Socs3, Cxcl1, Il1b, and Mmp9. In vitro validation corroborated the mRNA and protein expression predictions. Conclusions: Our study highlights the pivotal role of Socs3, Cxcl1, Il1b, and Mmp9 in MIRI development, their significance in immune cell infiltration, and their diagnostic accuracy. These findings offer valuable insights for MIRI diagnosis and treatment, presenting potential molecular targets for future research.

After high gas mines coal mining reaches deep, the issue of rockburst has become increasingly prominent. Aiming at solving the problem of rock burst in high gas mines, the coupling mechanism of anti-rockburst and pressure relief in gas drainage boreholes along seam has been explored. The research results indicate that gas drainage boreholes can reduce the stress environment of coal, making the peak stress transfer to deep coal. The pressure relief effect of gas drainage boreholes is slightly weaker than that of large diameter pressure relief boreholes. Moreover, the presence of gas pressure can weaken the mechanical properties of coal. The compressive strength, elastic modulus, cohesion, and internal friction angle of coal all show varying degrees of attenuation with the increase of gas pressure. Besides, a stress analysis was conducted on borehole surrounding rock, and mathematical derivation was also carried out. The expressions for radial stress and circumferential stress of the coal at the boundary of the plastic zone of the borehole surrounding rock, as well as the analytical solution for the boundary of the plastic zone, are obtained. In addition, the gas in pressure relief borehole act on the coal in the pressure relief zone, causing deterioration of the mechanical properties of the coal around the pressure relief boreholes. The expansion range of the radius of the borehole pressure relief zone will increases, and the borehole pressure relief effect will enhance, promoting the formation of coal weakening zones. The above is the coupling mechanism of anti-rockburst and pressure relief in gas drainage boreholes, which has been confirmed by numerical simulation for reliability.

Background: Managing systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) is pivotal in acute aortic dissection (AAD) care. However, no prior studies have jointly analyzed the trajectories of these parameters. This research aimed to characterize their joint longitudinal trajectories and investigate the influence on AAD prognosis. Methods: We included AAD patients from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Using group-based multi-trajectory modeling (GBMTM), we identified combined trajectories of SBP, DBP, and HR within the initial 24 h of intensive care unit (ICU) admission. Cox proportional hazard regression, log-binomial regression, and logistic regression were employed to assess the association between trajectory groups and mortality outcomes. Results: Data from 337 patients were analyzed. GBMTM identified five combined trajectory groups. Group 1 featured rapidly declining SBP and DBP with high pulse pressure and low HR; Group 2 showed high to moderate SBP with slight rebound and persistently low HR; Group 3 displayed persistently moderate BP and HR; Group 4 was characterized by moderate blood pressure with persistently high HR; and Group 5 had high to moderate SBP with slight rebound, high but gradually declining DBP, and slightly high HR. Group 3 demonstrated a lower risk of mortality, with an adjusted hazard ratio of 0.32 (95 % CI, 0.14–0.74), and the adjusted relative risks for in-hospital, 30-day, and 1-year mortalities were 0.37 (95 % CI, 0.15–0.87), 0.25 (95 % CI, 0.10–0.62), and 0.41 (95 % CI, 0.22–0.79), respectively. The time-independent C-index curve demonstrated that the multi-trajectory groups had higher C-index values than any univariate trajectory groups or admission values of SBP, DBP, and HR. Conclusions: Utilization of GBMTM can yield data-driven insights to identify distinct subphenotypes in AAD patients. The combined trajectories of SBP, DBP, and HR within 24 h of ICU admission significantly influenced the mortality rate.

Drought is one of the most hazardous environmental factors due to its severe damage on plant growth, development and productivity. Plants have evolved complex regulatory networks and resistance strategies for adaptation to drought stress. As a conserved epigenetic regulation, DNA methylation dynamically alters gene expression and chromosome interactions in plants’ response to abiotic stresses. The development of omics technologies on genomics, epigenomics and transcriptomics has led to a rapid increase in research on epigenetic variation in non-model crop species. In this review, we summarize the most recent findings on the roles of DNA methylation under drought stress in crops, including methylating and demethylating enzymes, the global methylation dynamics, the dual regulation of DNA methylation on gene expression, the RNA-dependent DNA methylation (RdDM) pathway, alternative splicing (AS) events and long non-coding RNAs (lnc RNAs). We also discuss drought-induced stress memory. These epigenomic findings provide valuable potential for developing strategies to improve crop drought tolerance.

When employing the open stope mining method for extracting materials in underground mines, it is necessary for personnel and equipment to operate within a specified range of the goaf area, thus, adoption of appropriate mining parameters in the mining field is crucial for promoting safe production practices. In this study, the Harazi iron mine is taken as the research subject, with theoretical analysis combined with numerical simulation that enables the authors to simulate and analyze the width parameter of the mining field. Theoretical analysis utilizing the Matthew stability chart method confirms that the width of the mining field in Harazi iron mine should not exceed 9 m. Based on this finding, the mechanical response characteristics accompanying the mining process at different widths within the mining field limits are analyzed via the Flac3D numerical analysis software. As a result of this analysis, the optimal width of the mining field in Harazi iron mine is determined to be 8 m. The method utilized in this article provides a rational approach to determining structural parameters of the mining field and can effectively aid in promoting mine safety practices.

Abstract Red ginseng has been used in traditional medicine for centuries in Asia. In this study, we evaluated four types of red ginseng grown in different areas (Chinese red ginseng, Korean red ginseng A, Korean red ginseng B, and Korean red ginseng C) for their ability to inhibit lung tumor formation and growth induced by the carcinogen benzo(a)pyrene (B(a)P) in A/J mice and found that Korean red ginseng B was the most effective at lowering the tumor load among the four red ginseng varieties. Moreover, we analyzed the levels of various ginsenosides (Rg1, Re, Rc, Rb2, Rb3, Rb1, Rh1, Rd, Rg3, Rh2, F1, Rk1, and Rg5) in four kinds of red ginseng extract and found that Korean red ginseng B had the highest level of ginsenoside Rg3 (G-Rg3), which suggested that G-Rg3 may play an important role in its therapeutic efficacy. This work revealed that the bioavailability of G-Rg3 was relatively poor. However, when G-Rg3 was coadministered with verapamil, a P-glycoprotein inhibitor, the G-Rg3 efflux in Caco-2 cells was lowered, the small intestinal absorption rate of G-Rg3 in the rat models was increased, the concentration levels of G-Rg3 were elevated in the intestine and plasma, and its tumor-preventive abilities in the tumorigenesis rat model induced by B(a)P were also augmented. We also found that G-Rg3 reduced B(a)P-induced cytotoxicity and DNA adduct formation in human lung cells and rescued phase II enzyme expression and activity through Nrf2 pathways, which may be the potential mechanisms underlying the inhibitory effects of G-Rg3 on lung tumorigenesis. Our study showed a potentially vital role of G-Rg3 in targeting lung tumors in murine models. The oral bioavailability of this ginsenoside was augmented by targeting P-glycoprotein, which allowed the molecule to exert its anticancer effects.

