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In this paper, we propose a new and unified approach for nonparametric regression and conditional distribution learning. Our approach simultaneously estimates a regression function and a conditional generator using a generative learning framework, where a conditional generator is a function that can generate samples from a conditional distribution. The main idea is to estimate a conditional generator that satisfies the constraint that it produces a good regression function estimator. We use deep neural networks to model the conditional generator. Our approach can handle problems with multivariate outcomes and covariates, and can be used to construct prediction intervals. We provide theoretical guarantees by deriving non-asymptotic error bounds and the distributional consistency of our approach under suitable assumptions. We also perform numerical experiments with simulated and real data to demonstrate the effectiveness and superiority of our approach over some existing approaches in various scenarios., 50 pages, including appendix. 5 figures and 6 tables in the main text. 1 figure and 7 tables in the appendix

In order to acquire scientific evidence for the application of thiamethoxam (TMX) in Agaricus bisporus cultivation, residue and dissipation experiments for field trials were performed with the application of TMX in compost and casing soil, respectively. An effective QuEChERS method was established to analyze TMX and its two metabolites, clothianidin (CLO) and thiamethoxam-urea (TMX-urea), in compost, casing soil, and fruiting bodies. The results indicated that the TMX dissipation half-lives (t1/2) at dosages of 10 and 50 mg kg−1 were 19.74 d (day) and 28.87 d in compost and 33.54 d and 42.59 d in casing soil, individually. TMX, CLO, and TMX-urea were observed after TMX application in compost and casing soil. For TMX applied to the casing soil, only TMX residues were detected in fruiting bodies with bioconcentration factors (BCFs) of 0.0003~0.0009. In addition, both the chronic risk quotient (RQ) and acute risk quotient (HQ) values of TMX in fruiting bodies were far less than 1, which means the dietary health risks to humans were acceptable. However, in the TMX application to the compost, these analytes were not detected in the fruiting bodies. This suggested that the application of TMX in compost was safer than in casing soil during A. bisporus cultivation.

Deep learning based medical volumetric segmentation methods either train the model from scratch or follow the standard "pre-training then finetuning" paradigm. Although finetuning a well pre-trained model on downstream tasks can harness its representation power, the standard full finetuning is costly in terms of computation and memory footprint. In this paper, we present the first study on parameter-efficient transfer learning for medical volumetric segmentation and propose a novel framework named Med-Tuning based on intra-stage feature enhancement and inter-stage feature interaction. Given a large-scale pre-trained model on 2D natural images, our method can exploit both the multi-scale spatial feature representations and temporal correlations along image slices, which are crucial for accurate medical volumetric segmentation. Extensive experiments on three benchmark datasets (including CT and MRI) show that our method can achieve better results than previous state-of-the-art parameter-efficient transfer learning methods and full finetuning for the segmentation task, with much less tuned parameter costs. Compared to full finetuning, our method reduces the finetuned model parameters by up to 4x, with even better segmentation performance.

The research community has witnessed the powerful potential of self-supervised Masked Image Modeling (MIM), which enables the models capable of learning visual representation from unlabeled data. In this paper, to incorporate both the crucial global structural information and local details for dense prediction tasks, we alter the perspective to the frequency domain and present a new MIM-based framework named FreMAE for self-supervised pre-training for medical image segmentation. Based on the observations that the detailed structural information mainly lies in the high-frequency components and the high-level semantics are abundant in the low-frequency counterparts, we further incorporate multi-stage supervision to guide the representation learning during the pre-training phase. Extensive experiments on three benchmark datasets show the superior advantage of our proposed FreMAE over previous state-of-the-art MIM methods. Compared with various baselines trained from scratch, our FreMAE could consistently bring considerable improvements to the model performance. To the best our knowledge, this is the first attempt towards MIM with Fourier Transform in medical image segmentation.

There is a key problem in the medical visual question answering task that how to effectively realize the feature fusion of language and medical images with limited datasets. In order to better utilize multi-scale information of medical images, previous methods directly embed the multi-stage visual feature maps as tokens of same size respectively and fuse them with text representation. However, this will cause the confusion of visual features at different stages. To this end, we propose a simple but powerful multi-stage feature fusion method, MF2-MVQA, which stage-wise fuses multi-level visual features with textual semantics. MF2-MVQA achieves the State-Of-The-Art performance on VQA-Med 2019 and VQA-RAD dataset. The results of visualization also verify that our model outperforms previous work.

