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With the development of precision medicine, molecular targeted therapy has been widely used in the field of cancer, especially in non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a well-recognized and effective target for NSCLC therapies, targeted EGFR therapy with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has achieved ideal clinical efficacy in recent years. Unfortunately, resistance to EGFR-TKIs inevitably occurs due to various mechanisms after a period of therapy. EGFR mutations, such as T790M and C797S, are the most common mechanism of EGFR-TKI resistance. Here, we discuss the mechanisms of EGFR-TKIs resistance induced by secondary EGFR mutations, highlight the development of targeted drugs to overcome EGFR mutation-mediated resistance, and predict the promising directions for development of novel candidates.

This study proposed an inverse modelling procedure for evaluating the anisotropic hydraulic conductivity and its variation induced by excavation in fractured rocks by integrating a strain-dependent hydraulic conductivity model. The time-series measurements of both hydraulic head and discharge were used to construct the objective function for improving the reliability, which was solved with a combined method of orthogonal design, transient groundwater flow modelling, artificial neural network and genetic algorithm-based optimization for reducing the computational cost. The proposed methodology proves its effectiveness by successful inverse modelling of the groundwater flow around the underground caverns at the Jinping-I Hydropower Station.

Models used for data interpretation of constant rate tests (CRTs) are commonly derived with the assumption of Darcian flow in an idealized geometry, hence disregarding the non-Darcian nature of fluid flow and the complexity of flow geometry. In this study, an Izbash's law-based analytical model is proposed by means of Laplace transform and linearization approximation for interpretation of non-Darcian flow in a generalized radial formation where the flow dimension may become fractional between 1 and 3. The source storage and skin effects are also considered in the model development. The proposed model immediately reduces to Barker's (1988) model for Darcian flow in the generalized radial formation and to Wen et al.'s (2008a) model for non-Darcian flow in a two-dimensional confined aquifer. A comparison with numerical simulations shows that the proposed model behaves well in low non-Darcian flow condition or at late times. The proposed model is finally applied for data interpretation of the constant rate pumping tests performed at Ploemeur, showing that the estimated hydraulic properties (i.e., hydraulic conductivity, specific storage coefficient, non-Darcy exponent, and the dimension of flow geometry) are well representative of the hydrogeologic conditions on the field scale at the test site after the exploitation of groundwater. The proposed model is an extension of the generalized radial flow (GRF) model, which would be of significance in the problem of choosing an appropriate dimension of flow geometry in which non-Darcian flow occurs.

A series of chiral β-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were synthesized asymmetrically, and their antitumor activities were evaluated in vitro and in vivo. The cocrystal structure of tubulin in complex with compound 9 was determined by X-ray crystallography, which showed that 9 binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was first identified and demonstrated to be critically important for their antiproliferative activities.

A homogeneous polysaccharide (PPB) was purified from fruiting bodies of Phellinus baumii. And in vitro antitumor and immunomodulation activities were investigated on HeLa, SGC-7901 and RAW264.7 cell lines. PPB inhibited the proliferation of HeLa and SGC-7901 cells significantly, and flow cytometric studies revealed that PPB could mediate the cell cycle in the G0/G1 and S phases. Furthermore, PPB could promote the growth and phagocytosis of RAW264.7 cells, activate the secretion of cytokines such as TNF-α and IL-6, which indicated that PPB had low toxicity. The results make PPB as a candidate adjuvant in cancer therapy.

Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19 nM, which is 5 times more potent than that of Ilomastat (IC50=0.94 nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50=1.58 μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50 μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t1/2z was achieved compared with these of the lead compound Ilomastat.

AIM: To explore whether ectopic expression of human melanopsin can effectively and safely restore visual function in rd1 mice. METHODS: Hematoxylin-eosin staining of retinal sections from rd1 mice was used to detect the thickness of the outer nuclear layer to determine the timing of surgery. We constructed a human melanopsin-AAV2/8 viral vector and injected it into the subretinal space of rd1 mice. The Phoenix Micron IV system was used to exclude the aborted injections, and immunohistochemistry was used to validate the ectopic expression of human melanopsin. Furthermore, visual electrophysiology and behavioral tests were used to detect visual function 30 and 45d after the injection. The structure of the retina was compared between the human melanopsin-injected group and phosphate buffer saline (PBS)-injected group. RESULTS: Retinas of rd1 mice lost almost all of their photoreceptors on postnatal day 28 (P28). We therefore injected the human melanopsin-adeno-associated virus (AAV) 2/8 viral vector into P30 rd1 mice. After excluding aborted injections, we used immunohistochemistry of the whole mount retina to confirm the ectopic expression of human melanopsin by co-expression of human melanopsin and YFP that was carried by a viral vector. At 30d post-injection, visual electrophysiology and the behavioral test significantly improved. However, restoration of vision disappeared 45d after human melanopsin injection. Notably, human melanopsin-injected mice did not show any structural differences in their retinas compared with PBS-injected mice. CONCLUSION: Ectopic expression of human melanopsin effectively and safely restores visual function in rd1 mice.

In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on “Hit” we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC50 = 2934, 2301 μM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 μM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC50 is 0.96 μM and could interfere stability and formation of the active dimeric iNOS. It’s anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo, acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment.

In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure–activity relationships, four series (A–D) of total 90 new pyrazolo[4,3-d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure–activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1H-pyrazolo[4,3-d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC50 = 3.17 μM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 μM). This compound also showed potent inhibition of iNOS with IC50 value of 1.12 μM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. W...