The loess deposits widely distributed in the eastern Tibetan Plateau (ETP) are important archives for reconstructing the paleoenvironmental changes and dust transportation history of the Tibetan Plateau. A lack of sufficient investigations on the source of the ETP loess has limited our understanding of dust transportation and paleoenvironmental implications. Quartz luminescence sensitivity holds great potential for tracing eolian dust sources. Numerous quartz luminescence sensitivity investigations have provided new insights into the dust sources and transportation of the Chinese loess. However, studies on luminescence sensitivity and its significance for the ETP loess provenance are scarce. In this work, we selected quartz grains in loess from different sites of the ETP to investigate the variation of luminescence sensitivity by testing the 110°C thermoluminescence (TL) peak and optically stimulated luminescence (OSL) sensitivities of quartz grains and discussed the provenance implications for the ETP loess based on quartz luminescence sensitivities. Our results show the quartz luminescence sensitivities of loess at different locations were significantly different in the ETP. The luminescence sensitivity values of the Machang (MC), Xiaojin (XJ), and Wenchuan (WCH) sections were much higher than those of the Xinshi (XS) and Zhouqu (ZQ) sections. The sensitivity values of the 110°C TL peaks and OSL in the paleosol and loess layers show distinct differences. The quartz luminescence sensitivities of the ETP loess are mainly influenced by the dust sources. Our results show that the luminescence sensitivities of quartz grains have great potential for identifying the loess sources in the ETP.

Objective: We aimed to construct a novel prognostic model based on N6-methyladenosine (m6A)-related autophagy genes for predicting the prognosis of lung squamous cell carcinoma (LUSC). Methods: Gene expression profiles and clinical information of Patients with LUSC were downloaded from The Cancer Genome Atlas (TCGA) database. In addition, m6A- and autophagy-related gene profiles were obtained from TCGA and Human Autophagy Database, respectively. Pearson correlation analysis was performed to identify the m6A-related autophagy genes, and univariate Cox regression analysis was conducted to screen for genes associated with prognosis. Based on these genes, LASSO Cox regression analysis was used to construct a prognostic model. The corresponding prognostic score (PS) was calculated, and patients with LUSC were assigned to low- and high-risk groups according to the median PS value. An independent dataset (GSE37745) was used to validate the prognostic ability of the model. CIBERSORT was used to calculate the differences in immune cell infiltration between the high- and low-risk groups. Results: Seven m6A-related autophagy genes were screened to construct a prognostic model: CASP4, CDKN1A, DLC1, ITGB1, PINK1, TP63, and EIF4EBP1. In the training and validation sets, patients in the high-risk group had worse survival times than those in the low-risk group; the areas under the receiver operating characteristic curves were 0.958 and 0.759, respectively. There were differences in m6A levels and immune cell infiltration between the high- and low-risk groups. Conclusions: Our prognostic model of the seven m6A-related autophagy genes had significant predictive value for LUSC; thus, these genes may serve as autophagy-related therapeutic targets in clinical practice.

AbstractTo study the response characteristics of coal samples to impact load under different surrounding pressures, the self-developed magnetic drop hammer impact device was used to measure the change of ultrasonic wave velocity before and after drop hammer impact, the internal damage of coal samples was quantitatively characterized, and then, the damage factor, damage difference, and crack development direction of briquette samples were analyzed. Based on the Griffith strength theory, the relationship between stress intensity factor, crack development angle, and surrounding pressure ratio of coal samples with composite cracks was deduced. It was found that a certain surrounding pressure would slow crack expansion and reduce the amount of damage increase. The damage degree of briquette samples caused by impact load under no surrounding pressure is the largest, followed by that at the surrounding pressure ratio of 0 and 2 and that at the surrounding pressure ratio of 1 is the smallest. When the amount of damage difference of the sample is positively correlated with the number of impacts, the crack development is directional; when the amount of damage difference of the sample is nonpositively correlated with the number of impacts, the direction of crack development is random. It is therefore reasonable to predict the direction of crack expansion by the trend in the amount of damage difference. Besides, the difference in impact load between briquette and raw coal samples under different surrounding pressure ratios was discussed, and the fractal dimension of the sample surface under different surrounding pressure ratios was compared and analyzed. It is found that the fractal dimension of raw coal is larger than that of briquette, indicating that the crack development of raw coal is higher after impact; the damage amount of raw coal is larger than that of briquette, indicating that raw coal is easier to be damaged after impact.

As an essential part of artificial intelligence, a knowledge graph describes the real-world entities, concepts and their various semantic relationships in a structured way and has been gradually popularized in a variety practical scenarios. The majority of existing knowledge graphs mainly concentrate on organizing and managing textual knowledge in a structured representation, while paying little attention to the multimodal resources (e.g., pictures and videos), which can serve as the foundation for the machine perception of a real-world data scenario. To this end, in this survey, we comprehensively review the related advances of multimodal knowledge graphs, covering multimodal knowledge graph construction, completion and typical applications. For construction, we outline the methods of named entity recognition, relation extraction and event extraction. For completion, we discuss the multimodal knowledge graph representation learning and entity linking. Finally, the mainstream applications of multimodal knowledge graphs in miscellaneous domains are summarized.

It is a significant challenge in lung cancer chemophotothermal (CPT) therapy to develop multifunctional theranostic nanoagent (MTN) for precise targeting and successful tumor treatments, especially for lung metastasis. To overcome this problem, we effectively design and construct multifunctional black phosphorus (BP) nanoagents, BPs/G-Rg3@PLGA. BPs quantum dots (BPsQDs) are co-loaded onto poly(lactic-co-glycolic acid) (PLGA) with subsequent conjugations of a cancer therapeutic compound, ginsenoside Rg3 (G-Rg3), in this composite nanoagent. The in vivo delivery findings suggest that BPs/G-Rg3@PLGA has an excellent affinity for primary tumors and metastatic lung tumors. Furthermore, when paired with near-light irradiation, BPs/G-Rg3@PLGA shows superior controllable CPT therapy synergetic therapeutics, significantly increasing photothermal tumor ablation effectiveness. Mechanistically, heating causes rapid G-Rg3 release from the non-complex, and thermal therapy induces apoptosis, culminating in the reduction of lung cancer metastasis. Additionally, in vivo and in vitro findings support the biocompatibility of BPs/G-Rg3@PLGA. This thesis identifies a versatile BPs-based MTN for lung cancer metastasis control.

