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Myeloid‐derived suppressor cells (MDSCs) are responsible for antitumor immunodeficiency in tumor‐bearing hosts. Primarily, MDSCs are classified into 2 groups: monocytic (M)‐MDSCs and polymorphonuclear (PMN)‐MDSCs. In most cancers, PMN‐MDSCs (CD11b+Ly6ClowLy6G+ cells) represent the most abundant MDSC subpopulation. However, the functional and phenotypic heterogeneities of PMN‐MDSC remain elusive, which delays clinical therapeutic targeting decisions. In the 4T1 murine tumor model, CD11b+Ly6Glow PMN‐MDSCs were sensitive to surgical and pharmacological interventions. By comprehensively analyzing 64 myeloid cell‐related surface molecule expression profiles, cell density, nuclear morphology, and immunosuppressive activity, the PMN‐MDSC population was further classified as CD11b+Ly6GlowCD205+ and CD11b+Ly6GhighTLR2+ subpopulations. The dichotomy of PMN‐MDSCs based on CD205 and TLR2 is observed in 4T07 murine tumor models (but not in EMT6). Furthermore, CD11b+Ly6GlowCD205+ cells massively accumulated at the spleen and liver of tumor‐bearing mice, and their abundance correlated with in situ tumor burdens (with or without intervention). Moreover, we demonstrated that CD11b+Ly6GlowCD205+ cells were sensitive to glucose deficiency and 2‐deoxy‐d‐glucose (2DG) treatment. Glucose transporter 3 (GLUT3) knockdown by siRNA significantly triggered apoptosis and reduced glucose uptake in CD11b+Ly6GlowCD205+ cells, demonstrating the dependence of CD205+ PMN‐MDSCs survival on both glucose uptake and GLUT3 overexpression. As GLUT3 has been recognized as a target for the rescue of host antitumor immunity, our results further directed the PMN‐MDSC subsets into the CD205+GLUT3+ subpopulation as future targeting therapy., We confirmed that CD205+ PMN‐MDSCs were potent immunosuppressive cells in vitro as well as in vivo and sensitive to glucose deficiency and 2‐deoxy‐D‐glucose (2DG) treatment in vitro. GLUT3 knockdown by siRNA significantly reduced the survival and glucose uptake rate of CD205+ PMN‐MDSCs and markedly retarded transplanted 4T1 tumor growth. Our results implications that PMN‐MDSC subsets in peripheral organs are also phenotypically and functionally heterogeneous, and glucose metabolism patterns profoundly affected the anti‐tumor immunity.

2-hydroxy-6-tridecylbenzoic acid is alkylsalicylic acid monomer compound, abundantly existed in the ginkgo biloba extracts, however, the underlying mechanism of its anti-migration and anti-invasion effects in triple-negative breast cancer (TNBC) is not clear. Here, 2-hydroxy-6 -tridecylbenzoic acid inhibited MDA-MB-231 and 4 T-1 cells growth without toxicity to MCF-10A normal breast cells. Meanwhile, 2-hydroxy-6-tridecylbenzoic acid inhibited cells migration and invasion as well as EMT with the increase of E-cadherin expression accompanied by the decrease of N-cadherin, Vimentin, Snail, MMP-2 and MMP-9 expression. The inhibition was further demonstrated by the enhancement of cytochrome P450 (CYP) 1B1 expression through the activation of AMP activated protein kinase (AMPK) in MDA-MB-231 and 4 T-1 cells. Silencing of CYP1B1 and AMPK with siRNA blocked the inhibitory effects of migration and invasion, and reversed the EMT related genes. These findings may provide a novel mechanism of the 2-hydroxy-6-tridecylbenzoic acid as a molecular-targeted therapeutic drug for TNBC patients.

Plant development is highly dependent on energy levels. TARGET OF RAPAMYCIN (TOR) activates the proximal root meristem to promote root development in response to photosynthesis-derived sugars during photomorphogenesis in Arabidopsis thaliana. However, the mechanisms of how root tip homeostasis is maintained to ensure proper root cap structure and gravitropism are unknown. PLETHORA (PLT) transcription factors are pivotal for the root apical meristem (RAM) identity by forming gradients, but how PLT gradients are established and maintained, and their roles in COL development are not well known. We demonstrate that endogenous sucrose induces TOPOISOMERASE1α (TOP1α) expression during the skotomorphogenesis-to-photomorphogenesis transition. TOP1α fine-tunes TOR expression in the root tip columella. TOR maintains columella stem cell identity correlating with reduced quiescent centre cell division in a WUSCHEL RELATED HOMEOBOX5-independent manner. Meanwhile, TOR promotes PLT2 expression and phosphorylates and stabilizes PLT2 to maintain its gradient consistent with TOR expression pattern. PLT2 controls cell division and amyloplast formation to regulate columella development and gravitropism. This elaborate mechanism helps maintain root tip homeostasis and gravitropism in response to energy changes during root development.