MYB proteins are involved in diverse important biological processes in plants. Herein, we obtained the MYB superfamily from the allotetraploid Brassica napus, which contains 227 MYB-related (BnMYBR/Bn1R-MYB), 429 R2R3-MYB (Bn2R-MYB), 22 R1R2R3-MYB (Bn3R-MYB), and two R1R2R2R1/2-MYB (Bn4R-MYB) genes. Phylogenetic analysis classified the Bn2R-MYBs into 43 subfamilies, and the BnMYBRs into five subfamilies. Sequence characteristics and exon/intron structures within each subfamily of the Bn2R-MYBs and BnMYBRs were highly conserved. The whole superfamily was unevenly distributed on 19 chromosomes and underwent unbalanced expansion in B. napus. Allopolyploidy between B. oleracea and B. rapa mainly contributed to the expansion in their descendent B. napus, in which B. rapa-derived genes were more retained. Comparative phylogenetic analysis of 2R-MYB proteins from nine Brassicaceae and seven non-Brassicaceae species identified five Brassicaceae-specific subfamilies and five subfamilies that are lacking from the examined Brassicaceae species, which provided an example for the adaptive evolution of the 2R-MYB gene family alongside angiosperm diversification. Ectopic expression of four Bn2R-MYBs under the control of the viral CaMV35S and/or native promoters could rescue the lesser root hair phenotype of the Arabidopsis thaliana wer mutant plants, proving the conserved negative roles of the 2R-MYBs of the S15 subfamily in root hair development. RNA-sequencing data revealed that the Bn2R-MYBs and BnMYBRs had diverse transcript profiles in roots in response to the treatments with various hormones. Our findings provide valuable information for further functional characterizations of B. napus MYB genes.

We propose a scheme to produce spatially and temporally controlled spin-polarized photoelectrons by strong-field ionization of atoms. We calculate the momentum-resolved electron spin polarization from two spin-orbit coupled ionic states ($J=1/2$ and $J=3/2$) of krypton atoms in orthogonal two-color laser fields using the strong-field approximation, and obtain the instantaneous spin-polarization degree. With this scheme, the spin-up and -down photoelectrons can be well separated in the space, and the spin polarization is controlled on the sub-laser-cycle timescale. This study illustrates and reveals the mechanism of the generation of spin-polarized photoelectrons with an arbitrary spatially and temporally tailored laser field. We expect this work has implications for controlling the spatiotemporal spin polarization in strong-field physics.

Genome-wide identification, classification, expression analyses, and functional characterization of GRAS genes in oil crop, Brassica napus, indicate their importance in root development and stress response. GRAS proteins are a plant-specific transcription factor gene family involved in tissues development and stress response. We classified 87 putative GRAS genes in the Brassica napus genome (BnGRASs) into 13 subfamilies by phylogenetic analysis. The C-terminal GRAS domains of Brassica napus (B. napus) proteins were less conserved among subfamilies, but were conserved within each subfamily. A series of analyses revealed that 89.7% of the BnGRASs did not have intron insertions, and 24 specific-motifs were found at the N-terminal. A highly conserved microRNA 171 (miRNA171) target was observed specifically in the HAM subfamily across land plants. A total of 868 pairs of interaction proteins were predicted, the primary of which were transcription factors involved in transcriptional regulation and signal transduction. Integrated comparative analysis of GRAS genes across 26 species of algae, mosses, ferns, gymnosperms, and angiosperms revealed that this gene family originated in early mosses and was classified into 19 subfamilies, 14 of which may have originated prior to bryophyte evolution. RNA-Seq analysis demonstrated that most BnGRASs were widely expressed in different tissues/organs at different stages in B. napus, and 24 BnGRASs were highly/specifically expressed in roots. Results from a qRT-PCR analysis suggested that two BnGRASs belonging to SCR and LISCL subfamilies potentially have important roles in the stress response of roots.

Background Midgut and salivary gland α-amylases are digestive enzymes required for the development of insects and have been investigated in some insect species. However, α-amylases in the endoparasitioid wasps have not been reported. Pteromalus puparum (Hymenoptera: Pteromalidae) is a dominant endoparasitioid wasp that parasitizes many butterfly species, including the Brassicaceae pest Pieris rapae (Lepidoptera: Pieridae). Here, we studied the characteristics and functions of three α-amylases in P. puparum. Results We cloned three genes encoding α-amylases in P. puparum, PpAmy1, PpAmy2 and PpAmy3. The full length of the PpAmy1 cDNA is 1872 bp, encoding 496 amino acids, the PpAmy2 cDNA is 1863 bp long, encoding 518 amino acids, and PpAmy3 cDNA consists of 1802 bp encoding 521 amino acids. PpAmys are highly similar in amino acid sequences, but they have separate tissue distributions. Phylogenetic results show that gene duplications may occur between PpAmy2 and PpAmy3. PpAmy1 and PpAmy3 are most highly expressed in the digestive tract and the venom apparatus, respectively, while PpAmy2 is broadly expressed in all tissues. We report that PpAmy1 acts in the digestive tract, where it influences lifespan as demonstrated using RNAi and α-amylase rescue analyses, and there is no significant difference in longevity when PpAmy2 and PpAmy3 are knocked down. Conclusion PpAmys probably have roles in carbohydrate metabolism of P. puparum and its host/parasitoid relationships. The characterization and functional study of PpAmys lays the foundation for the protection and utilization of parasitoid resources, and the biological control of agricultural pests. © 2019 Society of Chemical Industry.