Additional file 1: Supplementary Information.

Avian reovirus (ARV) is the primary pathogen responsible for viral arthritis. In this study, 2340 samples with suspected viral arthritis were collected from 2019 to 2020 in 16 provinces of China to investigate the prevalence of ARV in China and to characterize the molecular genetic evolution of epidemic strains. From 113 samples analyzed by RT-PCR, 46 strains of avian reovirus were successfully isolated and identified. The genetic evolution of the σC gene showed that 46 strains were distributed in 1–5 branches, with the largest number of strains in branches 1 and 2. The σC gene homology among the strains was low, with approximately 62% homology in branches 4 and 5 and about 55% in the remaining branches. The strains circulating during the ARV epidemic in different provinces were distributed in different branches. The SPF chickens were immunized with inactivated vaccines containing strains from branches 1 and 4 to analyze the cross-immune protection elicited by different branches of ARV strains. A challenge protection test was performed using strains in branches 1, 2, 4, and 5. Our results showed that inactivated vaccines containing strains from branches 1 and 4 could fully protect from strains in branches 1, 4, and 5. The results of this study revealed the genetic diversity among the endemic strains of ARV in China from 2019 to 2020. Each genotype strain elicited partial cross-protection, providing a scientific basis for the prevention and control of ARV.

In recent years, managerial ownership has begun to be used as an incentive mechanism in China. Managerial ownership is one of the ways to realize the mixed ownership reform of state owned enterprises. Taking the mixed ownership reform of Chinese state-owned enterprises as the research object, this paper analyzes the impact of management ownership on the performance of mixed ownership enterprises. The conclusions are as follows: management ownership and corporate performance have a positive correlation in state-owned listed companies. The financial performance of the company increases with the proportion of management shareholding, ownership concentration and equity balance. There is a significant negative correlation between the proportion of independent directors and the rate of return on net assets, which shows that the independent directors of state-owned enterprises in China have not played their due role in the governance of state-owned enterprises.

The location pattern of different commercial stores in Shichahai, a historic conservation area in Beijing, was investigated from a street centrality perspective. Many previous studies have investigated the relationship between street centrality and land use patterns or commercial activities at interurban or intraurban scales. We considered Shichahai in this study to determine if street centrality applied at the street scale and if the street network was the only factor influencing the selection of store location. First, the nearest neighbor index, nearest neighbor hierarchical spatial cluster (NNHSC), and kernel density estimation (KDE) methods were used to provide baseline spatial distributions of commercial stores. Second, urban network analysis (UNA) tools were used to measure the street centrality indices under two conditions, with and without the weighting of cultural relics calculated by a principal component analysis (PCA). Finally, both store locations and centrality values at nodes were transformed to one unit (raster pixel) for a correlation analysis. The results showed that three of the four store types were clustered and had their own hotspots that were mostly located in the eastern and central parts of city blocks. The most momentous findings were determined from the street centrality indices. Among the three store types with correlation coefficients above 0.5, all centrality indices with landmark weighting, except straightness, had higher correlations, with closeness with landmark weighting having the highest correlation, followed by betweenness with landmark weighting. Therefore, we statistically concluded that street centrality could apply at the street scale and that the street network was not the only factor that influenced store location pattern, with landmarks also playing a significant role. The results provide guidance in determining the selection strategy for stores in a historic conservation area.

The three-dimensional (3D) nickel-cobalt double hydroxides nanosheets in situ grown on nitrogen-containing activated carbon (NAC/NiCo-DHs) were obtained via a simple solvothermal method. The NAC activated by low-cost green calcium chloride as a substrate greatly enhances the conductivity and specific surface area of the materials, and the unique sheet structure of NAC/NiCo-DHs facilitates the transport of charges. The electrochemical test results show that NAC/NiCo-DHs have a high specific capacitance of 1920 F g−1 at 1 A g−1, outstanding high-rate capability, with 85.4% retention after a 20-fold increase in current densities, and excellent cycling stability with 95.54% specific capacitance retained after 1000 cycles at 20 A g−1, and even after 2000 cycles, the capacitance retention rate of the material can still reach 71.37%. In addition, NAC/NiCo-DHs//AC device exhibits a maximum energy density and power density of 54.8 Wh kg−1 and 8000 W kg−1, and a remarkable cycling stability with 81.86% retention level after 2500 cycles at 5 A g−1, indicating that it has great potential as an energy storage device.