Immune‐based interventions are the most promising approach for new cancer treatments to achieve long‐term cancer‐free survival. However, the expansion of myeloid‐derived suppression cells (MDSCs) attenuates the therapeutic potential of immunotherapy. We recently showed that CD205+ granulocytic MDSCs (G‐MDSCs), but not T cells, are sensitive to glucose deficiency. Intermittent fasting (IF) may inhibit the growth of malignant cells by reducing serum glucose levels, but little is known regarding the influence of IF on MDSC expansion. Herein, we observed that IF selectively inhibited splenic accumulation of CD205+ G‐MDSCs in a 4T1 and 4T07 transplant murine breast cancer model. The efficiency of IF in suppressing tumor growth was comparable to that of docetaxel. Further examination revealed that CXCR4 expression was concentrated in CD205+ subsets of tumor‐induced G‐MDSCs. Downregulation of CXCR4 correlated with a reduction in CD205+ G‐MDSC trafficking from bone marrow to the spleen under IF treatment. In addition, ex vivo culture assays showed that glucose deficiency and 2‐deoxy‐D‐glucose (2DG) treatment selectively induced massive death of splenic CD205+ G‐MDSCs. Interestingly, 2DG emulated the phenomena of IF selectively suppressing the accumulation of CD205+ G‐MDSCs in the spleen, upregulating cleaved caspase 3 in the tumor, downregulating Ki67 in the lung, and retarding the growth of transplanted 4T1 and 4T07 murine breast tumors. These findings suggest that IF inhibited cell trafficking through the downregulation of CXCR4 and induced apoptosis by altering glucose metabolism; this, suppressed the accumulation of tumor‐induced splenic CD205+ G‐MDSCs and in turn enhanced antitumor immunity., We observed that intermittent fasting not only limits the growth of breast tumors but also inhibits the accumulation of immunosuppressive cells, suggesting that intermittent fasting has the potential to enhance the immune system of cancer hosts and is an adjuvant treatment option to improve the effectiveness of cancer immunotherapy.

Currently, the identification technology of rock-coal medium is not reliable and practical, so we cannot judge the cutting state of coal-winning machine in real time. Different dynamic responses over different medium types of rock-coal can indirectly reflect the physical and mechanical parameters of rock-coal. In this study, we establish the 3-D numerical model of cutting the rock and coal by the finite element numerical simulation software in which we obtain the whole process of numerical simulation of the roller cutting coal, mudstone, and sandstone, where different dynamic responses counterpart different types of rock and coal by means of numerical experiments. The results show that when the drum keeps the average speed of cutting coal and medium forward, the instantaneous speed which is close to the average speed will have a small jump. The average speed and the torque in the cutting process can be considered as good indices to evaluate the rock and coal types. The torque from high to low is as follows: sandstone, mudstone, and coal. The average speed from high to low is as follows: coal, mudstone, and sandstone. If the portion of rock is more, the torque is higher and the average speed is lower during cutting the roof foot. This research is helpful for identifying rock-coal medium types by using related instrument to record the dynamic responses of rock-coal medium types.

Spleen is an information-rich and easy-accessible peripheral lymphoid organ. It has complex cell composition because of the immunocytes maturity and settle down. Changes of the composition and function of these immunocytes are critical to body immune response. To understand the cell behaviors, specific cell subpopulations are required to be separated without heterogeneity. Density gradient centrifugation is one of the cell separation methods with high throughput. However, the greatest defect of this method is its low cell purity. In this study, the separation conditions of tumor-bearing mouse splenocytes were optimized by separation solutions with different density gradients. After separation, lymphocytes were located at the second layer with the proportion of 84.9%, monocytic-like myeloid-derived suppressor cells (Mo-MDSCs) were located at the fourth layer with the proportion of 54.2% and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were located at the sixth layer with the proportion of 85.5%. Cells in different layers were further determined by verifying the gene expression pattern of some chemokine receptors on cell surfaces. Furthermore, this method was also used to separate healthy mouse splenocytes. Therefore, this method will be highly useful to separate mouse splenocytes and has laid a foundation for further research on the changes and roles of immunocytes during the development of cancer.