With the increasing depth and intensity of coal mining, there is an increasing risk to the working face due to high static load and periodic breakage of the roof. The relation between the support and the surrounding rock under static–dynamic coupling loading disturbance is an important factor affecting the stability of the working face. In this study, a 3D physical modeling platform is developed to study the interaction between the shield and strata under dynamic and static disturbance. In the experiment, the static load is set to 0, 0.5, 1, and 2 MPa, respectively. The different dynamic load is realized by changing the fall height of the iron plate. The change in hydraulic support resistance is recorded by the pressure monitoring system. The displacement of the coal wall is monitored by using an infrared rangefinder. The results show that the change in static load and dynamic load will affect the support resistance and coal wall displacement. With the increase in dynamic load, coal wall displacement, and bracket resistance increase, the increase is not linear. The larger the dynamic load, the greater the increase. Static load change has little effect on bracket resistance, and the impact on coal wall displacement is large. With the increase in static load, coal wall displacement is reduced and then increased. In static load, for the stability of coal wall, there is a threshold; below the threshold, the static load can improve the stability of coal wall, exceed the threshold, but accelerate the destruction of coal wall. At the same time, the stability coefficient of the quarry bracket and surrounding rock is defined. The sensitivity analysis of the main parameters is carried out. The method of controlling the stability of the quarry bracket and surrounding rock is proposed.

Abstract Longwall face fall in the open face area is one of the most difficult ground control problems in mining thick coal seams in China especially under difficult geological conditions. This paper has proposed a new flexible bolting and grouting technology for face support. The flexible support method includes face support using flexible coir ropes and face grouting with cement and accelerator mixtures. Numerical and laboratory studies of pullout tests are performed to further improve the flexible support performance including optimization of boreholes and flexible bolts diameters, and selection of grouting materials. The results show that (a) The optimized rope‐borehole diameter ratio is around 0.5 to ensure the best face reinforcement; (b) The grouting material (a mixture of ultrafine cement, mineral powder and sodium silicate) shows advantages of low cost, effective waste disposal, reduced setting time, and good pullout limit force and is recommended for industrial application with sodium silicate at a proportion of 10% by weight and mineral powder at 30%. The application of the new flexible bolting and grouting method in Chenmanzhuang mine shows improved face stability and reduced capital cost.

The longwall panel of the Jiulishan coal mine is affected by floor-confined water, while the roof rock weighting makes the production management of some longwall panels difficult. This has caused engineering methods of roof cutting and pressure release to be considered. To explore the dynamic effects of roof cutting and pressure release method, the 14141 longwall panel was taken as the test point, and a variety of monitoring methods were used to comprehensively analyze the characteristics of roof rock weighting, front abutment pressure, and floor mining failure. The main results are as follows: first, the weighting interval, the weighting intensity distribution, and the gateway deformation are asymmetrical. Second, the peak point of the front abutment pressure is approximately 6 m away from the coal wall, the peak stress is 7.02 MPa, the concentration coefficient is 1.54, the range of the pressure increasing area is approximately 16.4 m, and the farthest end of the front abutment pressure effect area is 22.4 m away from the coal wall. Furthermore, the maximum depth of the floor failure is at the No.17 measuring point (A117) position under the condition of one electrode distance. The maximum damage depth is 9.8 m, and the horizontal distance between the location of the maximum failure depth and the working face is 4.1~10.3 m. Finally, compared with the formula calculation value without considering the effect of roof cutting and pressure release or the adjacent 14121 longwall panel, the weighting interval and the weighting intensity, the gateway deformation, the degree of coal wall spalling, the influence range of the front abutment pressure, and the degree of floor mining failure are significantly reduced. The research results provide scientific and technological support for roof cutting and pressure release as a technical method to prevent floor water inrush and reduce the roof rock weighting intensity on the longwall panel.

The aim of developing academic resilience and motivational intensity, as two constructs of positive psychology, is to increase learners' capability to compete with each other even in adverse conditions. Different types of academic resilience are conceptualized and germane literature about the relationship between academic resilience and academic achievement is provided. Literature showed that some socio-affective factors (e.g. peer relations, parents' high expectations, teachers' attention, and kindness, etc.), socio-economic factors (e.g. the financial contribution of parents' to education, economic and social class level, etc.), and affective factors (e.g. anxiety, self-efficacy, motivation and so on) can influence learners' academic achievement and policy makers' decision in providing an appropriate context for learning. In the end, the pedagogical implications are expounded to foster the language learning quality and to develop a language educational system. Suggestions for further research are provided to develop the existent literature on the relationship between academic, motivational intensity, and learners' academic achievement.

The westerlies play an important role in driving climate change in the Tibetan Plateau (TP). However, little is known about the history of the westerlies in the TP owing to limited observations and a lack of robust reconstructions. The widely distributed eolian loess in the eastern TP is one of the ideal materials to retrieve the intensity history for the westerlies. A detailed grain-size and endmember model analysis (EMMA) on the Ganzi loess sequence located in the eastern TP revealed that the EMMA decomposed the loess grain-size components into four endmembers: EM1 (modal size 1.42 μm) is related to pedogenesis, and EM2 (modal size 7.10 μm) is transported by the westerlies. Silt modes (EM3 and EM4) are transported by the TP winter monsoon or near-surface airflows. The mass accumulation rate (MAR) of EM2 indicated the westerly variations. Combined with the MAR, we reconstructed the history of westerly intensity since the last interglacial period from the Ganzi loess sequence. We found that the intensity of the westerlies showed typical glacial/interglacial variations since the last interglacial period in the eastern TP. The westerly intensity was strong with large fluctuations during the glacial period, whereas it was weak and stable during the Holocene and the last interglacial. The temperature gradient between high and low latitudes caused by changes in insolation and ice volume in the northern hemisphere were the dominant forcing mechanisms for the westerly intensity variations.

Constitutive models play a significant role in understanding the deformation behavior of materials and in optimizing the manufacturing process. In order to improve the reliability of calculation results, the high temperature flow behavior of TA31 titanium alloy obtained from an annealed hot-rolled plate has been investigated by a Gleeble-3500 thermo-mechanical simulator. The isothermal hot compression tests are conducted in the temperature range of 850 to 1050 °C and the strain rate range from 0.001 to 10 s−1 with a height reduction of 60%. The annealed TA31 shows a dynamic recovery characteristic during thermo-mechanical processing. The experimental data have been used to develop an Arrhenius-type constitutive model and a modified Johnson–Cook model under the consideration of coupling effect on strain, temperature, and strain rate, as well as the strain-softening phenomenon. The material parameters are determined by a global optimization method based on the initial values by means of a regression method. A comparation of the predicted results has been performed based on the modified Johnson–Cook model and those acquired from the Arrhenius-type model. The correlation coefficient and average absolute relative error of the modified Johnson–Cook model are 4.57% and 0.9945, respectively. However, when the optimization method has been applied, they are 15.77% and 0.9620 for the Arrhenius-type model, respectively. These results indicate that the modified Johnson–Cook model is more accurate and efficient in predicting the flow stress of annealed TA31 titanium alloy under a set of model material parameters. Furthermore, the simple mathematical expression of this model is helpful to incorporate it into the finite element software to obtain detailed and valuable information during the thermo-mechanical processing simulation for TA31 in further work.

