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Background and Purpose: Androgen receptor (AR), a ligand-activated transcription factor, is a master regulator in the development and progress of prostate cancer (PCa). A major challenge for the clinically used AR antagonists is the rapid emergence of resistance induced by some point mutations in the AR ligand binding domain (LBD), and therefore discovery of novel anti-AR therapeutics that can combat mutation-induced resistance is quite demanding. Therein, blocking the interaction between AR and DNA represents an innovative strategy to overcome resistance of traditional antagonists towards the AR LBD. Experimental Approach: In this study, an integrated docking-based virtual screening (VS) strategy based on the crystal structure of the DNA binding domain (DBD) of AR was conducted to search for novel AR antagonists, and then a series of bioassays including bio-layer interferometry (BLI) and RNA-seq were used to evaluate the biological activities of these compounds. Key Results: Among the tested compounds, 2-(2-butyl-1,3-dioxoisoindoline-5-carbox-amido)-4,5-dimeth-oxybenzoicacid (Cpd39) was identified as a potential hit, which was competent to block the binding of the AR DBD to androgen receptor response (ARE) and showed decent potency against AR transcriptional activity. Furthermore, Cpd39 was capable of effectively inhibiting the proliferation of PCa cell lines (i.e., LNCaP, PC3, DU145, and 22RV1) and reducing the expression of not only the full-length AR but also the splice variant AR-V7. Conclusion and Implications: The novel AR DBD-ARE blocker Cpd39 could serve as a starting point for the development of new therapeutics for castration-resistant PCa.

Local hypoxia is a universal phenomenon in most solid tumors. The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established. However, the effect of acute systemic hypoxia (exposing the whole body to 10% O2 environment) on cancer has not yet been investigated. In this study, we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC. Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice. Interestingly, the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight. Moreover, acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression. More importantly, the expressions of hypoxia response genes including hypoxia-inducible factor-1 α, vascular endothelial growth factor, and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment. Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin. This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.

Androgen receptor (AR) antagonists have been widely used for the treatment of prostate cancer (PCa). As a link between the AR and its transcriptional function, the activation function 2 (AF2) region has recently been revealed as a novel targeting site for developing AR antagonists. Here, we reported a series of

For Electric Management Information System (EMIS), different types of data are continuously generated from many sub-systems. It is essential to integrate these different data resources to perform better analysis and more accurate calculation about the Power Grid system. However, existing EMIS is combined with separate platforms, and the data formats are various. In this paper, we propose a unified searching service for EMIS based on the integration of electric big data. In the system, different sources are firstly configured to export their data into the Hadoop Distributed File System (HDFS). Then indexing is generated and the keywords of different data are generated by word2vec. Finally, a Mapreduce based processing, searching and recommending the system is developed. The microservice technology and Hadoop framework is applied to implement the proposed framework and the experimental results indicate the proposed method can effectively create a unified search service for the electric company.

The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2. The ligand-to-coactivator allosteric pathway, which involves the coactivator, helix 3 (H3), helix 4 (H4), the loop between H3 and H4 (L3), and helix 12 (H12), and ligands, was characterized. In addition, the interactions of residues on the function site BF-3, especially on the boundary of AF-2 and BF-3, are also affected by the ligands. The MM/GBSA free energy calculations demonstrated that the binding affinity between the coactivator and apo-AR is roughly weaker than those between the coactivator and antagonistic ARs but stronger than those between the coactivator and agonistic ARs. The results indicated that the long-range electrostatic interactions and the conformational entropies are the main factors affecting the binding free energies. In addition, the F876L mutation on AR-LBD affects the ligand-to-coactivator allosteric pathway, which could be the reason for point mutation induced tolerance for the antagonistic drugs such as enzalutamide. Our study would help to develop novel drug candidates against PCa.

Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of “bridge” inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK. The novel type-I1/2 inhibitors display excellent antiproliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs, crizotinib and ceritinib. Structural and molecular modeling analyses indicate that the inhibitor induces dramatic conformational transition and stabilizes unique DFG-shifted loop conformation, enabling persistent sensitivity to different genetic ...

