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With the relocation of heavy industries moving from downstream region to upstream and midstream regions in the Yangtze River Economic Belt (YREB), it is critical to encourage coordinated low carbon development in different regions within the YREB. This paper uncovers the evolution of CO2 emissions in different regions within the YREB for the period of 2000–2017. It decomposes regional CO2 emission changes using the temporal and cross-regional three-layer logarithmic mean Divisia index (LMDI) method. Besides, it decomposes industrial CO2 emission changes using the temporal two-layer LMDI method. The research results show that economic growth is the major driver for regional CO2 emission disparities. The mitigation drivers, such as energy intensity and energy structure, lead to a more decreased CO2 emission in the downstream region than in the upstream and midstream regions. In addition, it proposes several policy recommendations based upon the local realities, including improving energy efficiency, optimizing energy structure, promoting advanced technologies and equipment transfers, and coordinating the development in the upstream, midstream and downstream regions within the YREB.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell disorders. Studies have shown the involvement of an abnormal immune system in MDS pathogenesis. The gut microbiota are known to influence host immunity and metabolism, thereby contributing to the development of hematopoietic diseases. In this study, we performed gut microbiome and plasma metabolomic analyses in patients with MDS and healthy controls. We found that patients with MDS had a different gut microbial composition compared to controls. The gut microbiota in MDS patients showed a continuous evolutionary relationship from the phylum to the species level. At the species level, the abundance of Haemophilus parainfluenzae, Streptococcus luteciae, Clostridium citroniae, and Gemmiger formicilis increased, while that of Prevotella copri decreased in MDS patients compared to controls. Moreover, abundance of bacterial genera correlated with the percentage of lymphocyte subsets in patients with MDS. Metabolomic analysis showed that the concentrations of hypoxanthine and pyroglutamic acid were increased, while that of 3a,7a-dihydroxy-5b-cholestan was decreased in MDS patients compared to controls. In conclusion, gut microbiome and plasma metabolomics are altered in patients with MDS, which may be involved in the immunopathogenesis of the disease.

MDSCs, which are defined as a kind of negatively regulatory cells, could suppress T cell immune response in many tumor-bearing animal models and cancer patients. We supposed that MDSCs also contributed to the impaired antitumor immunity in MDS. Here we demonstrated that STAT3-ARG1 pathway could be a critical signal transduction pathway that regulated MDSCs-mediated immunosuppression. Increased MDSCs was revealed in MDS patients when compared to healthy controls. Especially, MDSCs performed higher activated STAT3 and CCR2 expression in high-risk MDS patients. The CCL2 and IL-6 levels in MDS patients were also higher than in healthy controls, which could drive recruitment and activation of MDSCs. Meanwhile, lower expression levels of CD3ζ chain, perforin and granzyme B were demonstrated in MDS patients, which were associated with downregulated activation of CD8+ T lymphocytes. The results were supported by the decreased perforin, granzyme B and IFN-γ levels in the mixed-culture system of MDSCs and CD8+ T lymphocytes in vitro. Notably, targeting STAT3 pathway by selective inhibitor could decrease ARG1 expression in MDSCs and partially reverse the lower expression levels of effector molecules on CD8+ T lymphocytes. Therefore, this study revealed the potential STAT3-ARG1 mechanism behind MDSCs and provided a promising STAT3 targeting strategy in MDS.

This study aims to measure China's CO2 emissions embodied in fixed capital formation (FCF) from 2007 to 2017 by using both a multi-regional input-output (MRIO) model and a single-region input-output model (SRIO). Then decoupling analysis was performed for uncovering the relationship between embodied CO2 emissions and added values at provincial level. Logarithmic Mean Divisia Index (LMDI) method was further conducted to identify driving factors underlying the growth of embodied CO2 emissions. Results show that CO2 emission from FCF doubled from 2436 million tons (Mt) in 2007 to 4820 Mt in 2012, and increased slightly to 5089 Mt in 2017. Electric power, gas, and water production and supply sector (EGW) and manufacturing industry (MFI) sector were two dominant emitters from supply-side perspective, while construction (CON) was the largest demanding sector driving the embodied emissions from upstream sectors. From geographical point of view, northern provinces were the major inter-regional net exporters of embodied CO2 emissions, while eastern and southern provinces were net importers of embodied CO2 emissions. Based on such results, policy recommendations are proposed considering the relation between supply and demand sector, inter-provincial CO2 emission transfer, and local economic development to mitigate CO2 emissions from China's FCF.