Aeolian sediments hold key information on aeolian history and past environmental changes. Aeolian desertification and extensive land degradation have seriously affected the eco-environment in the Gannan region on the eastern Tibetan Plateau. Understanding the history of aeolian activities can deepen our understanding of the impacts of climatic changes on aeolian activities in the future. This study uses a detailed chronology and multiple proxy analyses of a typical aeolian section in Maqu to reconstruct aeolian activities in the region during the Holocene. Our results showed that aeolian activities have occurred in the eastern Tibetan Plateau since the early Holocene. Magnetic susceptibility, grain size records, and paleosols formation indicated a trend of stepwise weakening in aeolian activities from the early Holocene to the present. The weakening of aeolian activities was divided into three stages: ∼10.0–8.0 ka BP, ∼8.0–4.0 ka BP, and ∼4.0 ka BP to the present. Paleosols were primarily formed after ∼8.0 ka BP, and episodically interrupted aeolian activities processes in the Gannan region. Aeolian activity may increase in the Gannan region as the climate gradually warms. Climatic changes and local hydrological conditions have jointly affected the history of aeolian activities in this region.

The short-chain dehydrogenase/reductase (SDR) from Empedobacter brevis ZJUY-1401 (EbSDR8, GenBank: ALZ42979.1) is a promising biocatalyst for the reduction of acetophenone to (R)-1-phenylethanol, but its industrial application is restricted by its insufficient tolerance to acetophenone. In this paper, we developed a chromogenic reaction-based high-throughput screening method and employed directed evolution to enhance the acetophenone tolerance of EbSDR8. The resulting variant, M190V, showed 74.8% improvement over the wild-type in specific activity when catalyzing the reduction of 200 mM acetophenone. Kinetic analysis revealed a 70% enhancement in its catalytic efficiency (kcat/Km). Molecular docking was conducted to reveal the possible mechanism behind the improved acetophenone tolerance, and the result implied that the M190V mutation is conducive to the binding and release of coenzyme. Aside from the improved catalytic performance when dealing with a high concentration of acetophenone, other features of M190V, such as a broad pH range (6.0 to 10.5), low optimal cosubstrate concentration (1% isopropanol), and a temperature optimum close to that of E. coli cells (35 °C), also contribute to its practical application as a whole-cell catalyst. In this study, we first designed a directed evolution means to engineer the enzyme and obtained the positive variant which has a high activity under high concentrations of acetophenone. After that, we optimized the catalytic performance of the variant to adapt to industrial applications.

Abstract Background A novel phosphatidyl nanoprodrug system can be selectively released parent drugs in cancer cells, triggered by the local overexpression of phospholipase D (PLD). This system significantly reduces the intrinsic disadvantages of conventional chemotherapeutic drugs. However, the separation and purification processes of phosphatidyl prodrug, the precursor of phosphatidyl nanoprodrug, have not been established, and the preparation of nanocrystals with good stability and tumor-targeting capability is still challenging. Results In this study, we established a successive elution procedure for the phosphatidyl prodrug—phosphatidyl mitoxantrone (PMA), using an initial ten-bed volume of chloroform/methanol/glacial acetic acid/water (26/10/0.8/0.7) (v/v/v/v) followed by a five-bed volume (26/10/0.8/3), with which purity rates of 96.93% and overall yields of 50.35% of PMA were obtained. Moreover, to reduce the intrinsic disadvantages of conventional chemotherapeutic drugs, phosphatidyl nanoprodrug—PMA nanoprodrug (NP@PMA)—was prepared. To enhance their stability, nanoparticles were modified with polyethylene glycol (PEG). We found that nanoprodrugs modified by PEG (NP@PEG–PMA) were stably present in RPMI-1640 medium containing 10% FBS, compared with unmodified nanoprodrug (NP@PMA). To enhance active tumor-targeting efficiency, we modified nanoparticles with an arginine-glycine-aspartic acid (RGD) peptide (NP@RGD–PEG–PMA). In vitro cytotoxicity assays showed that, compared with the cytotoxicity of NP@PEG–PMA against tumor cells, that of NP@RGD–PEG–PMA was enhanced. Thus, RGD modification may serve to enhance the active tumor-targeting efficiency of a nanoprodrug, thereby increasing its cytotoxicity. Conclusions A process for the preparation and purification of novel phosphatidyl prodrugs was successfully established, and the nanoprodrug was modified using PEG for enhanced nanoparticle stability, and using RGD peptide for enhanced active tumor-targeting efficiency. These procedures offer considerable potential in the development of functional antitumor prodrugs.

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) occurs more frequently in cancer patients than in the general population. A retrospective cross-sectional study was carried out in patients with solid tumor complicated with VTE admitted to the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 1st, 2008 and December 31th, 2017. The incidence of VTE in hospitalized cancer patients was 1.8%, twice the incidence of VTE in hospitalized non-cancer patients. The annual incidence of cancer-associated VTE in our center varied between 1.6% in 2015 and 0.4% in 2009 with an overall average incidence of 1.3% over the research decade. BMI values of 549(67.7%) cancer patients were within the normal range, but none of patients had BMI greater than 35 kg/m 2 . 747(92.1%) cancer patients had ECOG PS score ≤ 2 and 481(59.3%) had distant metastasis. Patients with pancreatic, bladder, ovarian and endometrial cancer had the highest incidence of VTE. Upper extremity DVT (47.2%) was more common in cancer patients and might be closely associated with CVC (74.9%), while lower extremities DVT (36.1%) intended to PE development (15.0%). The annual incidence rates showed a fluctuating and upward trend over the research decade. VTE occurrence was closely related to tumor stage, tumor site, catheterization and anti-neoplasm therapy in cancer patients.

Microcharcoal is a proxy of biomass burning and widely used in paleoenvironment research to reconstruct the fire history, which is influenced by the climate and land cover changes of the past. At present, microcharcoal characteristics (amount, size, shape) are commonly quantified by visual inspection, which is a precise but time-consuming approach. A few computer-assisted methods have been developed, but with an insufficient degree of automation. This paper proposes a new methodology for microcharcoal statistical analysis based on digital image processing by ImageJ software, which improves statistical efficiency by 80–90%, and validation by manual statistical comparison. The method is then applied to reconstruct the fire-related environmental change in the Weiyuan loess section since about 40 thousand years before present (ka BP), northwest China with a semi-arid climate, found that the microcharcoal concentration is low in cold and dry climate and high in warm and humid climate. The two main contributions of this study are: 1) proposal of a new, reliable and high efficient automatic statistical method for microcharcoal analysis; and 2) using the new method in a semi-arid section, revealing the paleofire evolution patterns in the semi-arid region was mainly driven by the biomass rather than the aridity degree found in humid regions.