Xenobiotic chemicals and their metabolites are mainly excreted out of our bodies by the urinary tract through the urine. Chemical-induced urinary tract toxicity is one of the main reasons that cause failure during drug development, and it is a common adverse event for medications, natural supplements, and environmental chemicals. Despite its importance, there are only a few in silico models for assessing urinary tract toxicity for a large number of compounds with diverse chemical structures. Here, we developed a series of qualitative and quantitative structure-activity relationship (QSAR) models for predicting urinary tract toxicity. In our study, the recursive feature elimination method incorporated with random forests (RFE-RF) was used for dimension reduction, and then eight machine learning approaches were used for QSAR modeling, i.e., relevance vector machine (RVM), support vector machine (SVM), regularized random forest (RRF), C5.0 trees, eXtreme gradient boosting (XGBoost), AdaBoost.M1, SVM boosting (SVMBoost), and RVM boosting (RVMBoost). For building classification models, the synthetic minority oversampling technique was used to handle the imbalance data set problem. Among all the machine learning approaches, SVMBoost based on the RBF kernel achieves both the best quantitative (q

Androgen receptor (AR), as a member of the nuclear receptor (NR) superfamily, regulates the gene transcription in response to the sequential binding of diverse agonists and coactivators. Great progress has been made in studies on the pharmacology and structure of AR, but the atomic level mechanism of the bidirectional communications between the ligand-binding pocket (LBP) and the activation function-2 (AF2) region of AR remains poorly understood. Therefore, in this study, molecular dynamics (MD) simulations and free energy calculations were carried out to explore the interactions among water, agonist (DHT) or antagonist (HFT), AR, and coactivator (SRC3). Upon the binding of an agonist (DHT) or antagonist (HFT), the LBP structure would transform to the agonistic or antagonistic state, and the conformational changes of the LBP would regulate the structure of the AF2 surface. As a result, the binding of the androgen DHT could promote the recruitment of the coactivator SRC3 to the AF2, and on the contrary, the binding of the antagonist HFT would induce a perturbation to the shape of the AF2 and then weaken its accommodating capability of the coactivators with the LXXLL motif. The simulation results illustrated that the DHT-AR binding affinity was enhanced by the association of the coactivator SRC3, which would reduce the conformational fluctuation of the AR-LBD and expand the size of the AR LBP. On the other hand, the coactivator-to-HFT allosteric pathway, which involves the SRC3, helix 3 (H3), helix 4 (H4), the loop (L1-3) between helix 1 (H1) and H3, and HFT, was characterized. The HFT's skewness and different interactions between HFT and the LBP were observed in the SRC3-present AR. The mutual communications between the AF2 surface and LBP, together with the processes involving the interplay of the ligand binding and coactivator recruitment events, would help in understanding the association of coactivators and rationally develop potent drugs to inhibit the activity of AR.

Basic information is that the expression based on ``sports analytics'' is widely used these days. Sports Analytics based pitches have different applications in football that affect the assortment of fields. For example, these may indicate a competitor or group's performance, competitor's ability and market reputation, and a potential physical problem. The ever-increasing number of conferences and pioneers are happy to incorporate such "tools" into their teaching courses to improve their strategies. The show is divided into two important parts. The first is a written audit of existing progress in this regard. The latter part is primarily focused on research directed with football information. In these tests, using appropriate calculations, the player's condition on the field could be traced. By gathering information from past years, can predict a player's goal-scoring performance over the next season. Besides, to be more precise, the player can adjust the shots' size in each match, which corresponds to the objective scoring probability.