Most of the International Prognostic Scoring System (IPSS) high-risk patients with myelodysplastic syndrome partly responded to hypomethylating therapy even with transient remission, while arsenic trioxide (ATO) had partial effect in patients with MDS. Therefore, we sought to investigate the effects and possible mechanisms of the combination of ATO and decitabine (DAC) in MDS cells. In our study, the MUTZ-1 and SKM-1 cells were treated with ATO, DAC or both. Cell viability, cell apoptosis, levels of reactive oxygen species (ROS) and expressions of the endoplasmicreticulum (ER) stress-associated genes and proteins were examined. Results showed the combination of ATO and DAC synergistically inhibited the proliferation and induced apoptosis of MDS cells. Through the RNA-sequence and GSEA gene function analysis, ER stress-related pathway played an important role in apoptosis of MDS cells induced by the combination of ATO and DAC. ER stress-related genes DNA damage inducible transcript 3, GRP78, and activating transcription factor-6 were significantly highly expressed in combination group than those in single agent groups; proteins were confirmed by western blot. The levels of ROS significantly increased in the combination group. Furthermore, the apoptosis of (ATO+DAC) group MDS cells could be partially reversed by antioxidant agent N-acetylcysteine, accompanied by decreased expression of intracellular ROS and ER stress-related genes. These results suggested that the combination of ATO and DAC synergistically induced the apoptosis of MDS cells by increased ROS-related ER stress in MDS cells.

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases which are prone to progress into acute myeloid leukemia (AML). Iron overload (IOL) caused by transfusion occurred in most MDS patients. But how IOL influences MDS progression has not been clarified yet.Herein, we collected clinical data from 143 MDS patients to investigate the impacts of IOL on patients survival and AML transformation.We found that median survival time, 3-year survival rate, leukemia-free survival (LFS) time were significantly shorter in patients with IOL than those with non-iron overload (NIOL) (Elevated intracellular iron and ROS in CD34

Background Hepatocellular carcinoma (HCC) is characterized by widespread epidemiology and extraordinary heterogeneity, with challenging prognosis prediction. Ferroptosis is a regulatory cell death driven by iron-dependent lipid peroxidation. The main aim of this study was to determine the predictive value of ferroptosis-related genes (FRGs) in HCC. Methods Herein, the data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) public databases. In the ICGC cohort, a multigenic signature was constructed using the LASSO Cox regression model. Next, patients in the TCGA cohort were used to verify the reliability of the model. Results Results showed that 30.07% of the differentially expressed genes (DEGs) in the ICGC cohort were associated with ferroptosis. Among them, 35 genes were identified as intersected genes associated with overall survival in both cohorts. Moreover, an 8-gene signature for prediction of HCC patients was constructed and the patients were divided it into low-risk and high-risk groups. The results indicated that the overall survival (OS) of patients in the high-risk group was lower than OS of patients in the low-risk group (P 1, P

As a promising approach to assist the fifth-generation (5G) communication system, geostationary (GEO) satellite communication technology is expected to be utilized to provide an efficient and reliable coverage for the terrestrial cellular network. Most multi-beam GEO satellites work on the low-inclination GEO orbit. Due to various unexpected factors, e.g., the imperfect satellite orbit, attitude, and antenna deformation, the practical satellite beam pointing on the earth surface will deviate unfortunately from its designed theoretical location. Although the center boresight-to-ground point of the satellite multi-beam antenna can be maintained via the control of attitude bias and track retention, the practical beam pointing center would still experience inevitable deviations, causing unwanted ground coverage drifting in engineering applications. To combat this, in this paper, we first provide a comprehensive calculation approach for the actual beam pointing on the ground of a satellite multi-beam, which is also validated via the theoretical analysis on the measurement from a ground-based calibration station. On this basis, a simple yet effective data-driven model is established to characterize the dynamical deviating trends induced by various unexpected influences. Finally, a novel beam pointing calibration scheme is designed, based on the Kalman filter. By tracking the coupling coefficients between elevation angle and azimuth angle in our simple model, a pre-deformation is added to the designed beam. Our proposed approach for the beam pointing calibration is validated by the numerical simulations. An improvement of 78.26% is achieved in maximum ground-surface pointing deviation distance.