BACKGROUND: In this study, we aimed to explore the tumour associated immune signature of breast cancer (BC) and conduct integrative analyses with immune infiltrates in BC. METHODS: We downloaded the transcriptome profiling and clinical data of BC from The Cancer Genome Atlas (TCGA) database. The list of immune-related signatures was from the Innate database. The limma package was utilized to conduct the normalization, and we screened the differential immune signatures in BC. A univariate Cox regression model and the LASSO method were used to find the hub prognostic immune genes. The TAIG risk model was calculated based on the multivariate Cox regression results, and a receiver operating characteristic (ROC) curve was generated to assess the predictive power of TAIG. Moreover, we also conducted a correlation analysis between TAIG and the clinical characteristics. Additionally, we utilized the METABRIC cohort as the validation data set. The TIMER database is a comprehensive resource for performing systematic analyses of immune infiltrates across various malignancies. We evaluated the associations of immune signatures with several immune cells based on TIMER. Furthermore, we used the CIBERSORT algorithm to determine the fractions of immune cells in each sample and compared the differential distributions of immune infiltrates between two TAIG groups using the Wilcoxon rank-sum test. RESULTS: A total of 1,178 samples were obtained from the TCGA-BRCA database, but only 1,045 breast tumour samples were matched with complete transcriptome expression data. Meanwhile, we collected a total of 1,094 BC patients from the METABRIC cohort. We found a list of 1,399 differential immune signatures associated with survival, and functional analysis revealed that these genes participated in cytokine-cytokine receptor interactions, Th1 and Th2 cell differentiation and the JAK-STAT signalling pathway. The TAIG risk model was established from the multivariate Cox analysis, and we observed that high TAIG levels correlated with poor survival outcomes based on Kaplan-Meier analysis. The Kruskal-Wallis test suggested that high TAIG levels correlated with high AJCC-TNM stages and advanced pathological stages (P

Aiming at improving the harmonic spectra spreading effect, two randomized pulse position modulation strategies are proposed for three-phase four-leg inverters. Based on the volt-second balance law and the fixed switching frequency, the first proposed strategy places the center randomly during one carrier cycle with a limited degree of freedom, and the second proposed strategy randomly changes the carrier slope in each carrier cycle. To get better randomization effect of the proposed strategies, Well Equidistributed Long-period Linear algorithm was introduced to generate random numbers. In order to verify the validity of the proposed strategies, the modulation strategies are implemented with dSPACE DS1007-based real-time operating system. The experimental results show that the proposed strategies have dispersed the discrete harmonics to a wider sideband. Compared with the first strategy, a larger degree of freedom can be achieved in the second proposed strategy with lower harmonic spikes.

Pilose antler (PA) is used to treat many diseases, but its effect on breast cancer is still unclear. Here, we report the effects of PA on the growth of the mouse mammary tumour in vitro and in vivo, and its effects on immune system of the tumor-bearing mice. The 4T1 mouse mammary tumour cells were cultured with media supplemented with water extract of PA (WEPA), and the female BALB/c mice transplanted with 4T1 cells were treated by gavage with WEPA. The results showed that WEPA promoted the proliferation of 4T1 cells in vitro, while inhibited the growth of 4T1 tumour in vivo. In addition, WEPA increased the proportion of CD4+ T cells, CD8+ T cells and NK cells and reduced myeloid-derived suppressive cells in mouse peripheral blood. These results suggest that WEPA can inhibit the growth of mouse 4T1 tumours through modulating immune system of the mouse.

Background We aimed to test the possibility of improving polypeptide production from soybean meal fermentation by engineered Aspergillus oryzae strains. Four different protease genes were cloned and transformed into wild-type A. oryzae , and the engineered A. oryzae strains were then used for soybean meal fermentation. Results The results showed different degrees of improvement in the protease activity of the four transformants when compared with wild-type A. oryzae . A major improvement in the polypeptide yield was achieved when these strains were used in soybean meal fermentation. The polypeptide conversion rate of one of the four transformants, A. oryzae pep, reached 35.9%, which was approximately twofold higher than that exhibited by wild-type A. oryzae . Amino acid content analysis showed that the essential amino acid content and amino acid composition of the fermentation product significantly improved when engineered A. oryzae strains were used for soybean meal fermentation. Conclusions These findings suggest that cloning of microbial protease genes with good physicochemical properties and expressing them in an ideal host such as A. oryzae is a novel strategy to enhance the value of soybean meal.

