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Correction for ‘Conformation dynamics of the intrinsically disordered protein c-Myb with the ff99IDPs force field’ by Xiang Guo et al., RSC Adv., 2017, 7, 29713–29721.

The KH3 domain of Nova-2 protein can precisely recognize the sequence-specific target RNA of human glycine receptor α2. However, the recognition mechanism between the protein and its target RNA is still hotly debated. In this study, molecular dynamic simulations in explicit solvent were utilized to understand the recognition mechanism. The structural analysis and the Kolmogorov-Smirnov P-test statistics reveal that the KH3 domain might obey a conformational selection mechanism upon RNA binding. However, the induced fit mechanism could not be completely ruled out. Unfolding kinetics indicates that the folding of RNA and KH3 happens first and then the binding between RNA and KH3 follows. Principle component analysis shows that the invariant Gly-Lys-Gly-Gly loop moves toward to the RNA molecule but the C-terminal domain moves away from the RNA molecule upon binding. These specific dominant motions were hypothesized to stabilize the complex structure. The hydrophobic and hydrogen bonding interactions were found to be the driving forces for the specific recognition, in contrast to the dominant electrostatic interactions for nonspecific recognition.

The bicyclic lactones, myrotheciumones A (I) and B (II), possessing a rare ring-fusion system are isolated from the secondary metabolites of M.

Protein kinase B (PKB) acts as a central node on the PI3K kinase pathway. Constitutive activation and overexpression of PKB have been identified to involve in various cancers. However, protein kinase A (PKA) sharing high homology with PKB is essential for metabolic regulation. Therefore, specific targeting on PKB is crucial strategy in drug design and development for antitumor. Here, we had revealed the selectivity mechanism for PKB inhibitors with molecular dynamics simulation and 3D-QSAR methods. Selective inhibitors of PKB could form more hydrogen bonds and hydrophobic contacts with PKB than those with PKA. This could explain that selective inhibitor M128 is more potent to PKB than to PKA. Then, 3D-QSAR models were constructed for these selective inhibitors and evaluated by test set compounds. 3D-QSAR model comparison of PKB inhibitors and PKA inhibitors reveals possible methods to improve the selectivity of inhibitors. These models can be used to design new chemical entities and make quantitative prediction of the specific selective inhibitors before resorting to in vitro and in vivo experiment.

Worldwide, many different grains are infected by various fungi that may produce trichothecene mycotoxins. Fungi that produce trichothecenes, as well as the trichothecenes themselves, are potential problems for public health. On the other hand, trichothecenes possess multiple biological activities. Reduced toxicity may result in their applications in the pharmaceutical field. Two new trichothecenes along with seven known trichothecenes were isolated from an endophyte of the herb plant Ajuga decumbens. Their structures were deduced from 1D and 2D NMR data. The results of MTT assays revealed that new trichothecene 2',3'-epoxymyrothecine A, 1, and myrothecine A, 3, exhibited much lower toxicity compared to other trichothecenes. New trichothecene 2',3'-epoxymyrothecine A, 1, could induce phosphorylation of JNK (c-Jun N-terminal protein kinase) protein and the PARP (poly ADP-ribose polymerase) cleavage, and eventually induce apoptosis in cancer cells. These results point out the possibility for application of trichothecenes as chemotherapeutic agent.

Novel 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers were designed, synthesized and evaluated for their activities against influenza A viruses H1N1 and H3N2 in Madin-Darby canine kidney cells. All the compounds showed low cytotoxicities in these anti-influenza tests. One of the epimers, 4-[(1S, 3R, 4R, 7R)-7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-3-yl]-3-oxo-3,4-dihydropyrazine-2-carboxamide 8a, with high antiviral activities (IC50 = 7.41, 5.63 μm for H3N2 and H1N1, respectively) and remarkable low cytotoxicity (TC50 > 200 μm), has great potential for further development as a novel anti-influenza A agent. Molecular docking of compound 8a with RNA-dependent RNA polymerase was performed to understand the binding mode between these inhibitors and the active site of RdRp and to rationalize some SARs.