Hongzhi Zhang, Huijuan Jiang, Huixiang Zhang, Juncai Liu, Xigang Hu, Lei Chen Department of Radiotherapy, Huaihe Hospital of Henan University, Kaifeng 475000, Henan, China Background: miR-4262 was identified as a tumor promoter in several cancers, but its exact role in gastric carcinoma is still largely unknown. Methods: The expression of miR-4262 was detected in gastric cancer tissues. Different concentrations of miR-4262 mimic and miR-4262 antagomir were respectively transfected into primary gastric carcinoma cells. After incubation for 72 h, the overexpression efficiencies were confirmed by qPCR, cell proliferation was detected with the CCK-8 assay, cell apoptosis was detected by using the PI/Annexin V Cell Apoptosis Kit, and cell invasion was detected with the Transwell invasion assay. The molecular mechanisms underlying the action of miR-4262 in gastric carcinoma cells were also explored. Results: In this study, we found that miR-4262 was significantly downregulated in gastric tissue from gastric cancer patients compared with that from the control group. Moreover, the level of miR-4262 was significantly lower in advanced gastric carcinoma. Additionally, lower level of miR-4262 was correlated with poorer prognosis and lower survival rate in gastric cancer patients. Then, different concentrations of miR-4262 mimic and miR-4262 antagomir were transfected into primary gastric carcinoma cells, respectively. The results showed that miR-4262 mimic suppressed proliferation and invasion and promoted cell apoptosis in a dose-dependent manner in gastric carcinoma cells. In contrast, miR-4262 antagomir increased proliferation and invasion and decreased cell apoptosis in a dose-dependent manner in gastric carcinoma cells. Furthermore, miR-4262 could directly target and suppress the expression of the proto-oncogene CD163. Conclusion: Our findings indicate that lower level of miR-4262 predicts poorer prognosis in gastric patients, and miR-4262 can target proto-oncogene CD163 to suppress gastric cancer cell proliferation and invasion. Keywords: miR-4262, gastric carcinoma, prognosis, proliferation and invasion, CD163

Inhibitors that target specific kinases or oncoproteins have become popular additions to or replacements for cytotoxic chemotherapies to treat many different types of cancer. However, many tumors lack a discernable target kinase and an amplified oncoprotein and/or rely on several cooperating mechanisms for progression. Thus, combinations of targeted therapies are essential for treating many cancers to avoid the rapid emergence of resistance. In this issue of the JCI, Ren et al. use an elegant kinase activity–profiling method and identify activity of the oncogene polo-like kinase-1 (PLK1) as an important driver of double-hit lymphoma (DHL), an aggressive subgroup of B cell lymphoma characterized by chromosomal translocations involving c-MYC and BCL2 or BCL6. Moreover, PLK1 activity was associated with MYC expression and poor prognosis in DHL patients. PLK1 inhibition with volasertib, alone and in combination with the BCL-2 inhibitor venetoclax, was efficacious in multiple DHL models, including mice harboring DHL patient–derived xenografts. Together, these data support PLK1 as a promising prognostic marker and therapeutic target for DHL.

Background Ferroptosis is a form of iron-dependent non-apoptotic cell death, with characteristics of loss of the activity of the lipid repair enzyme, glutathione (GSH) peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. The mechanism of ferroptosis in myelodysplastic syndrome (MDS) is unclear. Methods Cell viability assay, reactive oxygen species (ROS) assay, GSH assay, and GPX activity assay were performed to study the regulation of ferroptosis in MDS cells obtained from MDS patients, the iron overload model mice, and cell lines. Results The growth-inhibitory effect of decitabine could be partially reversed by ferrostatin-1 and iron-chelating agent [desferrioxamine (DFO)] in MDS cell lines. Erastin could increase the cytotoxicity of decitabine on MDS cells. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1. The concentration of hemoglobin in peripheral blood of iron overload mice was negatively correlated with intracellular Fe2+ level and ferritin concentration. Iron overload (IO) led to decreased viability of bone marrow mononuclear cells (BMMNCs), which was negatively correlated with intracellular Fe2+ level. Ferrostatin-1 partially reversed the decline of cell viability in IO groups. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in BMMNCs of IO mice. DFO could increase the level of GSH. Ferrostatin-1 and DFO could increase the GPX4 activity of BMMNCs in IO mice. Ferrostatin-1 could significantly reverse the growth-inhibitory effect of decitabine in MDS patients. Decitabine could significantly increase the ROS level in MDS groups, which could be inhibited by ferrostatin-1 or promoted by erastin. Ferrostatin-1 could significantly reverse the inhibitory effect of decitabine on GSH levels in MDS patients. Erastin combined with decitabine could further reduce the GSH level. Erastin could further decrease the activity of GPX4 compared with the decitabine group. Conclusion Ferroptosis may account for the main mechanisms of how decitabine induced death of MDS cells. Decitabine-induced ROS raise leads to ferroptosis in MDS cells by decreasing GSH level and GPX4 activity.

Malaria is a worldwide parasitic disease, which affects millions of lives every year. Various medications are recommended by WHO for prevention and treatment of malaria. However, adverse events caused by antimalarials were frequently reported, some of which were severe and fatal. Disorders of many organs related to antimalarials have been well recognized, whereas few studies concentrated on the relationship between antimalarials and oral-maxillofacial system health. Current review generalized the relevance of antimalarials to the health of oral-maxillofacial part and raised an urgent need to form a standard management for antimalarial-related oral-maxillofacial adverse events.