IntroductionRHPN2, a member of rhophilin family of rho-binding proteins, regulates actin cytoskeleton and vesicular trafficking, and promotes mesenchymal transformation in cancer. We have found that RHPN2 was significantly mutated in lung adenocarcinoma (LUAD). However, the role of RHPN2 in lung cancer is not fully understood.MethodsIn the present study, we investigated the expression of RHPN2 in 125 patients with LUAD by qRT-PCR and correlated its expression with clinical characteristics. The effects of RHPN2 on the proliferation and invasion of lung cancer cells were determined by CCK-8 and in vitro transwell assays, clonogenic assay, and xenograft mouse model. The RhoA pull down assay and Western blotting were performed to elucidate the mechanism of RNPN2 in tumorigenesis of lung cancer.ResultsRHPN2 was overexpressed in tumors from LUAD, and high levels of RHPN2 were associated with poor prognosis of LUAD patients. RHPN2 was required for proliferation and invasion of lung cancer cells. Intriguingly, overexpression of RHPN2 conferred the resistance to glutamine depletion in lung cancer cells. Mechanistic studies revealed that ectopic overexpression of RHPN2 promoted the stability of c-Myc protein via phosphorylation at Ser62 and increased c-Myc target glutamine synthetase (GS). Analysis of GS expression in clinical sample showed that the expression of GS was elevated in tumor cells. Kaplan-Meier analysis revealed that high levels of GS were significantly associated with worse overall survival time of the patients with LUAD.ConclusionsTaken together, this study suggested that RHPN2 was involved in tumorigenesis of lung cancer via modulating c-Myc stability and the expression of its target GS in lung adenocarcinoma, which links RHPN2 and glutamine metabolism.

The aim of this study is to explore the coupling relationship between fractures in overlying strata and gas seepage fields for pressure relief during mining of outburst-prone coal seam groups and to quantitatively characterize the distribution characteristics of favorable areas for coalbed methane (CBM) drainage in mining-induced fractures of overlying strata. For these purposes, by taking Shaqu No. 1 Coal Mine (Lvliang City, Shanxi Province, China) as a research object, this research studied migration and caving characteristics of overlying strata by combining physical similar material simulation, numerical simulation, and field measurement. Moreover, this study analyzed spatial distribution patterns of mining-induced fractures in overlaying strata, quantitatively characterized distribution parameters of asymmetric-oblique-quadrilateral fracture development zones in overlying strata, and precisely divided areas favorable for CBM drainage. On this basis, evolution laws of an asymmetric fracture-seepage community in overlying strata in outburst-prone coal seam groups were obtained, thus optimizing design parameters for directional drilling in the fracture zone in overlying strata. The research results demonstrate that, due to mining-induced influences, strata present different migration and rupture patterns along rupture lines on both sides. Because of different rupture angles α and β, mining-induced fractures in overlying strata are distributed as an asymmetric-oblique-quadrilateral fracture development body in space. Furthermore, based on the coupling relationship between fracture development states and pressure-relief gas seepage in the fracture development zone in overlying strata of the 4305 rear working face in the mine, this research obtained rupture angles α ∈ [74, 90) and ß ∈ (70, 82] on both sides of the fracture development zone. Moreover, the intervals favorable for CBM drainage for pressure relief on both sides of the fracture development zone in overlying strata of 4305 rear working face in the mine were separately determined as xaj ≤ 22.68 m and 24 m ≤ xβj ≤ 37.8 m. If the gas drainage system is designed in this zone, it is of great significance to precise and efficient pressure-relief CBM drainage in the fracture zone and ensure production safety in the mining space.

The dynamic hazards in the open face area caused by the impact load of the massive strong roof become increasingly severe with the increase in the cutting height of the longwall face and its depth of cover. Understanding the strata-shield interaction under the dynamic impact loading condition may relieve the dynamic hazards. In this paper, a 3D physical modelling platform is developed to study the interaction between the roof strata and the longwall shield under the dynamic impact load conditions. A steel plate is dropped to the coal face wall at a certain height above the immediate roof to simulate the free fall of the main roof and the dynamic impact loading environment. The occurrence of major roof falls is modelled at different height above the model and at different positions relative to the longwall faceline. The large-cutting-height and top-coal-caving mining methods are modelled in the study to include the nature of the immediate roof. The results show that the level of face and roof failures depends on the magnitude of the dynamic impact load. The position and height of the roof fall have an important influence to the stability of the roof and face. The pressures on the shield and the solid coal face are relieved for the top-coal-caving face as compared to the large-cutting-height face.

In order to improve ground control of the longwall mining, ground response and mining-induced stress in the longwall panel of a kilometer-deep coal mine are investigated in this study. Field measurements on abutment stress, roof displacement, and fracture development indicate that the region influenced by the longwall mining reaches 150 m ahead of the longwall face. Failure scope of the coal seam, where mining-induced fractures are well developed, ranges from 10 to 13 m inward the face line. Vertical stress concentration coefficient reaches 2.2. Based on the field measurements, a numerical model is moreover developed and utilized to examine the response of the principal stress to the longwall mining. The concentration coefficient, peak point location, and influence scope of the principal stress gradually become stable with an increase in face advancement. Regarding the major principal stress, the concentration coefficient and influence scope are 2.4 and 152 m, respectively, and the peak point locates 13 m inward the face line, which are consistent with the field measurements. With respect to the minor principal stress, the referred coefficient and scope are 1.5 and 172 m, respectively, and its peak point location is 21 m ahead of the face line. The major principal stress in the coal seam rotates from vertical to horizontal direction in the vertical plane parallel with face advance direction. The maximum rotation angle reaches 20°. The minor principal stress first rotates into the referred vertical plane and then it rotates from horizontal to vertical direction at the same speed with the major principal stress in the same plane. Rotation angle of the principal stress in roof strata is greatly enlarged, the rotation trace of which is influenced by the longwall mining and vertical distance above the seam. Based on the relation between rotation trace of the principal stress and face advance direction, the influence of stress rotation on the stability of roof structure is discussed.