Background Cyclin-dependent kinase 8 (CDK8) as a Mediator complex-associated transcriptional regulator has been shown to play important role in the initiation and progression of various cancers. The present study aimed to explore miR-152-3p-modulated post-transcriptional repression of CDK8 in hepatic carcinogenesis. Methods Eighty-nine pairs of hepatocellular carcinoma (HCC) and adjacent non-tumor tissues were collected for molecular biological analysis. Cell viability and apoptosis assays were detected using CCK8 and Annexin V-fluorescein isothiocyanate/propidium iodide (Annexinv-FITC) double staining, respectively. Bioinformatics algorithms and luciferase reporter assay were performed to validate CDK8 as a direct target of miR-152-3p. Gene and protein expression levels were monitored using RT-qPCR, western blotting or immunohistochemical (IHC) staining. Results CDK8 expression levels were up-regulated and miR-152-3p was down-regulated in HCC tissues. The correlation analysis had documented a significant negative correlation between miR-152-3p and CDK8 in the HCC tissues. Both CDK8 and miR-152-3p could serve as the independent prognostic factors for predicting the OS and DFS in HCC patients. Bioinformatics and experimental measurement revealed that CDK8 was a direct target of miR-152-3p. After co-transfection with the miR-152-3p mimics and the CDK8 overexpressed plasmids, the anti-proliferative and pro-apoptotic roles of miR-152-3p were restricted by CDK8. Conclusion The present results obtained forcefully proved that miR-152-3p exhibited an antineoplastic activity via targeting CDK8 and might be served as a potential therapeutic target for the treatment of HCC.

Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-α, with IC50 values of 2.64, 4.38 and 5.63 μM, respectively. Further studies showed that compound 4e inhibited cytokines secretion of macrophages through suppressing TLR4/p38 signaling pathway. Additionally, compound 4e showed in vivo anti-inflammatory activity in LPS-induced model of acute lung injury. These data suggested that compound 4e may be a promising lead structure for the treatment of ALI.

As key equipment in nuclear power plant, the reactor power control system is adopted to strictly control and regulate the reactor power of a PWR (pressurized water reactor) in a nuclear power plant. A well-optimized predictive control algorithm based on SDMC (stepped dynamic matrix controller) is developed and introduced in this paper and applied to the power regulation of a reactor power model. In addition, the test and verification of this application is conducted by two different methods and devices: the virtual verification platform and the physical DCS (digital control system). The result of the verification suggests that the application of SDMC gains a better performance in the maximum dynamic deviation, adjustment time, overshoot, and so on.

This paper proposes a superresolution two-dimensional (2D) direction of arrival (DOA) estimation algorithm for a rectangular array based on the optimization of the atomic l0 norm and a series of relaxation formulations. The atomic l0 norm of the array response describes the minimum number of sources, which is derived from the atomic norm minimization (ANM) problem. However, the resolution is restricted and high computational complexity is incurred by using ANM for 2D angle estimation. Although an improved algorithm named decoupled atomic norm minimization (DAM) has a reduced computational burden, the resolution is still relatively low in terms of angle estimation. To overcome these limitations, we propose the direct minimization of the atomic l0 norm, which is demonstrated to be equivalent to a decoupled rank optimization problem in the positive semidefinite (PSD) form. Our goal is to solve this rank minimization problem and recover two decoupled Toeplitz matrices in which the azimuth-elevation angles of interest are encoded. Since rank minimization is an NP-hard problem, a novel sparse surrogate function is further proposed to effectively approximate the two decoupled rank functions. Then, the new optimization problem obtained through the above relaxation can be implemented via the majorization-minimization (MM) method. The proposed algorithm offers greatly improved resolution while maintaining the same computational complexity as the DAM algorithm. Moreover, it is possible to use a single snapshot for angle estimation without prior information on the number of sources, and the algorithm is robust to noise due to its iterative nature. In addition, the proposed surrogate function can achieve local convergence faster than existing functions.

The plant-specific WUSCHEL-related homeobox (WOX) transcription factor gene family is important for plant growth and development but little studied in oil crops. We identified and characterized 58 putative WOX genes in Brassica napus (BnWOXs), which were divided into three major clades and nine subclades based on the gene structure and conserved motifs. Collinearity analysis revealed that most BnWOXs were the products of allopolyploidization and segmental duplication events. Gene structure analysis indicated that introns/exons and protein motifs were conserved in each subclade and RNA sequencing revealed that BnWOXs had narrow expression profiles in major tissues and/or organs across different developmental stages. The expression pattern of each clade was highly conserved and similar to that of the sister and orthologous pairs from Brassica rapa and Brassica oleracea. Quantitative real-time polymerase chain reaction showed that members of the WOX4 subclade were induced in seedling roots by abiotic and hormone stresses, indicating their contribution to root development and abiotic stress responses. 463 proteins were predicted to interact with BnWOXs, including peptides regulating stem cell homeostasis in meristems. This study provides insights into the evolution and expression of the WOX gene family in B. napus and will be useful in future gene function research.

The plant-specific WUSCHEL-related homeobox (WOX) transcription factor gene family is important for plant growth and development but little studied in oil crops. We identified and characterized 58 putative WOX genes in Brassica napus (BnWOXs), which were divided into three major clades and nine subclades based on the gene structure and conserved motifs. Collinearity analysis revealed that most BnWOXs were the products of allopolyploidization and segmental duplication events. Gene structure analysis indicated that introns/exons and protein motifs were conserved in each subclade and RNA sequencing revealed that BnWOXs had narrow expression profiles in major tissues and/or organs across different developmental stages. The expression pattern of each clade was highly conserved and similar to that of the sister and orthologous pairs from Brassica rapa and Brassica oleracea. Quantitative real-time polymerase chain reaction showed that members of the WOX4 subclade were induced in seedling roots by abiotic and hormone stresses, indicating their contribution to root development and abiotic stress responses. 463 proteins were predicted to interact with BnWOXs, including peptides regulating stem cell homeostasis in meristems. This study provides insights into the evolution and expression of the WOX gene family in B. napus and will be useful in future gene function research.