Ulaanbaatar, the capital city of Mongolia, is facing serious air pollution challenges&mdash, especially during the cold and long winter months&mdash, mainly due to fossil fuel combustion. This study investigates the socioeconomic drivers of the sulfur dioxide (SO2), nitrogen dioxide (NO2), and particulate matter (PM2.5) concentration changes in Ulaanbaatar between 2005 and 2015 by applying the index decomposition analysis (IDA) method. Five socio-economic driving forces are considered in the decomposition analysis. All the driving forces contributed to more air pollution concentration changes in 2015 than in 2005, despite the decreasing trends of decomposition results for the period of 2010&ndash, 2015. In general, economic growth, pollution intensity, and energy intensity significantly contributed to the changes of air pollutant concentrations, while energy structure and population growth had marginal effects. Finally, appropriate policy recommendations are proposed to the local government so that they can initiate feasible policies to effectively reduce air pollution, protect human health, and respond to climate change in Ulaanbaatar.

Background Ginkgotoxin including 4'-O-methylpyridoxine (MPN) and MPN-5'-glucoside (MPNG) is responsible for Ginkgo seed food poisoning. The purpose of the work reported was to prepare detoxified Ginkgo seed powder and at the same time to retain the nutritional and functional components of Ginkgo seed powder to the maximum extent. Results Resin adsorption technology was firstly employed to remove ginkgotoxin from water extract of Ginkgo seed powder. Under optimal conditions, the adsorption efficiency of the optimal resin for MPN could reach 100%, and that for MPNG could only reach 85.4 ± 0.93%. Resin adsorption alone could not effectively remove MPN and MPNG simultaneously. Endogenous enzymatic hydrolysis was next attempted to transform MPNG to MPN. MPNG could be completely hydrolyzed to MPN by endogenous enzyme(s) at 40 °C and pH 5.0 in 180 min. Ginkgotoxin only in the form of MPN in the enzymatic hydrolysate was then adsorbed with resin and the conditions were statistically optimized. The adsorption efficiency of MPN reached 98.89 ± 0.99% under the optimized conditions. Conclusions Removal of ginkgotoxin by combining endogenous enzymatic hydrolysis with resin adsorption could preserve the main nutritional and functional components of Ginkgo seed powder to the most extent, and did not change its main characteristics. The ginkgotoxin removal method developed in this work is a relatively simple and efficient approach. © 2020 Society of Chemical Industry.

This study aims to measure China's CO

// Huijuan Jiang 1, * , Ningbo Cui 1, * , Liyan Yang 1, * , Chunyan Liu 1 , Lanzhu Yue 1 , Lifang Guo 1 , Huaquan Wang 1 and Zonghong Shao 1 1 Department of Hematology, General Hospital, Tianjin Medical University, Tianjin 300052, China * These authors contributed equally to this work Correspondence to: Huaquan Wang, email: wanghuaquan@tmu.edu.cn Keywords: myelodysplastic syndromes, follicular helper T cell, CXCR5, PD-1, ICOS Received: February 06, 2017 Accepted: September 21, 2017 Published: October 06, 2017 ABSTRACT Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic diseases which have a high risk of progressing to acute myeloid leukemia. MDS patients have immunologic deficiency, including T and B cells dysfunction. Follicular T helper cells (Tfh, CD4 + CXCR5 + ) are an important subset of helper T cells which help to the formation of germinal centers and B cells differentiation. In this study, we investigated the proportion and function of Tfh using NUP98-HOXD13 transgenic (NHD13) mice model with MDS phenotype. The proportion of Tfh from bone marrow and spleen of NHD13 mice decreased compared with wild type (WT) mice tested by flow cytometry. In NHD13 mice spleens, there were decreased CXCR5 + cells and increased PD-1 + cells using immunohistochemistry. The active markers (ICOS, CD40L and OX40) expressed on Tfh of NHD13 mice were decreased. In contrast, PD-1 expression on Tfh of NHD13 mice was higher than that of WT mice. After coculture with Tfh from NHD13 mice, IgG and IgM production of B cells were decreased. In conclusion, the proportion and function of Tfh in the MDS mice model were altered. The dysfunction and reduction of Tfh may inhibit B cells differentiation and antibody production. Abnormal Tfh might contribute to the immune tolerance promoting the progression of MDS.