Background. A lack of knowledge and inadequate practices of health care providers (HCPs) are the main obstacles to effective cancer pain management (CPM). The main objective of the study was to evaluate the CPM knowledge, CPM practice, and attitudes towards pharmacists’ participation and advanced methods in CPM of physicians, nurses, and pharmacists in China. Methods. An open online survey was adopted using social media software (WeChat) as the platform to conduct a nationwide survey of HCPs involved in CPM in public medical institutions at all levels in China from March to June 2019. Results. A total of 1279 physicians, 2267 nurses, and 1466 pharmacists participated in the survey. Among the three types of professionals, nurses had the highest level of practical ability (61.63 ± 28.99) and best attitudes towards pharmacists’ participation and advanced methods in CPM (72.05 ± 33.71) and physicians had the best mastery of CPM-related knowledge (69.60 ± 28.45), while pharmacists performed the worst in these three aspects (50.04 ± 26.69, 61.49 ± 28.95, and 62.07 ± 36.46, respectively). Only 19.69% of the hospitals had a pharmacist to tumor patient ratio ≥1 : 50. Hierarchical analysis showed that passing a good pain management (GPM) ward program and participating in advanced training had positive impacts on the scores of all three parts in the three professions (ptrend

In the conventional analytical model used for heat generation in friction stir welding (FSW), the heat generated at the pin/workpiece interface is assumed to distribute uniformly in the pin volume, and the heat flux is applied as volume heat. Besides, the tilt angle of the tool is assumed to be zero for simplicity. These assumptions bring about simulating deviation to some extent. To better understand the physical nature of heat generation, a modified analytical model, in which the nonuniform volumetric heat flux and the tilt angle of the tool were considered, was developed. Two analytical models are then implemented in the FEM software to analyze the temperature fields in the plunge and traverse stage during FSW of AA6005A-T6 aluminum hollow extrusions. The temperature distributions including the maximum temperature and heating rate between the two models are different. The thermal cycles in different zones further revealed that the peak temperature and temperature gradient are very different in the high-temperature region. Comparison shows that the modified analytical model is accurate enough for predicting the thermal cycles and peak temperatures, and the corresponding simulating precision is higher than that of the conventional analytical model.

The optimization of an integrated coal gangue system of mining, dressing, and backfilling in deep underground mining is a multi-objective and complex decision-making process, and the factors such as spatial layout, node location, and transportation equipment need to be considered comprehensively. In order to realize the intellectualized location of the nodes for the logistics and transportation system of underground mining and dressing coal and gangue, this paper establishes the model of the logistics and transportation system of underground mining and dressing coal gangue, and analyzes the key factors of the intellectualized location for the logistics and transportation system of coal and gangue, and the objective function of the node transportation model is deduced. The PSO–QNMs algorithm is proposed for the solution of the objective function, which improves the accuracy and stability of the location selection and effectively avoids the shortcomings of the PSO algorithm with its poor local detailed search ability and the quasi-Newton algorithm with its sensitivity to the initial value. Comparison of the particle swarm and PSO–QNMs algorithm outputs for the specific conditions of the New Julong coal mine, as an example, shows that the PSO–QNMs algorithm reduces the complexity of the calculation, increases the calculation efficiency by eight times, saves 42.8% of the cost value, and improves the efficiency of the node selection of mining–dressing–backfilling systems in a complex underground mining environment. The results confirm that the method has high convergence speed and solution accuracy, and provides a fundamental basis for optimizing the underground coal mine logistics system. Based on the research results, a node siting system for an integrated underground mining, dressing, and backfilling system in coal mines (referred to as MSBPS) was developed.

A deterministic approach is frequently used in engineering design. In this quantitative design methodology, a safety factor, which is typically a strength-to-stress ratio, is derived as an index for the stability assessment of the engineering design. In underground coal mining applications such as pillar design, however, the inputs of pillar design are variables. This is widely overlooked in the deterministic approach. A probabilistic approach assessing the probability of failure or reliability of a system might be an alternative to the conventional quantitative methodology. This approach can incorporate the degree of uncertainty and deviations of variables and provide more versatile and reliable results. In this research, the reliability of case histories from stable and failed pillars of South Africa presented by Merwe and Mathey is examed. The updated Salamon and Munro strength formula (S-M formula) and Merwe and Mathey strength formula (M-M formula) are evaluated through a probabilistic approach. It is concluded that stable pillar cases have a reliability value greater than 0.83 while the reliability value of failed pillar cases are slightly larger than 0.50. There seems to be a positive relation between safety factor and reliability. The reliability of a pillar increases with pillar width but decreases with depth of cover, pillar height and entry width. The reliability analysis also confirms that M-M strength formula has a better distinction between the stable and failed pillar cases. Keywords: Pillar design, Probabilistic approach, Reliability, Monte Carlo simulation

PURPOSE: Gastric cancer studies indicated a potential correlation between circulating tumor cells (CTCs) in peripheral blood and tumor relapse/metastasis. The prevalence and significance of circulating tumor microemboli (CTM) in gastric cancer remain unknown. We investigated the prevalence and prognostic value of CTCs and CTM for progression-free survival (PFS) and overall survival (OS) in gastric cancer patients. METHODS:Eighty-one gastric cancer patients consented to provide 5 ml of peripheral blood before systematic therapy. CTCs and CTM were isolated using isolation by size of epithelial tumor cells and characterized by cytopathologists. For 41 stage IV gastric cancer patients, CTM was investigated as a potential biomarker to predict prognosis. RESULTS:CTCs were detected in 51 patients; the average count was 1.81. In clinical stage I, II, III, and IV patients, the average CTC counts were 1.40, 0.67, 1.24, and 2.71, respectively. CTM were detected in 3 of 33 clinical stage I to IIIb patients, at an average of 0.12 (0-2). CTM were detected in 13 of 53 clinical stage IIIc to IV patients, at an average of 1.26 (0-22). In stage IV patients, CTM positivity correlated with the CA125 level. PFS and OS in CTM-positive patients were significantly lower than in CTM-negative patients (P

Cancer testis (CT) antigens are expressed in various types of tumors and represent the potential targets for T cell-based immunotherapy. Analysis of CT gene expression and DNA methylation have indicated that certain CT genes are epigenetically regulated and studies have confirmed that certain CT antigens are regulated by DNA methylation. In this study, we explored the epigenetic regulation of MAGE-A3 and improved the clinical outcome of MAGE-A3-specific T cell therapy in esophageal squamous cell carcinoma (ESCC).We used molecular profiling datasets in The Cancer Genome Atlas to analyze CT gene expression in ESCC and its regulation by DNA methylation. We performed quantitative reverse transcription PCR (qRT-PCR), immunohistochemistry and bisulfite sequencing in ESCC cell lines and ESCC tissues. Functional assays, such as flow cytometry, cytotoxicity assays and ELISA, were performed to determine the demethylation agent, decitabine (5-aza-2′-deoxycytidine, DAC)-treated cancer cell improved antigen specific T cells response. ESCC tumor cell-xenograft mouse model and enzyme-linked immunospot (ELISPOT) assays were used to determine the function of DAC treatment in enhancing anti-MAGE-3 T cell responses in ESCC. Furthermore, we performed qRT-PCR and flow cytometry in the peripheral blood mononuclear cells (PBMC) of myelodysplastic syndromes (MDS) patients.MAGE-A3, one of the CT antigens, expressed at various levels in ESCC and was interfered by DNA methylation. We observed an efficient increase in MAGE-A3 expression in tumor cells and tissues after the treatment of decitabine and the expression of MAGE-A3 was affected by DNA methylation. Functional assays showed enhanced secretion of IFN-γ and cytolysis of MAGE-A3 antigen-specific T cells by DAC-treated target cells. In the tumor cell-xenograft mouse model and ELISPOT assays, DAC increased the expression of MAGE-A3 and T cell mediated tumor clearance in ESCC as well. Notably, the proportions of MAGE-A3-responsive T cells were elevated in DAC-treated patients with MDS, indicating DAC dismissed the epigenetic inhibition of MAGE-A3.DAC would probably improve the clinical outcome of MAGE-A3-specific T cell therapy by augmenting the expression of target gene.