To analyze the failure mechanism and energy-absorbing characteristics of composite thin-walled C-channels subject to the low-speed axial compression, 12 groups of T700/MTM28 specimens with three di...

Using a simple hydrothermal process, ZnO nanosheet balls (ZnO NSBs) were in situ synthesized on three-dimensional graphene foam grown by chemical vapor deposition using nickel foam as the template. The hybrid ZnO NSB/GF was acted as a free-standing electrode for electrochemical detection of dopamine in the presence of uric acid. The results show that ZnO NSBs with the diameter of ∼2 μm and sheet thickness of ∼50 nm are distributed on the surface of GF. The ZnO NSB/GF electrode exhibits a high sensitivity of 0.99 μA μM−1 for the determination of dopamine. It also shows a low detection limit, good selectivity, reproducibility and stability. And it is potential for use in clinical research.

Additional file 1.

Background: Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in limited objective response rate (≤ 60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Methods: The effects of PARPi combined with glycogen synthase kinase 3 (GSK3) inhibitors were investigated in vitro with respect to cell viability, cell cycle and apoptosis. The synergy was assessed by calculation of the combination index (CI). GSK3α null and GSK3β null cells were generated using CRISPR/Cas9 technique. The underlying mechanism was examined by western blotting, flow cytometry, qRT-PCR and fluorescence microscopy. This combination was also evaluated in the mouse xenograft model; tumor growth and tumor lysates were analyzed, and the immunohistochemistry assay was performed. All data are presented as mean ± SD. Comparison between two groups was performed with the Student’s t-test.Result: The data showed that ~25% of oncological drugs and kinase inhibitors that were evaluated displayed synergy with PARPi in HCT-15 cells. Among the tested agents, GSK3 inhibitors (GSK3i) exhibited the strongest synergistic effect with PARPi. Moreover, the synergistic antitumor effect of GSK3 and PARP inhibition was confirmed in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. Additionally, inhibition or genetic depletion of GSK3β was found to impair HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity.Conclusion: Our results provide a mechanistic understanding of combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

The introduction of alternative CO2-fixing pathways in photoautotrophic organism may improve the efficiency of biological carbon fixation such as minimizing the carbon loss due to photorespiration. Here, we analyzed the effects of creating a formate entry point into the primary metabolism of the cyanobacterium Synechocystis sp. PCC 6803. The formate-tetrahydrofolate ligase (FTL) from Methylobacterium extorquens AM1 was expressed in Synechocystis to enable formate assimilation and reducing the loss of fixed carbon in the photorespiratory pathway. Transgenic strains accumulated serine and 3-phosphoglycerate, and consumed more 2-phosphoglycolate and glycine, which seemed to reflect an efficient utilization of formate. However, labeling experiments showed that the serine accumulation was not due to the expected incorporation of formate. Subsequent DNA-microarray analysis revealed profound changes in transcript abundance due to ftl expression. Transcriptome changes were observed in relation to serine and glycine metabolism, C1-metabolism and particularly nitrogen assimilation. The data implied that ftl expression interfered with the signaling the carbon/nitrogen ratio in Synechocystis. Our results indicate that the expression of new enzymes could have a severe impact on the cellular regulatory network, which potentially hinders the establishment of newly designed pathways.