MCL is an aggressive B-cell lymphoma with poor prognosis due to emergence of drug resistant populations and lymphoma progression. Ibrutinib is a bruton's tyrosine kinase (BTK) inhibitor that was shown to have high response rates in MCL patients. However, as the use of this drug continues to grow in MCL and other B-cell lymphomas, emergence of resistance and fatal progression are of increasing clinical concern. Currently the mechanisms driving IR are poorly understood and no recurrent driver mutations have been identified in MCL. We have modeled acquired resistance to ibrutinib and implemented chemical proteomics and a cell-based drug screen approaches in IR MCL lines and primary samples, we have shown that MCL cells become resistant to ibrutinib through a kinome-adaptive reprogramming mechanism that lead to constitutive activation of the PI3K/AKT/mTOR pathway with increased levels of Myc and sustained transcription activation. The acquired IR MCL cells have increased rates of growth and augmented adhesion to stromal cells. Collectively, our published and preliminary studies indicate that IR MCL relies on global transcriptome remodeling and subsequent kinome reprogramming, leading to molecularly and clinically aggressive phenotype and resistance to ibrutinib therapy. Rather than there being a single mechanism of acquired IR, kinase networks are rewired in a plethora of ways in MCL cells as they become resistant to ibrutinib treatment. Adaptive remodeling of the kinome creates therapeutic challenges, where even combination targeted kinase inhibitor treatments are unlikely to be successful. Here, using genomic, chemical proteomic and drug screen profiling, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the aggressive phenotypes of IR. Accordingly, IR MCL cells are vulnerable to inhibitors of the transcriptional machinery and especially so to inhibitors of cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Further, CDK9 inhibition disables reprogrammed signaling circuits and prevents the emergence of IR in MCL. Finally and importantly, we provided that a novel and facile ex vivo image-based functional drug screening platform could predict clinical therapeutic responses of IR MCL and identified vulnerabilities that can be targeted to disable the evolution of IR. Disclosures Shain: Amgen: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Adaptive: Consultancy, Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; AbbVie: Research Funding; Karyopharm: Research Funding, Speakers Bureau. Shah:Kite/Gilead, Jazz, Incyte: Research Funding; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Moffitt Cancer Center: Current Employment.

Increasing evidence demonstrated that long non-coding RNA ANRIL serves as a fatal oncogene in many cancers, including nasopharyngeal carcinoma (NPC). However, little is known whether ANRIL regulated NPC cell radioresistance. Quantitative real-time PCR (qRT-PCR) was performed to examine the expression of lncRNA ANRIL and miR-125a in NPC tissues and cell lines. MTT assay was conducted to measure the cell viability of CNE2 and HONE1 cells. The apoptotic rate of CNE2 and HONE1 cells was determined by flow cytometry analysis. Colony survival was determined by clonogenic assay. Luciferase reporter assay was performed to verity the direct target of miR-125a. LncRNA ANRIL was evidently elevated in NPC tissues and cell lines. ANRIL inhibition suppressed proliferation, induced apoptosis, and enhanced radiosensitivity in NPC. Moreover, ANRIL could negatively modulate miR-125a expression. Furethermore, ANRIL upregulation reserved the inhibited proliferation, induced apoptosis, and enhanced radiosensitivity triggered by miR-125a overexpression. The expression of lncRNA ANRIL was upregulated in NPC tissues and cells. Moreover, knockdown of ANRIL repressed proliferation, promoted apoptosis, and improved radiosensitivity in NPC via functioning as a miR-125a sponge.

Hemorrhage and infection are two main causes of death in patients with myelodysplastic syndromes (MDS), and it is becoming increasingly clear that platelet dysfunction can also affect the process of hemostasis and anti-infection. The aim of this study was to evaluate activation function and immune-related function of platelets in MDS.We included 29 MDS patients and divided them into different subgroups (low-risk group and high-risk group; untreated group and treated group; pretransfusion group and post-transfusion group) according to IPSS-R score, hypomethylating agents (HMAs) therapy, and platelet transfusion history. Platelet light scatter properties, expression of CD41a, activation-associated phenotypes (CD62p and CD63), and immune-associated phenotypes (CD154 and TLR4) were detected by multiparameter flow cytometry.Expression of CD41a was decreased (P .05), and no difference was found in platelet light scatter properties between MDS patients and healthy subjects (P .05). Significantly decreased expression frequency and intensity of activation phenotype CD63 were found in patients with MDS (P .05). Low-risk MDS showed lower expression frequency while high-risk MDS showed reduced mean fluorescence intensity (MFI) of CD63. Decreased expression of CD154 and TLR4 was found in MDS patients (P .05) which was significantly elevated after HMAs therapy (P .05). Particularly, MFI of CD154 and TLR4 reduced in high-risk MDS patients (P .05).Myelodysplastic syndromes patients displayed defective expression of both activation- and immune-associated platelet phenotypes, with differential mechanisms between low-risk and high-risk groups regarding phenotype alterations. The findings confirmed impaired platelet phenotypes in MDS which may assist in the diagnosis and identification of MDS patients.