Recycling of lead-acid batteries is an important sector of the lead-acid battery industry, and green technologies with low energy consumption and pollutant emission are in urgent demand. A new pre-desulfurization process of damped lead battery paste sodium carbonate based on “surface update” was developed, and the optimum reaction conditions were investigated. According to the experimental results, the process can maintain the sulfur content of lead paste under 0.5% at the optimum reaction conditions: pH = 8–10 and a molar ratio of Na 2 CO 3 to PbSO 4 of 1.00–1.10:1. The desulfurization efficiency increases with the reaction temperature and can be qualified within 40 min in each experiment. The effect of “surface update” contributes to the enhancing effect in the desulfurization process. The new process has a great advantage in desulfurization efficiency compared with the traditional processes.

Androgen receptor (AR) is closely associated with a group of hormone-related diseases including the cancers of prostate, breast, ovary, pancreas, etc and anabolic deficiencies such as muscle atrophy and osteoporosis. Depending on the specific type and stage of the diseases, AR ligands including not only antagonists but also agonists and modulators are considered as potential therapeutics, which makes AR an extremely interesting drug target. Here, we at first review the current understandings on the structural characteristics of AR, and then address why and how AR is investigated as a drug target for the relevant diseases and summarize the representative antagonists and agonists targeting five prospective small molecule binding sites at AR, including ligand-binding pocket, activation function-2 site, binding function-3 site, DNA-binding domain, and N-terminal domain, providing recent insights from a target and drug development view. Further comprehensive studies on AR and AR ligands would bring fruitful information and push the therapy of AR relevant diseases forward.

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC50 = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases. Keywords: Androgen receptor, AR ligand, Virtual screening, AR agonist, AR antagonist

NIMA-related kinase 2 (Nek2) plays a significant role in cell cycle regulation, and overexpression of Nek2 has been observed in several types of carcinoma, suggesting it is a potential target for cancer therapy. In this study, we attempted to gain more insight into the binding mechanisms of a series of aminopyrazine inhibitors of Nek2 through multiple molecular modeling techniques, including molecular docking, molecular dynamics (MD) simulations and free energy calculations. The simulation results showed that the induced fit docking and ensemble docking based on multiple protein structures yield better predictions than conventional rigid receptor docking, highlighting the importance of incorporating receptor flexibility into the accurate predictions of the binding poses and binding affinities of Nek2 inhibitors. Additionally, we observed that the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations did not show better performance than the docking scoring to rank the binding affinities of the studied inhibitors, suggesting that MM/GBSA is system-dependent and may not be the best choice for the Nek2 systems. Moreover, the detailed information on protein–ligand binding was characterized by the MM/GBSA free energy decomposition, and a number of derivatives with improved docking scores were designed. It is expected that our study can provide valuable information for the future rational design of novel and potent inhibitors of Nek2.

High-efficient visual search ability is the key for the athletes to win their games. Visual search is an important way for the athletes to catch effective information on site within complicated environment as well as the manifestation of their regulating and controlling their mental status and skill abilities within complicated environment. Maintaining an appropriate level of anxiety during exercises and contests could ensure higher visual search efficiency and is helpful for better bringing the skills of the athletes into play. Excessive anxiety will have larger interferences on the visual search efficiency of the athletes and the visual research efficiency will be reduced, resulting in the abnormal performance of the skill levels of the athletes. To optimize and regulate the visual search efficiency of the athletes could ensure the athletes to bring their competitive skills into best play.

Parabens have been widely used in packaged foods, pharmaceuticals, and personal-care products. Considering their potential hydrolysis, we herein investigated structural features leading to the disruption of human androgen receptor (AR) and whether hydrolysis could alleviate such effects using the recombinant yeast two-hybrid assay. Parabens with an aryloxy side chain such as benzyl paraben and phenyl paraben have the strongest antiandrogenic activity. The antiandrogenic activity of parabens with alkyloxyl side chains decreases as the side chain length increases from 1 to 4, and no antiandrogenic effect occurred for heptyl, octyl, and dodecyl parabens with the number of alkoxyl carbon atoms longer than 7. The antiandrogenic activity of parabens correlates significantly with their binding energies (R2 = 0.84, p = 0.01) and were completely diminished after the hydrolysis, particularly for parabens with aryloxy side chains. The Km for the hydrolysis of parabens with aromatic moiety side chain is 1 order of ma...