Because the excessive apoptosis of articular chondrocytes contributes to extracellular matrix (ECM) loss and cartilage damage in rheumatoid arthritis (RA), inhibiting chondrocyte apoptosis might be a promising strategy for RA. Aquaporin1 (AQP1) is overexpressed in RA cartilage and synovial tissues, and play a vital pathogenic role in RA development. Particularly, we previously reported that acetazolamide (AZ) as an AQP1 inhibitor suppressed secondary inflammation and promoted ECM production in cartilage of adjuvant-induced arthritis rats. Here, we investigated the antiapoptotic effect of AZ on interleukin-1β (IL-1β)-induced apoptosis, a classic in vitro model of chondrocyte apoptosis. AZ treatment could inhibit IL-1β-induced apoptosis, evidenced by increasing cell viability, relieving apoptotic nuclear morphology, decreasing apoptosis rates, and restoring mitochondrial membrane potential. Additionally, AZ reversed IL-1β-induced decrease of Bcl-2 protein and reduced IL-1β-induced increases of Bax and caspase 3 protein, accompanied by inhibiting IκBα degradation and phosphorylation in cytoplasm, reducing NF-κB p65 protein level in nucleus and preventing NF-κB p65 translocation from cytoplasm to nucleus. In conclusion, our findings indicated that AZ could effectively attenuate IL-1β-induced chondrocyte apoptosis mediated by regulating the protein levels of apoptosis-related genes and inhibiting the activation of NF-κB signal pathway, suggesting that AZ might be of potential clinical interest in RA treatment.

We measure the laser-intensity-dependent photoelectron momentum and energy spectra and identify the emerged resonant $(4s,3d$, and $4f)$ states of multiphoton ionization of Ne at 400 nm. We employ parallelly polarized two-color fields involving a strong ionizing 400-nm field and a weak 800-nm field to probe the relative time delay of resonant states. By analyzing phase-resolved three-dimensional photoelectron momentum distributions, we find the time delay of resonant states has an anisotropic angle dependence. Using an intuitive model, we show that the angle-dependent time delay carries the information of subcycle evolution of quantum states and reflects the temporal coherent properties of multiphoton resonant states during absorption and emission of photons. We find that the relative time delays among the resonant ionization via $4s,3d$, and $4f$ states along the polarization depend on the number of photons absorbed. This study has implications for coherent imaging of electron wave packets in the multiphoton ionization regime.

We study the control of ionization dynamics of aligned ${\mathrm{N}}_{2}$ and ${\mathrm{O}}_{2}$ molecules in orthogonally polarized two-color (OTC) fields and calculate the photoelectron momentum distributions of molecules by solving the time-dependent Schr\"odinger equation and with a semiclassical model. In contrast with that of atoms in the OTC field, we show that the photoelectron momentum distribution is essentially dependent on the molecular outmost orbital, the alignment angle, and the phase of the OTC field. We illustrate the controlling of the molecular frame photoelectron angular distributions and the temporal and spatial double-slit interference effect for strong-field ionization of ${\mathrm{N}}_{2}$ molecules. For ${\mathrm{O}}_{2}$ molecules, it is shown that the ionization wave packets are splitting. The temporal and spatial double-slit interference effect is always present for ${\mathrm{O}}_{2}$, which is not able to be turned off using the OTC field. This work would have implications for probing molecular structures with a two-color synthesized laser field.

Music therapy in China has a 30- year history. The pioneers strove to build the training programs and to advocate for the profession. There are music therapy organizations and groups that were established for a variety of different needs and in response to the populations representing the most significant of those needs. The first graduate program of music therapy was started by Prof. Tian Gao at the Central Conservatory of Music in 1997. Currently, 13 music therapy programs in universities have been founded. In recent years, China’s public understanding of music therapy has improved as more trained music therapists have starting work here. Key words: Music Therapy, China Spanish:La musicoterapia en China tiene una historia de más de 30 años. Los pioneros se esforzaron para construir programas de formación y abogaron por la profesión. Hoy en día se cuentan con organizaciones de musicoterapia y diversos grupos que han sido establecidos en base a una variedad de necesidades diferentes y en respuesta a las poblaciones que representan la mayor parte de ellas. El primer programa de musicoterapia fue iniciado por el Prof. Tian Gao en el Conservatorio Central de Música en 1997. Actualmente se han fundado 13 programas de musicoterapia en diversas universidades. En años recientes, la comprensión del público en general con respecto a la musicoterapia ha mejorado a medida en que más musicoterapeutas capacitados han empezado a trabajar aquí.