Cognitive radio is an efficient spectrum sharing mechanism to solve the contradiction between spectrum shortage and spectrum underutility, where secondary users (SUs) are allowed to access the spectrum licensed to primary users (PUs) in an opportunistic manner. In cognitive radio networks with multiple access points (APs), due to the information exchange cost and system flexibility, APs may not cooperate with each other and there usually does not exist a central controller in practice. We propose a distributed user association scheme based on multi-agent reinforcement learning to achieve load balancing for cognitive radio networks with multiple independent APs. In our proposed scheme, APs execute reinforcement learning process independently to derive optimal policies on user association. In each iteration, APs make decisions on choosing SUs for association and then SUs choose the optimal AP for association based on the offers of all APs, the behaviors of APs and SUs is modeled as a dynamic matching game. Simulation results show that the proposed multi-agent reinforcement learning approach can highly improve the system performance with excellent robustness, compared to the conventional max-SINR method.

Multidrug resistance (MDR) is a critical reason of cancer chemotherapy failure. Ribophorin II (RPN2) has emerged as a vital regulator of MDR in multiple cancers including gastric cancer (GC). However, the roles and molecular mechanisms of RPN2 in MDR have not been well featured till now. The present study aimed to explore the roles and molecular mechanisms of RPN2 in MDR of drug-resistant GC cells. Results showed that the expressions of RPN2, multidrug resistance 1 (MDR1), and ATP binding cassette subfamily G member 2 (ABCG2) were upregulated in SGC7901/DDP and SGC7901/VCR cells. Knockdown of RPN2 alleviated MDR through downregulating MDR1 and ABCG2 expressions in SGC7901/DDP and SGC7901/VCR cells. RPN2 depletion inhibited the activation of MEK/ERK pathway. RPN2 overexpression enhanced MDR by upregulating P-glycoprotein (P-gp) and ABCG2 protein expressions in SGC7901/DDP or SGC7901/VCR cells, while this effect of RPN2 was abrogated by ERK knockdown or treatment with ERK inhibitor PD98059. Our findings suggested that RPN2 potentiated P-gp- and ABCG2-mediated MDR via activating MEK/ERK pathway in GC, hinting the critical values of RPN2 in ameliorating MDR and providing a promising target for GC therapy.

Membrane separation technology was tried to remove the ginkgotoxin (4′-O-methylpyridoxine and 4′-O-methylpyridoxine-5′-glucoside) from Ginkgo seeds powder for the first time in this work. 99.88 ± 0.99% of the ginkgotoxin could transfer to the extraction solvent from the Ginkgo seeds powder when the water was used as the extraction solvent for extracting twice at 25 °C and solid to solvent ratio of 1:40 (g/mL) for 20 min. The conditions of ginkgotoxin removal by membrane separation were next studied as: ultrafiltration membrane with cut-off molecular weight of 10000 Da was operated at 0.2–0.3 MPa with a permeate volume of 4.7 L, and nanofiltration membrane with cut-off molecular weight of 600 Da was operated at 0.4–0.5 MPa with a permeate volume of 3.0 L. All the ginkgotoxin could be removed under the selected membrane operation conditions. The main nutritional and functional components of Ginkgo seeds powder were well preserved after detoxification. The main characteristics or structure of the detoxified Ginkgo seeds powder were not obviously changed. The membrane separation technology could be used as an effective method for removing ginkgotoxin from Ginkgo seeds powder.

SUMMARY Ibrutinib, a bruton’s tyrosine kinase (BTK) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the aggressive phenotypes of IR. Accordingly, IR MCL cells are vulnerable to inhibitors of the transcriptional machinery and especially so to inhibitors of cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Further, CDK9 inhibition disables reprogrammed signaling circuits and prevents the emergence of IR in MCL. Finally, and importantly, we find that a robust and facile ex vivo image-based functional drug screening platform can predict clinical therapeutic responses of IR MCL and identify vulnerabilities that can be targeted to disable the evolution of IR., In brief Zhao et al. conduct unbiased proteomic, enhancer, and transcriptional profiling in combination with high-throughput drug screening to identify super-enhancer and kinome remodeling as an Ibrutinib resistance mechanism. CDK9 and BRD4 are vulnerabilities for Ibrutinib resistance necessary to sustain super-enhancers, and inhibition of CDK9 or BRD4 prevents the emergence of resistance., Graphical Abstract

This paper studies a dual-channel closed-loop supply chain consisting of one manufacturer and one retailer. Product customization is taken into consideration. The manufacturer sells customized products through his online direct sale channel and sells standard products through both an online direct sale channel and a traditional retail channel. In the reverse supply chain, three modes of collecting used products are considered: via the manufacturer, via the retailer or via both the manufacturer and the retailer simultaneously (joint collecting mode). Three pricing models are proposed accordingly to analyze the optimal decisions of supply chain members. Through model analysis and computational studies, we find that the retailer collecting mode is most effective for the overall supply chain. The price of the customized product is almost not affected by the collecting modes.