Policy Points Social policies might not only improve economic well-being, but also health. Health policy experts have therefore advocated for investments in social policies both to improve population health and potentially reduce health system costs. Since the 1960s, a large number of social policies have been experimentally evaluated in the United States. Some of these experiments include health outcomes, providing a unique opportunity to inform evidence-based policymaking. Our comprehensive review and meta-analysis of these experiments find suggestive evidence of health benefits associated with investments in early life, income support, and health insurance interventions. However, most studies were underpowered to detect health outcomes. CONTEXT: Insurers and health care providers are investing heavily in nonmedical social interventions in an effort to improve health and potentially reduce health care costs. METHODS: We performed a systematic review and meta-analysis of all known randomized social experiments in the United States that included health outcomes. We reviewed 5,880 papers, reports, and data sources, ultimately including 61 publications from 38 randomized social experiments. After synthesizing the main findings narratively, we conducted risk of bias analyses, power analyses, and random-effects meta-analyses where possible. Finally, we used multivariate regressions to determine which study characteristics were associated with statistically significant improvements in health outcomes. FINDINGS: The risk of bias was low in 17 studies, moderate in 11, and high in 33. Of the 451 parameter estimates reported, 77% were underpowered to detect health outcomes. Among adequately powered parameters, 49% demonstrated a significant health improvement, 44% had no effect on health, and 7% were associated with significant worsening of health. In meta-analyses, early life and education interventions were associated with a reduction in smoking (odds ratio [OR] = 0.92, 95% confidence interval [CI] 0.86-0.99). Income maintenance and health insurance interventions were associated with significant improvements in self-rated health (OR = 1.20, 95% CI 1.06-1.36, and OR = 1.38, 95% CI 1.10-1.73, respectively), whereas some welfare-to-work interventions had a negative impact on self-rated health (OR = 0.77, 95% CI 0.66-0.90). Housing and neighborhood trials had no effect on the outcomes included in the meta-analyses. A positive effect of the trial on its primary socioeconomic outcome was associated with higher odds of reporting health improvements. We found evidence of publication bias for studies with null findings. CONCLUSIONS: Early life, income, and health insurance interventions have the potential to improve health. However, many of the included studies were underpowered to detect health effects and were at high or moderate risk of bias. Future social policy experiments should be better designed to measure the association between interventions and health outcomes.

The novel three-dimensional (3D) Ni(HCO3)2/(Cu0.2Ni0.8)O nanomaterials with granular and needle-like structures are synthesized as electrode materials for supercapacitors by a facile one-step solvothermal method. In this work, nickel-copper bimetallic oxide obtained by introducing copper ions is committed to accelerating charge transport and improving the electronic conductivity of the composites to thereby obtain high-performance electrode materials. Herein, further optimization of material properties are obtained by revealing the optimum molar ratio between nickel and copper. The maximum specific capacitance of the prepared electrode materials are 2000 F g−1 at current density of 1 A g−1, which is evidently higher than that of the sample prepared without copper incorporation. An asymmetric supercapacitor device is fabricated using NC-d as the positive electrode and activated carbon as the negative electrode. The NC-d//AC device has high energy density and power density (52.9 Wh kg−1 at 160 W kg−1, and 22.2 Wh kg−1 at 8000 W kg−1), indicating the great potential of NC-d to practical application as supercapacitor electrode materials.

An environment-friendly and cost-effective route has been explored to prepare three-dimensional (3D) porous Co-doped α-Ni(OH)2 nanosheets vertically arranged on reduced graphene oxide (RGO) by one-pot methanol-mediated solvothermal synthesis. This process avoids the addition of any precipitating agent and oxidizing agent. Herein, methanol acts as solvent, structure-directing agent and it also can be oxidized to release OH−. In addition, Co doping is considered to be an effective approach to improve the electronic conductivity and electrochemical performance for energy conversion. Thus, experiments using different doping amounts of Co are performed. The different feed molar ratios of Co2+ to Ni2+ are simply controlled, and the ultrathin Co-doped α-Ni(OH)2/RGO nanosheets (Co2+:Ni2+ = 0.5:1) display the best capacitive property. The synthesized Co-doped α-Ni(OH)2/RGO nanosheet electrode exhibits the highest specific capacitance of 2322 F g−1 at current density of 1 A g−1, outstanding rate performance of 1933 F g−1 at 20 A g−1, and excellent lifetime cycle with 87.9% retention level after 1000 cycles at 10 A g−1. Moreover, an asymmetric supercapacitor is successfully manufactured with the Co-doped α-Ni(OH)2/RGO as a positive electrode and activated carbon as a negative electrode. The hybrid device delivers a maximum energy density of 38.9 Wh kg−1 and a maximum power density of 8000 W kg−1. Our supercapacitor exhibits a remarkable cycle stability along with 88.2% specific capacitance retained over 2000 cycles at 5 A g−1. These results may provide useful insights for fabricating high-performance electrode materials for energy storage applications.

Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15–55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2–4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3.2–37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40–510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 μg/mL, 2652.5 μg/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 mg·kg-1·d-1, for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 mg·kg-1·d-1, for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50=6.64 μmol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.