The coupling effect of freeze-thaw (F-T) temperature and dynamic load on the dynamic mechanical properties and fracture mechanism of saturated yellow sandstone was experimentally investigated in this research. The dynamic compression tests on the specimen after different F-T temperatures (i.e., −5°С, −10°С, −15°С, −20°С, −30°С, and 20°С) have been carried out with split-Hopkinson pressure bar (SHPB) setup under eight F-T cycle numbers. The density and P-wave velocity of the specimens were obtained before and after the F-T tests. After the F-T tests, the specimen microstructures were examined via the scanning electron microscope (SEM). The dynamic fracture process was visualized by the high-speed camera. The particle size distribution and fragment shapes of the specimens were analyzed using a classifying screen. In addition, the energy dissipation law of specimens during the impact test was also discussed. Experimental results show that the dynamic elastic modulus, strength of the specimen, and the average particle size decrease with decreasing F-T temperature. SEM results reveal that low F-T temperature leads to severer internal damage of the specimen by inducing freeze-swell holes, interconnected cracks, and pore clusters. In addition, the fragmentation shapes of the failed specimens exhibit double-cone failure, single-side slope failure, double-side slope failure, and split failure. The energy dissipation increases gradually with increasing F-T temperature. This study helps to prevent geological disasters and optimize engineering design in cold regions.

Fully grouted rock bolts are widely used in civil engineering and mining engineering, playing a significant role in keeping the stability and safety of excavations. In this paper, the load transfer mechanism of fully grouted rock bolts was studied with an analytical model. A trilinear model was used to depict the bond-slip behaviour of the bolt/grout interface. The displacement of the confining medium was involved in this analytical model. Then, the shear stress propagation along the bolt/grout interface was analysed in the elastic, elastic-softening, elastic-softening-debonding, softening-debonding, and debonding stages. Experimental pull-out tests were used to validate this analytical model. There was a good correlation between experimental and analytical results. A parametric study was conducted to evaluate the influence of Young’s modulus of the confining medium, the shear strength of the bolt/grout interface, and the residual shear strength of the bolt/grout interface on the load transfer performance of rock bolts. The results show that increasing Young’s modulus of the confining medium was beneficial for improving the load transfer performance of rock bolts. However, once Young’s modulus of the confining medium was beyond a critical limit, it had marginal effect on the peak load of rock bolts. Furthermore, increasing the shear strength of the bolt/grout interface and the residual shear strength of the bolt/grout interface led to rising of the peak load of rock bolts. However, compared with the residual shear strength of the bolt/grout interface, increasing the shear strength of the bolt/grout interface had more apparent effect in improving the peak load of rock bolts.

Al–Li alloy offersa great advantage over traditional alloys and it is the ideal material for today’s aerospace industry. Therefore, here we examined the Al–Cu–Li alloy as the third generation of Al–Li alloy. Deformation and heat treatment on the texture and precipitate type and distribution of Al–Cu–Li alloy were studied by mechanical properties test, XRD, and TEM analysis. The effect of texture and precipitate on the plane anisotropy of yield strength was discussed. The results showed thatBrass texture was mainly formed in the deformation process. On the one hand, increasethe pass deformation or cross rolling,the total volume fraction of the texture (S{123}〈634〉, G{011}〈100〉, {011}〈011〉) was increased, which lowered thesheet anisotropy. While on the other hand, the δ ′ phase precipitated rapidly during solution treatment and easily caused a coplanar slip, increasing plane anisotropy. However, owing to the difference distribution of the aged precipitated T _1 on the two group of {111} habit plane, the strengthening effect of the Al–Cu–Li alloy sheet was weak at 45° direction, but stronger atthe rolling direction (0°) and transverse direction (90°).

Background: Distiller's dried grains with solubles (DDGS) and soybean meal were used as the substrates for the production of polyunsaturated fatty acids (PUFA) in solid-state fermentation (SSF) by Mortierella alpine. These fermented products were fed to laying hens. PUFA enrichment from chicken breasts was studied. Methods: The maximum productivity of PUFA was achieved under optimized process condition, including 1% w/w yeast extract as additive, an incubation period of 5 days at 12°C, 10% v/w inoculum level, 75% moisture content, and pH 6.0. The hens were then fed with ration containing soybean DDGS, rapeseed oil, soybean oil, and peanut oil. The control group was fed with basal ration. Results: Under the optimal condition, M. alpine produced total fatty acids (TFA) of 182.34 mg/g dry substrate. It has better mycelial growth when soybean meal was added to DDGS (SDDGS). PUFA in fermentation product increased with higher soybean meal content. The addition of 70% soybean meal to DDGS substrate yielded 175.16 mg of TFA, including 2.49 mg eicosapentaenoic acid (EPA) and 5.26 mg docosahexaenoic acid (DHA). The ratios of ω-6/ω-3 found in chicken breasts fat were all lower than that found in control by 36.98, 31.51, 18.15, and 12.63% for SDDGS, rapeseed oil, soybean oil, and peanut oil, respectively. Conclusions: This study identified an optimized SSF process to maximize PUFA productivity by M. alpine as the strain. This PUFA-enriched feed increased the PUFA contents as well as the proportions of ω-6 and ω-3 in chicken breasts and liver.

Background: Thin stillage was used as the substrate to produce intracellular selenium-enriched polysaccharides (ISPS) from Cordyceps sinensis to increase the value of agricultural coproducts. Methods: Fermentation parameters were optimized using response surface methodology (RSM) to improve the production of ISPS. Then, the effects of ISPS on the antioxidant activities in vitro, as well as the glycosylated serum protein concentration, malondialdehyde level, and total antioxidant capacity of streptozotocin-induced diabetic rats were studied. Results: The optimized conditions were as follows: sodium selenite concentration, 33.78 µg/L; incubation time, 8.24 days; and incubation temperature, 26.69°C. A maximum yield of 197.35 mg/g ISPS was obtained from the validation experiments, which was quite close to the predicted maximum yield of 198.6839 mg/g. FT-IR spectra indicated that ISPS has been successfully selenylation modified with similar structure to polysaccharide of intracellular polysaccharides. The in vitro scavenging effects of 1.0 mg/mL ISPS on hydroxyl, superoxide, and 1,1-diphenyl-2-picrylhydrazyl radicals were 74.62±4.05, 71.45±3.63, and 79.48±4.75%, respectively. The reducing power of ISPS was 0.45±0.01 (absorbance at 700 nm). Fasting blood glucose and glycosylated serum protein of group C (rats with diabetes that received drinking water with ISPS) were significantly lower than those of group B (rats with diabetes) (P