The receptor tyrosine kinase Tie-2 is involved in vessel remodeling and maturation, and has been regarded as a potential target for the treatment of various solid tumors. The absence of novel, potent and selective inhibitors severely hampers the understanding of the therapeutic potential of Tie-2. In the present work, we describe the discovery of novel type-I inhibitors of Tie-2 by structure-based virtual screening. Preliminary SAR was also performed based on one active compound, and several novel inhibitors with low micro-molar affinity were discovered. To directly compare the efficiency between different filtering strategies in selecting VS candidates, two methods were separately carried out to screen the same chemical library, and the selected VS candidates were then experimentally assessed by in vitro enzymatic assays. The results demonstrate that the hit rate is improved when stricter drug-likeness criteria and less number of molecules for clustering analysis are used, and meanwhile, the molecular diversity of the compounds still maintains. As a case study of TIE-2, the information presented in this work underscores the importance of selecting an appropriate selection strategy in VS campaign, and the novel inhibitors identified and the detailed binding modes of action provide a starting point for further hit-to-lead optimization process.

Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa). The antagonistic drugs, which suppress the activity of AR, are widely used in the treatment of PCa. However, the molecular mechanism of antagonism about how ligands affect the structures of AR remains elusive. To better understand the conformational variability of ARs bound with agonists or antagonists, we performed long time unbiased molecular dynamics (MD) simulations and enhanced sampling simulations for the ligand binding domain of AR (AR-LBD) in complex with various ligands. Based on the simulation results, we proposed an allosteric pathway linking ligands and helix 12 (H12) of AR-LBD, which involves the interactions among the ligands and the residues W741, H874, and I899. The interaction pathway provides an atomistic explanation of how ligands affect the structure of AR-LBD. A repositioning of H12 was observed, but it is facilitated by the C-terminal of H12, instead of by the loop between helix 11 (H11) and H12. The bias-exchange metadynamics simulations further demonstrated the above observations. More importantly, the free energy profiles constructed by the enhanced sampling simulations revealed the transition process between the antagonistic form and agonistic form of AR-LBD. Our results would be helpful for the design of more efficient antagonists of AR to combat PCa.

Angiopoietin (ANG) ligands and their downstream TIE receptors have been validated as the second vascular signaling system involving vessel remodeling and maturation. Among them, the ANG/TIE-2 signaling pathway is involved in numerous life-threatening diseases and has become an attractive potential therapeutic target. Several large-molecule inhibitors targeting the ANG/TIE-2 axis have recently entered clinical phase for the therapy of various solid tumors, but selective small-molecule inhibitors of TIE-2 are still quite limited. In the present work, structure-based virtual screening was performed to search for type-I inhibitors of TIE-2. Of the only 41 compounds selected by our strategy, 8 molecules with the concentration of 25 μg/mL exhibit over 50% inhibitory rate against TIE-2 in in vitro enzymatic activity assay, and the IC50 values of 2 hits are lower than 1 μM. Further optimization and SAR analysis based on compound TP-S1-30 and 31 were carried out by using substructure searching strategy, leading to the discovery of several sub-100 nM inhibitors. Among them, the most potent compound, TP-S1-68, showed an inhibitory IC50 of 0.149 μM. These novel inhibitors of TIE-2 discovered in this study and the analogs of the active core scaffolds can serve as the starting points for further drug development.