In this paper, we design a positioning system for permanent magnet based on three-axis digital magnetic sensor array to achieve accurate positioning of capsule endoscope. The permanent magnet is equivalent to a magnetic dipole model and fixed in the capsule, the host computer receives the magnetic flux density data measured by the magnetic sensor array through serial port. We propose a method combining particle swarm optimization and Levenberg-Marquard (L-M) algorithm to calculate position and direction parameters of the permanent magnet, and display real-time trajectory tracking through the graphical interface in MATLAB. The system takes 0.2 seconds to complete positioning once, and positioning error of the system is 0.479 cm.

To improve photosynthetic efficiency, a synthetic formate assimilation (FA) pathway is designed in this study to function as an additional carbon-fixing route, which possibly also reduce the photorespiratory loss of CO2 via the inhibition of glycine decarboxylation. To establish FA, genes encoding the proteins 10-formyl-THF ligase (FTL), 5,10-methylene-THF dehydrogenase (MtdA), and 5,10-methenyl-THF cyclohydrolase (FchA) from M. extorquens AM1 were transferred into the model cyanobacterium Synechocystis sp. PCC 6803.

Background: Post-stroke depression has seriously affected the rehabilitation and quality of life of patients, and there is no reliable treatment plan at present. Nursing plays an important role in the recovery of patients, some studies have pointed out that traditional Chinese medicine emotional therapy has advantages in improving post-stroke depression and promoting rehabilitation, but it is lack of evidence-based basis. The purpose of this study is to systematically evaluate the effect of traditional Chinese medicine emotional therapy on the improvement of post-stroke depression. Method: We will search CNKI, Wanfang, VIP and CBM, PubMed, Embase, Web of Science and the Cochrane Library database, and search the randomized controlled trial on traditional Chinese medicine emotional therapy in patients with post-stroke depression from the establishment of the database to February 2021. The language is limited to English and Chinese. The quality of the included study is independently extracted and the literature quality is evaluated by 2 researchers. And meta-analysis is performed on the included literature using RevMan5.3 software. Result: In this study, the effect of traditional Chinese medicine emotional therapy on the improvement of post-stroke depression is evaluated by patient psychiatric scale score, compliance evaluation, quality of life evaluation and other indicators. Conclusion: This study will provide reliable evidence-based basis for establishing a reasonable and effective nursing scheme for patients with post-stroke depression. Ethics and dissemination: Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. OSF Registration number: DOI 10.17605/OSF.IO/KA7G3

Blumea aromatica is a traditional Chinese medicine used for treating various diseases such as rheumatoid arthritis, eczema, and pruritus. Previous studies on B. aromatica used a mass defect-filtering strategy via the ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and reported the presence of several labdane diterpenoids (LADs). To determine the actual structures of these LADs and investigate their biological activities, seven previously undescribed LADs (aromatin D-J) were isolated from the whole B. aromatica herb. The structures of these isolated compounds were characterized using high-resolution mass spectrometry and extensive 1D and 2D NMR analyses. In addition, the absolute configurations of these compounds were determined by comparing the experimental and calculated electronic circular dichroism (ECD) spectra as well as using X-ray crystallographic analysis. All isolated compounds were evaluated for their ability to activate adenylate cyclase by measuring the levels of cyclic adenosine 3',5'-monophosphate (cAMP) in rat ventricular tissue. Aromatin E, F, and J showed moderate activities with an increase in cAMP levels by 67%, 69%, and 64%, respectively, compared with the control group.

Fructooligosaccharide was isolated from Polygonatum Cyrtonema Hua (PFOS) for the first time. Structure characterized using FT-IR, MALDI-TOF-MS, NMR, AFM, and TEM, indicated that PFOS was graminan-type fructan with a degree of polymerization ranging from 5 to 10. A murine model of lipopolysaccharide (LPS)-induced peritonitis was used to evaluate the in vivo anti-inflammatory and lung protective efficacy of PFOS. The result shown that pretreatment with PFOS (1.0 mg/mL) in peritonitis-induced mice could significantly inhibit the level of pro-inflammatory cytokines (TNF-α, IL-1β) in serum (P 0.001), increase mice survival rate from 12.5 % to 54 % (P0.05), and alleviated lung injury through ameliorating the damage of the pulmonary cellular architecture and reducing inflammatory monocyte accumulation in lung tissue. This effect of oligosaccharides could explain the traditional usage of P. cyrtonema as a tonic medicine for respiratory problems and it could be used as a potential natural ingredient with anti-inflammatory activity.