Based on field experiments at Nanyue Mountain Meteorological Station and Huaihua National Reference Climatological Station in Hunan Province, the camera images of icing weather phenomena, such as glaze, rime and mixing rime, are collected minutely from January to March in 2018. The convolution neural network technology is employed for modelling and training using the camera images of the icing field experiment at Nanyue station, and the results of identification are examined by the camera images. Furthermore, based on deep learning, the environmental layout requirements of ice accretion image identification are discussed. The main conclusions are as follows. When identifying icing weather phenomena at Nanyue station, the probability of correction (PC) is 99.21%, the false acceptance rate (FAR) is 0.28%, and the probability of omission (PO) is 0.51%. The probability of icing identification increases significantly in the initial stage of ice accretion, while that in the sustained stage is stably around 99.0%, and in the dissipation stage it gradually decreases. False acceptance and omission occur occasionally during the initiation and dissipation stages, the transition period between daytime and night, and the nighttime when the pictures are not clear enough. The test results show that the artificial intelligence identification model established in this paper can extract the key features of icing in different stages of an icing lifetime, and the identification result is good. In addition, the false acceptance and omission can be further eliminated by using the meteorological conditions criteria and judging the consistency of identification. This method can provide important technical support for the automatic observation of icing weather phenomena.

An ensemble of the three-dimensional variational data assimilation (En3DA) method for convective-scale weather has been developed. It consists of an ensemble of three-dimensional variational data assimilations and forecasts in which member differences are introduced by perturbing initial conditions and/or observations, and it uses flow-dependent error covariances generated by the ensemble forecasts. The method is applied to the assimilation of simulated radar data for a supercell storm. Results indicate that the flow-dependent ensemble covariances are effective in enabling convective-scale analyses, as the most important features of the simulated storm, including the low-level cold pool and midlevel mesocyclone, are well analyzed. Several groups of sensitivity experiments are conducted to test the robustness of the method. The first group demonstrates that incorporating a mass continuity equation as a weak constraint into the En3DA algorithm can improve the quality of the analyses when radial velocity observations contain large errors. In the second group of experiments, the sensitivity of analyses to the microphysical parameterization scheme is explored. Results indicate that the En3DA analyses are quite sensitive to differences in the microphysics scheme, suggesting that ensemble forecasts with multiple microphysics schemes could reduce uncertainty related to model physics errors. Experiments also show that assimilating reflectivity observations can reduce spinup time and that it has a small positive impact on the quality of the wind field analysis. Of the threshold values tested for assimilating reflectivity observations, 15 dBZ provides the best analysis. The final group of experiments demonstrates that it is not necessary to perturb radial velocity observations for every ensemble number in order to improve the quality of the analysis.

In metazoan genome, the mechanism of gene expression regulation between transcriptional regulatory elements and their target gene is spatiotemporal. Active promoters possess many specific chromosomal features, such as hypersensitive to DNaseI and enrichment of specific histone modifications. In this article, we proposed a novel method which possesses a high efficiency to find promoters in vitro. A promoter-trap library was constructed with totally 706 random mouse genomic DNA fragment clones, and 260 promoter-active fragments of the library were screened by transient transfection into 4T1 cells. To demonstrate the accuracy of this promoter finding method, 13 fragments with promoter activities were randomly selected for published DNase-seq and ChIP-seq data analysis, downstream transcripts prediction and expression confirmation. qRT-PCR results showed that six predicted transcription units were successfully amplified in different mouse tissues/cells or in reconstituted mouse mammary tumors. Our results indicate that this promoter finding method can successfully detect the promoter-active fragments and their downstream transcripts., Highlights • Currently, the active promoters can be found from different perspectives by using several technologies. • In metazoan genome, finding active promoters in natural genome context is still a challenge now. • A novel promoter finding approach based transient transfection in vitro was proposed. • The mechanism of gene expression regulation between transcriptional regulatory elements and their target gene is complex.

Wind energy is a promising renewable energy resource which is cheap, eco-friendly and inexhaustible. A wind energy generating system with wind turbine, generator and converters is established to capture and integrate wind energy and transfer it to the grid. This paper discusses the modeling of the wind energy generating system, including wind speed, wind turbine, generator, generator side converter, grid side converter. After the introduction of the three traditional MPPT methods (TSR, PSF, HCS), a fuzzy slope HCS method is proposed to ensure the rapidity and accuracy of the system. Finally, simulation in Simulink shows that the method is feasible and able to capture most wind energy.