Purpose: Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. Experimental Design: We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured. To study MDSC chemotaxis in vivo, BALB/C nude mice were injected subcutaneously with TE7 cells and treated with metformin. Migration of adoptively transferred MDSCs was analyzed using flow cytometry and immunohistochemistry. Results: The frequency of tumor-infiltrated polymorphonuclear (PMN)-MDSCs was increased compared to their circulating counterparts. There was a significant correlation between PMN-MDSCs accumulation in tumors and ESCC prognosis. Moreover, PMN-MDSCs displayed immunosuppressive activity in vitro. Treatment with metformin reduced MDSC migration in patients. Metformin inhibited CXCL1 secretion in ESCC cells and tumor xenografts by enhancing AMPK phosphorylation and inducing DACH1 expression, leading to NF-κB inhibition and reducing MDSC migration. Knockdown of AMPK and DACH1 expression blocked the effect of metformin on MDSC chemotaxis. Conclusions: A novel anti-tumor effect of metformin, which is mediated by reducing PMN-MDSC accumulation in the tumor microenvironment via AMPK/DACH1/CXCL1 axis.

Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader–Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

Hepatocellular carcinoma (HCC) occurs more frequently in men than in women. It is commonly agreed that estrogen plays important roles in suppressing HCC development, however, the underlying mechanism remains largely unknown. Since estrogen is mainly metabolized in liver and its metabolites affect cell proliferation, we sought to investigate if the liver-specific cytochrome P450 1A2 (CYP1A2) mediated the inhibitory effect of estrogen on HCC. In this study, the expression of estrogen-metabolizing enzyme CYP1A2 was determined in HCC tissues and cell lines. Cell proliferation and apoptosis were assessed in cells with or without CYP1A2 overexpression. The levels of 17β-estradiol (E2) and its metabolite 2-methoxyestradiol (2-ME) were determined. A xenograft tumor model in mice was established to confirm the findings. It was found that CYP1A2 expression was greatly repressed in HCC. E2 suppressed HCC cell proliferation and xenograft tumor development by inducing apoptosis. The inhibitory effect was significantly enhanced in cells with CYP1A2 overexpression, which effectively conversed E2 to the cytotoxic 2-ME. E2 in combination with sorafenib showed an additive effect on HCC. The anti-HCC effect of E2 was not associated with estrogen receptors ERα and ERβ as well as tumor suppressor P53 but enhanced by the approved anti-HCC drug sorafenib. In addition, HDAC inhibitors greatly induced CYP1A2 promoter activities in cancer cells, especially liver cancer cells, but not in non-tumorigenic cells. Collectively, CYP1A2 metabolizes E2 to generate the potent anti-tumor agent 2-ME in HCC. The reduction of CYP1A2 significantly disrupts this metabolic pathway, contributing the progression and growth of HCC and the gender disparity of this malignancy.

Several types of epidermal growth factor receptor (EGFR) gene alternations have been observed in human tumors. Here we present a novel EGFR variant with aberrant splicing of exon 4 (named as de4 EGFR). Variant-specific polymerase chain reaction showed that de4 EGFR was expressed in some glioma (4/40), prostate cancer (3/11), and ovarian cancer (3/9) tissues but not in tissues adjacent to tumors or normal tissues. de4 EGFR displayed an enhanced transformation and a higher metastasis-promoting capacity in comparison to wild-type EGFR. With minimal EGF-binding activity, de4 EGFR underwent ligand-independent autophosphorylation and self-dimerization. Moreover, in serum-starved condition, de4 EGFR expression in U87 MG cells significantly upregulated the extracellular signal-regulated kinase and AKT phosphorylation and expression of JUN and Src. Importantly, E-cadherin expression was barely detectable in the U87 MG cells expressing de4 EGFR and restored expression of E-cadherin in these cells inhibited their metastatic behaviors. Taken together, we identified a novel EGFR variant with increased metastasis-promoting activity that may become a promising new target for cancer therapy.

Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1) in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis.

A novel human gene, FN1BP1 (fibronectin 1 binding protein 1), was identified using the human placenta cDNA library. Northern blotting showed a transcript of ∼2.8 kb in human placenta, liver, and skeletal muscle tissues. This mRNA transcript length was similar to the full FN1BP1 sequence obtained previously. We established a conditionally induced stable cell line of Hep3B-Tet-on-FN1BP1 to investigate the preliminary function and mechanism of the secretory FN1BP1 protein. Cell-proliferation and colony-conformation assays demonstrated that FN1BP1 protein suppressed Hep3B cell growth and colonization in vitro. Analysis of Atlas human cDNA expression indicated that after FN1BP1 Dox-inducing expression for 24 h, 19 genes were up-regulated and 22 genes were down-regulated more than two-fold. Most of these gene changes were related to cell-cycle-arrest proteins (p21cip1, p15, and cyclin E1), transcription factors (general transcription factors, zinc finger proteins, transcriptional enhancer factors), SWI/SNF (SWItch/Sucrose NonFermentable) complex units, early-response proteins, and nerve growth or neurotrophic factors. Down-regulated genes were subject to colony-stimulating factors (e.g., GMSFs), and many repair genes were involved in DNA damage (RAD, ERCC, DNA topoisomerase, polymerase, and ligase). Some interesting genes (p21cip1, ID2, GMSF, ERCC5, and RPA1), which changed in the cDNA microarray analysis, were confirmed by semi-qRT-PCR, and similar changes in expression were observed. FCM cell-cycle analysis indicated that FN1BP1 over-expression could result in G1 phase arrest. FN1BP1 might inhibit cell growth and/or colony conformation through G1 phase arrest of the Hep3B cell cycle. These results indicate the potential role of FN1BP1 as a treatment target for hepatocellular carcinoma.

Compound Danshen Formula (CDF) is a widely used Traditional Chinese Medicine (TCM) which has been extensively applied in clinical treatment of cardiovascular diseases (CVDs). However, the underlying mechanism of clinical administrating CDF on CVDs is not clear. In this study, the pharmacological effect of CDF on CVDs was analyzed at a systemic point of view. A systems-pharmacological model based on chemical, chemogenomics and pharmacological data is developed via network reconstruction approach. By using this model, we performed a high-throughput in silico screen and obtained a group of compounds from CDF which possess desirable pharmacodynamical and pharmacological characteristics. These compounds and the corresponding protein targets are further used to search against biological databases, such as the compound-target associations, compound-pathway connections and disease-target interactions for reconstructing the biologically meaningful networks for a TCM formula. This study not only made a contribution to a better understanding of the mechanisms of CDF, but also proposed a strategy to develop novel TCM candidates at a network pharmacology level.