Overconsumption of Ginkgo biloba seeds leads to poisoning. 4’-O-methylpyridoxine (MPN) and 4’-O-methylpyridoxine-5’-glucoside (MPNG) are responsible for poisoning by intaking ginkgo seeds. It had been reported that heat treatment could increase the MPNG content but decrease the MPN content in ginkgo seeds. However, the definite mechanism for the transformation of MPN and MPNG in ginkgo seeds undergoing heat treatment has not been elucidated to this day. In this work, a Chinese ginkgo cultivar was firstly employed to investigate the effect of heat treatment on the levels of MPN and MPNG. Similar syngenetic succession between the MPN and MPNG contents was also found. Several groups of experiments were further designed to explore the interconversion mechanism between MPN and MPNG under heat treatment. The results showed that non-enzymatic and enzymatic glycosylation mechanisms could not explain the transformation between MPN and MPNG. Enzymatic hydrolysis mechanism could better explain the dynamic relationship between the MPN and MPNG. Therefore, inactivating the endogenous enzymatic hydrolysis before HPLC analysis is needed to accurately determine the contents of MPN and MPNG in the ginkgo seeds.

Changes in bone marrow niches can lead to the occurrence of myelodysplastic syndrome (MDS). As an important part of the bone marrow niche, osteoblasts serve a key role in the progression of MDS. The present study investigated the quantity and function of osteoblasts and, through in vitro assays, detected changes in signaling pathways and the association with progression in MDS patients. The ratios of osteoprogenitors (CD34+OCN+) and OCN+CD34-Lin- osteoblasts in MDS patients were significantly less than those of normal controls. The results of this study demonstrated that the quantity and activity of osteoblasts in MDS patients were lower than those in normal controls. Furthermore the activity of osteoblasts in patients correlated with the severity of MDS. The quantity of osteoblasts cultured in vitro from high-risk and very high-risk MDS patients (WHO Classification-Based Prognostic Scoring System score 3-6) was decreased. The levels of T-cell immunoglobulin and mucin domain-containing 3 (TIM3) and Jagged 1 were also increased in the osteoblasts in vitro. These results indicated that osteoblasts are abnormally altered in MDS patients, and that there are associations between abnormal changes of osteoblasts and the severity of MDS.

With the rapid development of urban economy, urban residents pay more attention to their living environment, livability has become a hot spot of the current era. Community environment is the basis for the survival and development of residents. Its advantages and disadvantages are related not only to the physical and mental health of residents, but also to the level of urban economic development and community construction. From four aspects of life convenience, travel convenience, residential safety and environmental comfort, combined with taxi trajectory data, POI data, geographical conditions census data and other multi-source data, measure the equilibrium distribution of basic public service facilities within the community by spatial mean, construct dynamic assessment method of urban community livability based on time interval community hot spot and community activity, it overcomes the shortcomings of single data source and long evaluation time in the past community evaluation. The evaluation index system of community livability in Wuhan is determined, using entropy method to calculate the weight of indicators at all levels and livable index weight at each period, obtains community livable index, analyze and evaluate community livability in the main urban areas of Wuhan from time and space level. It can provide decision-making basis for urban construction department to build livable communities, so as to improve the quality of life of urban residents, and provide help for the daily life of residents, buying and renting a house.