High-pressure packer test (HPPT) is an enhanced constant head packer test for characterizing the permeability or coupled hydromechanical properties of fractured rocks under high-pressure groundwater flow conditions. The interpretation of the HPPT data, however, requires further investigations due to the non-Darcy flow prone to occur in the tested rocks at high flow velocities. In this study, two analytical models were presented based on the Forchheimer's law and Izbash's law, respectively, for interpretation of the HPPT data, which can be readily reduced to Hvorslev equation in laminar flow condition. The proposed models were applied to data interpretation and hydraulic parameter estimation for the HPPTs performed in fractured sedimentary rocks located at about 450 m depth in central Hainan Island, and validated by numerical simulations on the tests. The results indicate that both of the proposed models well reproduce the non-Darcy flow behavior observed in the HPPTs before the initiation of hydraulic fracturing. Overall, the Forchheimer's law-based model is advantageous for its clear physical meanings, but the Izbash's law-based model could be more convenient when the obtained P–Q curves are divided into different phases according to the flow conditions in the fracture system. Also pointed out were the theoretical flaws in an existing Izbash's law-based analytical model, which lead to a misestimate of hydraulic conductivity and an inconsistency between the analytical solutions and numerical results.

Two series of novel 1,5-naphthyridine and 1,6-naphthyridine derivatives were designed and synthesized based on the c-Met kinase inhibitor MK-2461 under the guidance of scaffold hopping strategy. All were tested on c-Met kinase and in vitro anti-tumor activities against Hela and A549 cell lines. The results indicated that 1,6-naphthyridine was a more promising c-Met inhibitory structure core compared with 1,5-naphthyridine. Among them, 26b and 26c showed the best enzymic and cytotoxic activities. The western blot experiments implied that the cytotoxic activity of 26c might be partially through suppressing the phosphorylation of c-Met kinase.

Analogues or isosteres of α,γ-diketoacid (DKA) 1a show potent inhibition of hepatitis C virus (HCV) NS5B polymerase through chelation of the two magnesium ions at the active site. The anti-HCV activity of the flavonoid quercetin (2) could partly be attributed to it being a structural mimic of DKAs. In order to delineate the structural features required for the inhibitory effect and improve the anti-HCV potency, two novel types of quercetin analogues, 7-O-arylmethylquercetins and quercetin-3-O-benzoic acid esters, were designed, synthesized and evaluated for their anti-HCV properties in cell-based assays. Among the 38 newly synthesized compounds, 7-O-substituted derivative 3i and 3-O-substituted derivative 4f were found to be the most active in the corresponding series (EC50 = 3.8 μM and 9.0 μΜ, respectively). Docking studies suggested that the quercetin analogues are capable of establishing key coordination with the two magnesium ions as well as interactions with residues at the active site of HCV NS5B.

The test was simulated for the thin-walled cylinder structure of aeroengine stator casing. Based on the software of LMS-TEST, the experiment of the structure with bolted flange joints was successfully completed for the vibration test analysis and the paper completed the testing under different pre-tightening force. Through the analysis of the measured data, the corresponding spectrum and difference value curve were obtained, the research results showed that the nonlinear characteristics of the bolted flange joint was significant influence on the dynamic responses of the structure, the various nonlinear vibration phenomenon and the signal asymmetry were obvious under different pre-tightening force, which was closely related to the state of the bolted pre-tightening force. By the information of the spectrum and acceleration difference curve, the extent of the bolt tightness can be determined, which can provide relevant reference information for the diagnosis of bolted joint status in the aeroengine stator casing.

We perform a joint experimental and theoretical study on momentum- and energy-resolved photoelectron spin polarization in multiphoton ionization of Xe atoms by circularly polarized fields. We experimentally measure the photoelectron momentum distributions of Xe atoms in circularly polarized near-infrared (800 nm) and ultraviolet (400 nm) light, respectively. We analyze the momentum- and energy-resolved photoelectron spin polarization by comparing the experimental photoelectron momentum distributions with the simulations, although we cannot derive the spin polarization solely from the experiment. We show that the use of circularly polarized ultraviolet light at 400 nm can create better than 90% spin polarization with focal volume effect considered, which enables the separation of the spin states by momentum gating. This paves the way to produce high-degree spin-polarized electron sources from strong-field multiphoton ionization.

Traditional steganography algorithms embed secret information by modifying the content of the images, which makes it difficult to fundamentally resist the detection of statistically based steganalysis algorithms. To solve this problem, we propose a novel generative steganography method based on generative adversarial networks. First, we represent the class labels of generative adversarial networks in binary code. Second, we encode the secret information into binary code. Then, we replace the labels with the secret information as the driver to generate the encrypted image for transmission. Finally, we use the auxiliary classifier to extract the label of the encrypted image and obtain the secret information through decoding. Experimental results and analysis show that our method ensures good performance in terms of steganographic capacity, anti-steganalysis and security.

In order to evaluate the effects of mesh generation techniques and grid convergence on pump performance in centrifugal pump model, three widely used mesh styles including structured hexahedral, unstructured tetrahedral and hybrid prismatic/tetrahedral meshes were generated for a centrifugal pump model. And quantitative grid convergence was assessed based on a grid convergence index (GCI), which accounts for the degree of grid refinement. The structured, unstructured or hybrid meshes are found to have certain difference for velocity distributions in impeller with the change of grid cell number. And the simulation results have errors to different degrees compared with experimental data. The GCI-value for structured meshes calculated is lower than that for the unstructured and hybrid meshes. Meanwhile, the structured meshes are observed to get more vortexes in impeller passage. Nevertheless, the hybrid meshes are found to have larger low-velocity area at outlet and more secondary vortexes at a specified location than structured meshes and unstructured meshes.