Multidrug resistance (MDR) is a major cause of tumor treatment failure; therefore, drugs that can avoid this outcome are urgently needed. We studied triptolide, which directly kills MDR tumor cells with a high potency and a broad spectrum of cell death. Triptolide did not inhibit P-glycoprotein (P-gp) drug efflux and reduced P-gp and MDR1 mRNA resulting from transcription inhibition. Transcription factors including c-MYC, SOX-2, OCT-4, and NANOG were not correlated with triptolide-induced cell killing, but RPB1, the largest subunit of RNA polymerase II, was critical in mediating triptolide's inhibition of MDR cells. Triptolide elicited antitumor and anti-MDR activity through a universal mechanism: by activating CDK7 by phosphorylating Thr170 in both parental and MDR cell lines and in SK-OV-3 cells. The CDK7-selective inhibitor BS-181 partially rescued cell killing induced by 72-hour treatment of triptolide, which may be due to partial rescue of RPB1 degradation. We suggest that a precise phosphorylation site on RPB1 (Ser1878) was phosphorylated by CDK7 in response to triptolide. In addition, XPB and p44, two transcription factor TFIIH subunits, did not contribute to triptolide-driven RPB1 degradation and cell killing, although XPB was reported to covalently bind to triptolide. Several clinical trials are underway to test triptolide and its analogues for treating cancer and other diseases, so our data may help expand potential clinical uses of triptolide, as well as offer a compound that overcomes tumor MDR. Future investigations into the primary molecular target(s) of triptolide responsible for RPB1 degradation may suggest novel anti-MDR target(s) for therapeutic development. Mol Cancer Ther; 15(7); 1495–503. ©2016 AACR.

MoS2 nanoflowers (NFs) prepared by hydrothermal synthesis were mixed with graphene oxide (GO) suspension prepared by Hummers method. Then, the mixture was spray coated on indium tin oxide (ITO) glass. After heatment, MoS2 NFs-reduced GO/ITO (MoS2 NFs-rGO/ITO) was obtained and used as a working electrode to electrochemically detect dopamine and uric acid simultaneously. The results are as follows: MoS2 NFs with the diameter of ~ 1 μm are composed by nanosheets and the graphene with a high transparence and large number of folds is coated on the surface of MoS2 NFs. A large number of holes form in the electrode so that bioactive molecules can easily enter and contact with the hybrid. The electrode exhibits a high sensitivity (2.29 and 1.88 μA μM−1) for the determination of dopamine and uric acid. The electrode also shows a low detection of limit, good anti-interference and stability. And it can be used for detecting real biomolecules.

The development of novel nanomaterials brings new opportunity and challenge for high sensing detection of biomolecules. The authors describe the preparation of 3-dimentional hollow graphene balls (3D HGBs) using nickel nanoparticles (Ni-NPs) as the template. The Ni-NPs were synthesized by chemical reduction of nickel chloride and then graphene was coated onto their surface via carburization and carbonization. After etching Ni-NPs, 3D HGBs with few layers and a typical size of 100 nm were obtained. They were sprayed onto indium tin oxide glass to obtain a working electrode for electrochemical determination of levodopa in the presence of uric acid. Due to the unique hollow porous structure of the 3D HGBs, the electrode exhibits a sensitivity of 0.69 μA·μM−1·cm−2 and a 1 μM limit of detection. It is selective, reproducible and stable. It was applied to the determination of levodopa in spiked human plasma samples and it is of potential use in clinical research.

Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel α-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double-strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC50 of 0.3 μM. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different-mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy.

Sustained pulmonary vasoconstriction and excessive pulmonary vascular remodelling are two major causes of elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension. The purpose of this study was to investigate whether chloroquine induced relaxation in the pulmonary artery (PA) and attenuates hypoxia-induced pulmonary hypertension (HPH).Isometric tension was measured in rat PA rings pre-constricted with phenylephrine or high KChloroquine attenuated agonist-induced and high KChloroquine is a potent pulmonary vasodilator that may directly or indirectly block VDCC, store-operated Ca

In recent years, managerial ownership has begun to be used as an incentive mechanism in China. Managerial ownership is one of the ways to realize the mixed ownership reform of state owned enterprises. In this paper, the impact of executive stock ownership on corporate performance of China's state-owned listed companies that mixed ownership has been achieved is analyzed. The conclusions are as follows: the state-owned listed companies management ownership and corporate performance has a positive correlation. The financial performance of the company increases with the proportion of management shareholding, ownership concentration and equity balance. There is a significant negative correlation between the proportion of independent directors and the rate of return on net assets, which shows that the independent directors of state-owned enterprises in China have not played its due role in the governance of state-owned enterprises.