Objective To study the influence of blood extracts from pilose antler on the immune system in healthy mice and tumor-bearing mice. Methods A mouse mammary tumor transplantation model was established and both the healthy and the tumor-bearing mice were gavaged with the blood extracts of pilose antler. The percentages of mouse peripheral blood CD3

Ginkgolic acids (GA) have been reported to exhibit anticancer properties, however, the mechanisms remain unclear. This study aims to investigate the mechanisms of GA C13:0 that was isolated from Ginkgo biloba exocarp (GBE) for anti-proliferation, pro-apoptosis and anti-migration effects in human MCF-7 and mouse 4T-1 breast cancer cells. The cytotoxic effect, apoptosis induction and migration inhibition were measured using MTT, TUNEL and Wound healing assays. The expression of mRNA and protein were determined using qPCR and Western blot. Our results showed that no cytotoxicity was found at concentrations of C13:0 below 100µM. The effects of GA C13:0 was further demonstrated by up-regulation of the Bax/Bcl-2 apoptosis pathway and the expression of Apaf-1 protein in the mitochondria. In addition, GA C13:0 also suppressed cell migration and epithelial to mesenchymal transition (EMT) with the increase of E-cadherin expression accompanied by the decrease of Snail, MMP-2, MMP-9 and Vimentin expression. Moreover, GA C13:0 induced cytochrome P450 (CYP) 1B1 expression in aryl hydrocarbon receptor (AhR) pathway. Notably, the up-regulation of CYP1B1 also might play a pivotal regulatory role in mitochondrial and EMT pathways in MCF-7 and 4T-1 cells. Our results may have implications for the development of anticancer agents containing GA as functional additives.

This study aims to isolate the potential antiproliferative and cytotoxic compounds from ginkgo biloba sarcotestas (GBS) and investigates the underlying mechanism in human MDA-MB-231 and mouse 4T-1 triple-negative breast cancer cells. Our results showed that 2-Hydroxy-6-tridecylbenzoic acid was isolated by cytotoxicity-guided fractionation where different fractions were assessed using MTT assay against MDA-MB-231 and 4T-1 cells. Colony formation assay showed that 2-Hydroxy-6-tridecylbenzoic acid significantly inhibited cell proliferation. The inhibition was associated with the enhancement of cytochrome P450 (CYP) 1B1 expression in a dose- and time-dependent manner and no significant change of CYP1A1 expression by qPCR and Western blot assays in MDA-MB-231 and 4T-1 cells. The mechanism was further demonstrated by the activation of aryl hydrocarbon receptor (AhR) pathway with the upregulation of AhR, AhR nuclear translocator (ARNT) and AhR-dependent xenobiotic response elements (XRE) activity. These findings may have implications for development of anticancer agents containing 2-Hydroxy-6-tridecylbenzoic acid as functional additives.

Forecasters and research meteorologists tested a real-time three-dimensional variational data assimilation (3DVAR) system in the Hazardous Weather Testbed during the springs of 2010–12 to determine its capabilities to assist in the warning process for severe storms. This storm-scale system updates a dynamically consistent three-dimensional wind field every 5 min, with horizontal and average vertical grid spacings of 1 km and 400 m, respectively. The system analyzed the life cycles of 218 supercell thunderstorms on 27 event days during these experiments, producing multiple products such as vertical velocity, vertical vorticity, and updraft helicity. These data are compared to multiradar–multisensor data from the Warning Decision Support System–Integrated Information to document the performance characteristics of the system, such as how vertical vorticity values compare to azimuthal shear fields calculated directly from Doppler radial velocity. Data are stratified by range from the nearest radar, as well as by the number of radars entering into the analysis of a particular storm. The 3DVAR system shows physically realistic trends of updraft speed and vertical vorticity for a majority of cases. Improvements are needed to better estimate the near-surface winds when no radar is nearby and to improve the timeliness of the input data. However, the 3DVAR wind field information provides an integrated look at storm structure that may be of more use to forecasters than traditional radar-based proxies used to infer severe weather potential.

A real-time, weather-adaptive three-dimensional variational data assimilation (3DVAR) system has been adapted for the NOAA Warn-on-Forecast (WoF) project to incorporate all available radar observations within a moveable analysis domain. The key features of the system include 1) incorporating radar observations from multiple Weather Surveillance Radars-1988 Doppler (WSR-88Ds) with NCEP forecast products as a background state, 2) the ability to automatically detect and analyze severe local hazardous weather events at 1-km horizontal resolution every 5 min in real time based on the current weather situation, and 3) the identification of strong circulation patterns embedded in thunderstorms. Although still in the early development stage, the system performed very well within the NOAA's Hazardous Weather Testbed (HWT) Experimental Warning Program during preliminary testing in spring 2010 when many severe weather events were successfully detected and analyzed. This study represents a first step in the assessment of this type of 3DVAR analysis for use in severe weather warnings. The eventual goal of this real-time 3DVAR system is to help meteorologists better track severe weather events and eventually provide better warning information to the public, ultimately saving lives and reducing property damage.