E-cadherin is a major component of tubular adherent proteins that maintain intercellular contacts and cell polarity in epithelial tissue. It is involved in pathological processes of renal cell carcinoma and fibrotic diseases via epithelial–mesenchymal transition. Although studies have shown E-cadherin is significantly downregulated in acute kidney injury (AKI), its function in AKI is unknown. Here, we evaluated cell damage and inflammation in cisplatin-stimulated tubular epithelial cell lines after disrupting E-cadherin and restoring it with PPBICA, a small molecule identified by high-throughput screening. We also determined the therapeutic potential of restoring E-cadherin in vivo. Results show cisplatin reduced E-cadherin expression both in mouse kidney and proximal tubular epithelial cell lines (mTECs). PPBICA restored E-cadherin levels, which increased cell viability while attenuating programmed cell death. This may be mediated via deactivation of the RIPK1/RIPK3 axis and decreased caspase3 cleavage. In addition, PPBICA suppressed inflammatory response in cisplatin-treated mTECs, which correlated with suppressed NF-κB phosphorylation and promoter activity. In contrast, disruption of E-cadherin promoted cell damage and inflammation. PPBICA failed to further attenuate kidney damage in E-cadherin knockdown cells, indicating that PPBICA protects against mTECs through E-cadherin restoration. We also found that peritoneal injection of PPBICA in mice prevented loss of renal function and tubular damage by suppressing NF-κB-driven renal inflammation and RIPK-regulated programmed cell death. This was driven by restoration of E-cadherin in cisplatin nephropathy. Additionally, PPBICA attenuated cisplatin-induced kidney damage in an established AKI model, indicating its therapeutic potential in the treatment of AKI. In conclusion, E-cadherin plays functional roles in tubule integrity, programmed cell death, and renal inflammation. Our results underscore the potential of E-cadherin restoration as a novel therapeutic strategy for AKI.

We study the intensity-dependent photoelectron differential momentum distributions from tunneling ionization of Kr and Xe atoms in circularly polarized laser fields. We measure the width of photoelectron momentum distribution along the laser propagation direction in conjunction with the most probable momentum in the polarization plane. The predictions of the available tunneling models do not agree with the measurement. We further present a semiclassical model for strong-field tunneling ionization of atoms in circularly polarized laser fields, in which we include the effect of the initial orbitals with different magnetic quantum numbers. Using this model, we quantify the relative contributions of the initial orbitals with different magnetic quantum numbers to the photoelectron differential momentum distributions. We achieve good agreement with the measurement, which does not depend on calibration of the laser intensity. Both the atomic orbitals and the long-range Coulomb potential have significant effects on the quantitative description of strong-field tunneling ionization of atoms.

We perform high-resolution measurement of ellipticity-resolved momentum distributions from tunneling ionization of atoms along the major and minor axes in strong elliptically polarized fields, respectively. With developing a subcycle nonadiabatic strong-field tunneling theory for arbitrary laser polarization, we show that the electron initial conditions for positions and momenta after the tunneling are nonadiabatically intertwined with the instantaneous laser field. We extract the transverse and longitudinal momentum distributions at the tunnel exit with respect to the field ellipticity. We calibrate the laser intensity with ab initio calculation by solving the time-dependent Schr\"odinger equation. The nonadiabatic effects are confirmed experimentally and theoretically. Disentangling the effect of the long-range Coulomb potential from the laser field, we have further demonstrated that the momentum-time structure of the tunneling wave packet in strong laser fields can be approximatively imaged when treating the Coulomb effect perturbatively.

We measure photoelectron momentum distributions of Ar atoms in orthogonally polarized two-color laser fields with comparable intensities. The synthesized laser field is used to manipulate the oscillating tunneling barrier and the subsequent motion of electrons onto two spatial dimensions. The subcycle structures associated with the temporal double-slit interference are spatially separated and enhanced. We use such a spatiotemporal interferometer to reveal sub-barrier phase of strong-field tunneling ionization. This study shows that the tunneling process transfers the initial phase onto momentum distribution. Our work has the implication that the sub-barrier phase plays an indispensable role in photoelectron interference processes.

We previously reported that penta-acetyl geniposide ((Ac)5GP, an acetylated derivative of geniposide) exhibited better pharmacological functions than geniposide, a major active component of Gardenia jasminoides Ellis. This study demonstrated the antidepressant-like effects of (Ac)5GP and its involved mechanisms using a rat depression model caused by chronic unpredictable mild stress (CUMS). Behavioral tests including sucrose preference, open field and forced swimming were applied to evaluate depression symptoms. IL-1β, IL-6 and TNF-α mRNA and protein levels in prefrontal cortex (PFC) were respectively measured by quantitative PCR and ELISA. The protein levels of IκBα, p-IκBα, NF-κB p65, NLRP3, pro- and mature-IL-1β in PFC were determined by western blot. The activity of hypothalamic–pituitaryadrenal (HPA) axis was also measured. (Ac)5GP treatment alleviated the CUMS-induced depressive-like behaviors in rats, as indicated by increased sucrose intake, increased total crossing and rearing numbers, improved central activity and reduced immobility time. (Ac)5GP reversed the CUMS-induced elevations of IL-1β, IL-6 and TNF-α mRNA and protein levels in PFC. (Ac)5GP reduced degradation and phosphorylation of IκBα and protein level of nuclear NF-κB p65 in PFC. (Ac)5GP also decreased the mRNA and protein levels of NLRP3 and reduced the ratio of mature-IL-1β protein over total IL-1β protein (pro-IL-1β + mature-IL-1β) in PFC. Moreover, (Ac)5GP reduced serum levels of adrenocorticotropic hormone/corticosterone and mRNA level of hypothalamic corticotrophin-releasing hormone. In conclusion, (Ac)5GP treatment improved the depressive-like behaviors in CUMS rats perhaps by suppressing neuroinflammation in PFC and inhibiting activations of NF-κB and NLRP3 and also attenuating HPA axis hyperactivity.