Purpose: To investigate whether fructopyrano-(1→4)-glucopyranose (FG) inhibits the proliferation of liver cancer cells and angiogenesis in a vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) dependent manner. Methods: Bel-7402, HepG2 and SMMC-7721 cells with high expression of VEGF and VEGFR were screened. Bel-7402 cells and human microvascular endothelial cells (HMEC) were treated with FG for 48 h. CCK-8 assay was used to detect cell proliferation. Wound healing assay was used to investigate effect of FG on the migration of HMECs. Tube formation assay was done to test influence of FG on the angiogenesis of HMECs, and qRT-PCR and western blot assay were performed to detect mRNA and protein expression of VEGF, Fit-1 and KDR. Nude mice were inoculated with Bel-7402 cells, and influence of FG on tumor growth, microvessel density (MVD) and VEGF expression in tumor was investigated. Results: Bel-7402 cells had a significantly higher expression of VEGF and VEGFR when compared with HepG2 cells and SMMC-7721 cells. FG could markedly reduce the mRNA and protein expressions of VEGF, Fit-1 and KDR in Bel-7402 cells and inhibit the proliferation of Bel-7402 cells in a concentration dependent manner. In addition, FG was able to remarkably inhibit the proliferation, migration and angiogenesis of HMECs, exerting anti-angiogenetic effect. In cancer-bearing nude mice, FG was found to inhibit the tumor growth, reduce MVD in tumors and decrease the VEGF in tumors. Conclusions: FG can inhibit proliferation of liver cancer cells and suppression angiogenesis in liver cancer in a VEGF/VEGFR dependent manner.

The purpose of the study was to explore how the new media and cyber environment prompt changes of the television programs toward an omni-media pattern of use. By using the Phoenix Group's news program, Omni Media Online as an example, the case study examines the audience's changing interests in programs' content as well as watching channels. Both audiences from television and new media platforms demonstrated a trend of merging audience composition and changing habit in China's media industry. When two-way communication could be built with multi-channel interaction, it brings more public opinions to live news broadcast. A survey was conducted to learn the relationships between modern audience and the program, taking the Phoenix Group as an example. It is important to know what viewers want based on their watching experience so that proper reform can be carried out draw their attentions.

A variety of α-carbolines is readily prepared by reaction of 2-nitrophenylacetonitrile with chromones (I) or benzylidene acetones (VI).

An effective and convenient method has been developed for the preparation of 2 or 2,4-substituted α-carbolines via a one-pot tandem reaction of α,β-unsaturated ketones with 2-nitrophenylacetonitrile in the presence of zinc dust, acetic acid and triethylamine. This protocol presents a simple, rapid and pot/step economical strategy for preparing biologically interesting α-carbolines with moderate anti-tumor activities.

The current IP network's gateway protocol of routing system can only provide the attainable services of data transmission and do not have the ability to regulating the use of the whole network, which causes the transmissive data streams of the network may gather on the same chain. Thus that can cause local server congestion at the network and the utilization of the network resource coming down. Form the view of the network traffic engineering, this article designs and implement combine the type of data stream with estimating of data flow rate, forming flow characteristics, divide priority according to that . According to the priority make the data flows carry through network traffic transfer algorithm. The simulation's results show that the algorithm can achieve the goal of transferring traffic and balancing the network's load, increasing the throughput of the network. Packet's transmission delay decline in the overall, achieving the goal of the automatic controlling of network's resources and improving the performance of network.

Furnace system for the methanol conversion into the large time delay, time-varying, nonlinear and other characteristics, combination of fuzzy control and neural network control, design a set of fuzzy neural network control system. Through MATLAB simulation test, the system applied to large time delay control of the methanol conversion furnace system, compared with the traditional PID control, has strong robustness, fast response, adaptability and so on.