An ion chromatographic method with on-line sample pretreatment was developed for the trace analysis of seven common anions in concentrated matrices. The pretreatment column used in this study consisted of polystyrene-divinylbenzene (PS-DVB) and multi-walled carbon nanotubes (MWCNTs). It was too hydrophobic to retain different inorganic anions, but it showed a strong affinity for organic compounds. Thus, this chromatographic system could be used to detect trace anions in organic solvents, organic acids and relevant salts. The addition of MWCNTs decreased the surface areas of stationary phases and the retention times of organic matrices were shortened. Compared with conventional column-switching technique, only a single instrument (ICS2100) was needed in this system, including a pump, a conductivity detector, an eluent generator, a six-port valve and a ten-port valve. An electrochemical self-generating suppressor (ESGS) was adopted to convert the eluent of KOH into water for the matrix elimination. Two different eluent were employed in the chromatographic system, one for separation and the other for matrix elimination. The sample pretreatment and analysis were realized simultaneously. After optimization of this system, a calibration study was conducted by preparing and analyzing eight concentrations (between 5 and 5000 μg L −1 ) of mixture standards of seven anions in deionized water. The linearity was between 0.9990 and 0.9998, and the detection limits ranged from 0.41 to 3.17 μg L −1 . A spiking study was performed on three representative organic chemicals with satisfactory recoveries between 88.1% and 118.5% when the concentrations of the matrices did not exceed 10 g L −1 .

A polymer-based chromatographic stationary phase with embedded or grafted multi-walled carbon nanotubes (MWCNTs) has been developed. Three different synthetic methods were utilized to combine the nano-fibers with the substrate of polystyrene-divinylbenzene (PS-DVB). After optimizing the synthetic conditions, this novel polystyrene-divinylbenzene-carbon nanotube (PS-DVB-CNT) stationary phase was characterized by scanning electron microscopy, Raman spectroscopy, thermogravimetric analysis, chemical adsorption and desorption measurement, and mechanical stability test. Compared to PS-DVB particles, PS-DVB-CNT particles have certain improvement in physical and chromatographic performances because the addition of MWCNTs has altered the structures of the particles. The novel stationary phase owns satisfactory resolution, wide pH endurance, and long lifetime, which can be used as an extent to normal HPLC.

To research the responsibility and mechanism of auditory event-related potentials (AERP) evoked by pure-tone and different Chinese speech (including single-syllable words, two-syllable words and munbers) stimuli respectively. Meanwhile, to explore feasibility of using different Chinese speech forms as stimulation to evoke AERP in Chinese people.AERPs were measured in 37 young normal post-graduated students (70 ears) with pure-tone and three different Chinese speech forms as stimuli. The mean incidence rates, latencies and amplitudes of AERPs were analyzed, the waveforms of AERPs were quantitatively scored. Then all data were statistically analyzed and compared.The typical wave P1, N1, P2, N2 and P3 of AERPs could be recorded by both pure-tone and three different Chinese speech stimuli, in which the Chinese two-syllable word was most likely to evoked AERP than pure-tone and remains of Chinese speech forms, and the differences were statistical significance (Chi2 = 0.046, P0.05). The quantitative scores and amplitudes of P3 evoked by pure-tone and three different Chinese speech stimuli were analyzed in 56 ears, whose results showed no significant difference (P0.05) among different stimuli. However, the waveforms of AERPs were smoother and much satisfied evoked by Chinese character and two-syllable word than pure-tone and Chinese number stimuli. The latencies of P3 evoked by number stimulus were significant longer than by other stimuli (P0.05). Nevertheless, the latencies of P3 were no significant differences among the other stimuli (P0.05).Besides pure-tone and Chinese single-syllable words, other Chinese speech such as two-syllable words and numbers could be used to evoke AERP with satisfied waveform, which indicated that the Chinese character, two-syllable words and numbers were available to apply for AERP measurement as stimuli for Chinese people.

The vanadium-doped TiO2 nanoparticles were prepared by a sol–gel method with Ti(OBu)4 as a precursor. The powders were characterized by XRD, FT-IR, TEM, XPS and UV–Vis absorption spectrum. The photocatalytic activity of the powders for methyl orange degradation was investigated under a fluorescent lamp. The results show that the doping V presents mainly in the form of V5+, and vanadium doping can restrain the crystal growth and promote the phase transfer from anatase to rutile. Vanadium doping can widen the light absorption range of TiO2, and the absorption threshold wavelength is red shifted from 380 nm to about 650 nm. As a result, the photocatalytic activity of the V–TiO2 nanoparticles is higher than that of P25 under the fluorescent lamp.