Through this research, the design dynamic similitude relations, model material, model of soil box, loading system, measurement system of "Y" type and numerical simulation of the realization of the dynamic model test, the finite element will be prepared for the shaking table model test study on the mechanical response of ground fissures under strong earthquake.

Sixteen furoxan-based nitric oxide (NO) releasing coumarin derivatives (6a-c, 8a-g, 10a, 13a,b, 15, and 17a,b) were designed, synthesized, and evaluated against the A549, HeLa, A2780, A2780/CDDP, and HUVEC cell lines. Most derivatives displayed potent antiproliferation activities. Among them, 8b exhibited the strongest antiproliferation activity on the four sensitive cell lines mentioned above and three drug resistant tumor cell lines A2780/CDDP, MDA-MB-231/Gem, and SKOV3/CDDP with IC50 values from 14 to 53 nM and from 62 to 140 nM, respectively. Furthermore, 8b inhibited the growth of A2780 in vivo and displayed lower toxicity on nontumorigenesis T29, showing good selectivity against malignant cells in vitro. Preliminary pharmacological studies showed that 8b induces apoptosis, arrests the cell cycle at the G2/M phase in the A2780 cell line, and disrupts the phosphorylation of MEK1 and ERK1. Overall, the NO-releasing capacity and the inhibition of ERK/MAPK pathway signaling may explain the potent antineoplastic activity of these compounds.

According to the problem of bionic shark gill jet can reduce friction on shark surface, a model of bionic jet surface was established based on shark surface was analyzed by measurements, and its numerical simulation was processed by using RNG k-ε turbulence model. The results show that: the gill jet can reduce frictional resistance on shark surface, and the best drag reduction can be got when the speed of main field is 5m/s, furthermore the maximum drag reduction rate can be up to 17.15%. The pressure of jet hole upstream is reduced which due to the barrier to the facing fluid by the jet, so that the pressure resistance of jet surface is reduced as well. Besides, jet fluid is blocked in the boundary layer by mainstream fluid, which caused the fluid velocity of jet hole downstream is reduced, the thickness of boundary layer is increased, and the normal velocity gradient of wall is reduced, so as to achieve the effect of drag reduction.

Mycoplasma suis belongs to the haemotrophic mycoplasmas, which colonise the red blood cells of a wide range of vertebrates. Adhesion to red blood cells is the crucial step in the unique lifecycle of M. suis . In addition to MSG1 protein, α-enolase is the second adhesion protein of M. suis , and may be involved in the adhesion of M. suis to porcine red blood cells (RBC). To simulate the environment of the RBC, we established the cDNA library of swine peripheral blood mononuclear cells (PBMC). The yeast two-hybrid (Y2H) system was adopted to screen α-enolase interactive proteins in the PBMC line. Alignment with the NCBI database revealed four interactive proteins: beta-actin, 60S ribosomal protein L11, clusterin precursor and endonuclease/reverse transcriptase. However, the M. suis α-enolase interactive proteins in the PBMC cDNA library obtained in the current study provide valuable information about the host cell interactions of the M. suis α-enolase protein.

In this paper, the methods for rubidium (Rb) and cesium (Cs) recovery from brines including salt lake brine, geothermal water and concentrated seawater were summarized, and the main problems existed were also pointed out. More details for Rb and Cs recovery from salt lake brines through fractional precipitation, ion exchange and solvent extraction were discussed, and the new trend for Rb and Cs recovery in the future were also carried out.

The Cu2O/ZnO heterojunction with novel hollow microspheres was prepared via a facile one-step hydrothermal method. The morphology was significantly changed from octahedron to hollow microsphere after adding zinc acetate. The microsphere Cu2O/ZnO materials exhibited superior photocatalytic hydrogen yields (129.6 μmol/g), almost 10.3 times higher than pure Cu2O. The separation of photogenerated electron-hole pairs were effectively promoted due to the formation of p-n heterojunction between ZnO and Cu2O. In addition, the hollow structure and shell permeability of Cu2O/ZnO microsphere could also improve the utilization of visible light.

The plant-specific Teosinte-branched 1/Cycloidea/Proliferating (TCP) transcription factor genes are involved in plants&rsquo, development, hormonal pathways, and stress response but their evolutionary history is uncertain. The genome-wide analysis performed here for 47 plant species revealed 535 TCP candidates in terrestrial plants and none in aquatic plants, and that TCP family genes originated early in the history of land plants. Phylogenetic analysis divided the candidate genes into Classes I and II, and Class II was further divided into CYCLOIDEA (CYC) and CINCINNATA (CIN) clades, CYC is more recent and originated from CIN in angiosperms. Protein architecture, intron pattern, and sequence characteristics were conserved in each class or clade supporting this classification. The two classes significantly expanded through whole-genome duplication during evolution. Expression analysis revealed the conserved expression of TCP genes from lower to higher plants. The expression patterns of Class I and CIN genes in different stages of the same tissue revealed their function in plant development and their opposite effects in the same biological process. Interaction network analysis showed that TCP proteins tend to form protein complexes, and their interaction networks were conserved during evolution. These results contribute to further functional studies on TCP family genes.