Severe aplastic anemia (SAA) is an autoimmune disease in which bone marrow failure is mediated by activated myeloid dendritic cells (mDCs) and T lymphocytes. Recent research has identified a strong immunomodulatory effect of pyruvate kinase M2 (PKM2) on dendritic cells in immune-mediated diseases. In this study, we aimed to explore the role of PKM2 in the activation of mDCs in SAA. We observed conspicuously higher levels of PKM2 in mDCs from SAA patients compared to normal controls at both the gene and protein levels. Concurrently, we unexpectedly discovered that after the mDC-specific downregulation of PKM2, mDCs from patients with SAA exhibited weakened phagocytic activity and significantly decreased and shortened dendrites relative to their counterparts from normal controls. The expression levels of the costimulatory molecules CD86 and CD80 were also reduced on mDCs. Our results also suggested that PKM2 knockdown in mDCs reduced the abilities of these cells to promote the activation of CD8+ T cells (CTLs), leading to the decreased secretion of cytotoxic factors by the latter cell type. These findings demonstrate that mDC activation requires an elevated intrinsic PKM2 level and that PKM2 improves the immune status of patients with SAA by enhancing the functions of mDCs and, consequently, CTLs.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by cytopenia and dysplasia. Anemia is the most common symptom in patients with MDS. Mitophagy and mitochondrial dysfunction might be involved in the development of MDS. In this study, we investigated the change of mitophagy in erythroid precursors in MDS patients. We found that NIX-mediated mitophagy was impaired in bone marrow nucleated red blood cells (NRBC) of MDS patients, associated with an increased amount of damaged mitochondria and increased ROS level which might lead to apoptosis and ineffective erythropoiesis. The results showed that the amount of mitochondria in GlycoA+NRBC positively correlated with the count of ring sideroblasts in bone marrow samples. Meanwhile, the level of autophagy-associated marker LC3B in GlycoA+NRBC had a positive correlation with hemoglobin (Hb) levels, and the amount of mitochondria in GlycoA+NRBC had a negative correlation with Hb levels in high-risk MDS patients. Our results indicated that mitophagy might involve the pathogenesis of anemia associated with MDS. Autophagy might be a novel target in treatments of MDS patients.

Long non-coding RNAs (lncRNAs) may serve as miRNA sponges to modulate the expressions of miRNA target genes. LncRNA X-inactive specific transcript (XIST) has been demonstrated to be upregulated and act as an oncogene in non-small cell lung cancer (NSCLC). However, the sponge role of XIST in NSCLC progression remains largely unknown. In this study, we demonstrated that XIST was substantially upregulated and miR-137 was aberrantly downregulated in NSCLC tissues and cells. XIST was identified to function as a competitive endogenous RNA (ceRNA) for miR-137 to promote NSCLC cell viability and invasion. Additionally, our results suggested that miR-137 targeted the 3’UTR of paxillin (PXN) to suppress NSCLC cell viability and invasion. Meanwhile, miR-137 was negatively correlated with PXN expression while XIST was positively correlated with PXN expression. More importantly, XIST positively regulated PXN levels by sponging miR-137 in vitro and in vivo. Collectively, our study provided the evidence for the cross-talk between XIST, miR-137, and PXN, shedding light on the therapy for NSCLC.

Objective To investigate the frequencies and biological characteristics of CD25 positive hematopoietic stem cells (HSC) in myelodysplastic syndromes. Methods The expression of CD25 on HSC in bone marrow derived from patients with untreated MDS patients, untreated AML patients and normal controls were accessed by flow cytometry (FCM). The correlation analysis was done between CD25+ HSC and clinical parameters in MDS patients. Results The expression of CD25 on HSC (CD34+CD38− cells) in MDS patients (28.81%) was significantly higher than that in normal controls (9.41%, P = 0.020), which similar to that in AML patients (32.54%, P = 0.410). The CD25 expression on HSC was positively correlated with the CD123 expression on HSC (r = 0.602, P = 0.008). The expression of CD25 on HSC in high-risk MDS group (53.27%) based on IPSS score was significantly higher than that in low-risk MDS group (18.66%, P = 0.003). In MDS patients, CD25+ HSC were negatively correlated with the counts of neutrophils (r = −0.684, P = 0.002) and platelets (r = −0.561, P = 0.015), while positively correlated with the percentage of blasts in bone marrow (r = 0.596, P = 0.009). The CD25 expression on erythroblasts had a significant positive correlation with red blood cell counts in MDS patients (r = 0.536, P = 0.012). Conclusions CD25 was over-expressed on HSC in MDS patients, especially in high-risk MDS patients. Increased CD25+ HSC was correlated with progression of MDS. Low-expression of CD25 on erythroblasts might correlate with anemia in MDS patients. CD25 could be a specific marker of LSC in MDS, and could involve in the mechanisms of development and progression of MDS.

The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies., Ibrutinib has demonstrated high response rates in B-cell lymphomas but a lot of ibrutinib-treated patients relapse with resistance. This study unified TME-mediated de novo and acquired drug resistance through B-cell receptor signalling and PI3K-AKT-mTOR axis and provides a combination therapeutic strategy against B-cell malignancies.

An efficient synthesis of ODM-201's diastereomers has been developed from (R)-methyl 3-hydroxybutanoate or (S)-methyl 3-hydroxybutanoate, respectively, with high overall yield and excellent diastereomeric purity. The key step in this synthesis is the preparation of the key intermediate (R)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid or (S)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid through intramolecular 1,3-dipolar cycloaddition of the vinyl diazo carbonyl compounds.