Auxin response factor (ARF) is a member of the plant-specific B3 DNA binding superfamily. Here, we report the results of a comprehensive analysis of ARF genes in allotetraploid Brassica napus (2n = 38, AACC). Sixty-seven ARF genes were identified in B. napus (BnARFs) and divided into four subfamilies (I-IV). Sixty-one BnARFs were distributed on all chromosomes except C02; the remaining were on Ann and Cnn. The full length of the BnARF proteins was highly conserved especially within each subfamily with all members sharing the N-terminal DNA binding domain (DBD) and the middle region (MR), and most contained the C-terminal dimerization domain (PBI). Twenty-one members had a glutamine-rich MR that may be an activator and the remaining were repressors. Accordingly, the intron patterns are highly conserved in each subfamily or clade, especially in DBD and PBI domains. Several members in subfamily III are potential targets for miR167. Many putative cis-elements involved in phytohormones, light signaling responses, and biotic and abiotic stress were identified in BnARF promoters, implying their possible roles. Most ARF proteins are likely to interact with auxin/indole-3-acetic acid (Aux/IAA) -related proteins, and members from different subfamilies generally shared many common interaction proteins. Whole genome-wide duplication (WGD) by hybridization between Brassica rapa and Brassica oleracea and segmental duplication led to gene expansion. Gene loss following WGD is biased with the An-subgenome retaining more ancestral genes than the Cn-subgenome. BnARFs have wide expression profiles across vegetative and reproductive organs during different developmental stages. No obvious expression bias was observed between An- and Cn-subgenomes. Most synteny-pair genes had similar expression patterns, indicating their functional redundancy. BnARFs were sensitive to exogenous IAA and 6-BA treatments especially subfamily III. The present study provides insights into the distribution, phylogeny, and evolution of ARF gene family.

The growing demand for accurate performance simulations of high-power Li-ion traction batteries requires a fast and effective method. In this paper, an advanced estimation model is proposed to evaluate Li-ion traction battery performance in pure electric vehicle (PEV) applications. The estimation model, which combines road load simulation and lumped parameter analysis, can predict vehicle traction power requirements and entire battery performance parameters both for charge (regenerative braking or grid charging) and discharge (traction power) processes. The model is validated for a battery pack in aPEVoperating over three representative driving cycles: (i) the new European driving cycle (NEDC), (ii) 60km/h constant speed driving cycle, and (iii) 30min maximum speed driving cycle. The results show that the combined performance model output corresponds well with measured data. Thus, this new proposed model can be used to validate battery pack performance during in-vehicle use with reasonable accuracy.

Take the electromagnetic test of WT-8D satellite cloud image receiving system at a meteorological satellite ground station as an example, the test philosophy is analyzed, the test arrangement is made, and the maximum permissible value of level interference under the test requirements is calculated. By comparing the measuring data and the maximum permissible value of level interference, the relations between the antenna frequency and the value of level, the location of interference source, the intensity of interference source, and the generation laws of interference are all grasped. Aiming at the interference source, two methods are proposed respectively in this paper to inhibit the interference, one in the frequency domain and the other in the spatial domain. Then the method of information sharing of meteorological satellite cloud image is analyzed and discussed. As a conclusion, the receiving and transmittal quality of the meteorological satellite cloud image are improved, to prepare for the anti-electromagnetic interference in high tech local area in the future.

Neospora caninum is the etiologic agent of bovine neosporosis, which affects the reproductive performance of cattle worldwide. The transmembrane protein, NcSRS2, and dense-granule protein, NcGRA7, were identified as protective antigens based on their ability to induce significant protective immune responses in murine neosporosis models. In the current study, NcSRS2 and NcGRA7 genes were spliced by overlap-extension PCR in a recombinant adenovirus termed Ad5-NcSRS2-NcGRA 7, expressing the NcSRS2-NcGRA7 gene, and the efficacy was evaluated in mice. The results showed that the titer of the recombinant adenovirus was 10(9)TCID50/ml. Three weeks post-boost immunization (w.p.b.i.), the IgG antibody titer in sera was as high as 1:4,096. IFN-γ and IL-4 levels were significantly different from the control group (P0.01). This research established a solid foundation for the development of a recombinant adenovirus vaccine against bovine N. caninum.

Deuteron momentum distributions from the dissociative ionization of ${\mathrm{D}}_{2}$ in intense elliptically polarized laser fields have been explored in a joint experimental and numerical study. The asymmetrical charge localization in the dissociative ${{\mathrm{D}}_{2}}^{+}$ offers a large torque, and thus an elliptically polarized laser field efficiently rotates the molecular ion during its dissociation, resulting in the emission of deuterons finally deviating from the bond direction at the instant of tunneling ionization of ${\mathrm{D}}_{2}$. The rotating torque of the molecular ions increases with the field ellipticity, leading to an ellipticity-dependent tilt angle for the deuteron momentum distribution. Due to the notable rotation of ${{\mathrm{D}}_{2}}^{+}$ during its dissociation, the photoelectron angular distributions in the laboratory frame and the molecular frame are distinct, which illustrates that the axial recoil approximation is broken for discussing the photoelectron angular distributions of molecules in elliptically polarized laser fields.

We study strong-field tunneling of atoms in intense elliptically polarized laser fields in natural tunneling geometry. We obtain the temporal- and spatial-dependent tunneling ionization rates, the transverse and longitudinal momentum distributions, and the position distributions of the tunnel exit in parabolic coordinates. The tunneling electron wave packets at the tunnel exit are three dimensionally characterized for both momentum and spatial distributions. The conjunction between the tunneling point and the classical propagation of the widely used semiclassical model are naturally connected. We further calculate the ellipticity-dependent photoelectron momentum distributions on the detector, which are validated by comparison with the exact results through numerically solving the time-dependent Schr\"odinger equation. The theory clarifies crucial questions about strong-field tunneling ionization, which has important implications for the attoclock with elliptical or circular fields, photoelectron holography, molecular orbital imaging, etc.