Intrinsically disordered proteins or intrinsically disordered protein regions comprise a large portion of eukaryotic proteomes (between 35% and 51%). These intrinsically disordered proteins were found to link with cancer and various other diseases. However, widely used additive force field parameter sets are insufficient in quantifying the structural properties of intrinsically disordered proteins. Therefore, we explored to a systematic correction of a base additive force field parameter set (chosen as Amber ff99SBildn) to correct the biases that was first demonstrated in simulations with the base parameter set. Specifically, the φ/ψ distributions of disorder-promoting residues were systematically corrected with the CMAP method. Our simulations show that the CMAP corrected Amber parameter set, termed ff99IDPs, improves the φ/ψ distributions of the disorder-promoting residues with respect to the benchmark data of intrinsically disordered protein structures, with root mean-squared percentage deviation less than 0.15% between the simulation and the benchmark. Our further validation shows that the chemical shifts from the ff99IDPs simulations are in quantitative agreement with those from reported NMR measurements for two tested IDPs, MeV NTAIL , and p53. The predicted residue dipolar couplings also show high correlation with experimental data. Interestingly, our simulations show that ff99IDPs can still be used to model the ordered state when the intrinsically disordered proteins are in complex, in contrast to ff99SBildn that can be applied well only to the ordered complex structures. These findings confirm that the newly proposed Amber ff99IDPs parameter set provides a reasonable tool in further studies of intrinsically disordered protein structures. In addition, our study also shows the importance of considering intrinsically disordered protein structures in general-purposed force field developments for both additive and non-additive models.

U12, one of 20 derivatives synthesized from ursodeoxycholic acid (UDCA), has been found to have anticancer effects in liver cancer cell lines (SMMC-7721 and HepG2) and to protect normal liver cells from deoxycholic acid (DCA) damage (QSG-7701). Its anticancer mechanism was investigated using computer-aided network pharmacology and comparative proteomics. Results showed that its anti-malignancy activities were activated by mTOR/S6K1, cyclinD1/CDK2/4 and caspase-dependent apoptotic signaling pathways in hepatocellular carcinoma cells (HCC). The action of U12 may be similar to that of rapamycin. Animal testing confirmed that U12 exerted better anti-tumor activity than UDCA and had less severe side effects than fluorouracil (5-Fu). These observations indicate that U12 differs from UDCA and other derivatives and may be a suitable lead for the development of compounds useful in the treatment of HCC.

The silica-alumina sol bonding agent, prepared by the sol gel route from ethyl silicate and aluminium isopropanol, was utilized in the refractory castables. The influence of structure on the heat transfer has been investigated using different sorts of refractory matrix. The results indicated that the heat conductivity of sol-gel bonded castables was considerably affected by their structure. The phase composition of matrix, porosity, pore size distribution and pore size structure were the most important factors. Thermal conductivity has been measured from the ambient temperature up to 1250 °C. The influence of crystalline phases and the glassy phase formation and the influence of the pore size distribution on the thermal conductivity were also described in this work.

In the present study, the effect of the heat shock protein 27 (HSP27) signaling pathway on the proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) induced by high glucose (HG) was investigated. HUVEC proliferation in the indicated conditions was measured by the alamarBlue® assay. Apoptosis in HUVECs cultured with HG was analyzed by an Annexin V‑fluorescein isothiocyanate/propidium iodide apoptosis detection kit. HSP27 activity was evaluated by western blotting with specific phospho‑HSP27 antibody. HUVEC proliferation induced by HG was observed to be reduced by the HSP27 inhibitor quercetin in a concentration‑dependent manner, with a concomitant increase in apoptosis. The phosphorylation of HSP27 induced by HG was blocked by the specific phosphoinositide 3‑kinase (PI3K) inhibitor LY294002 and the specific extracellular signal‑regulated kinase (ERK) 1/2 inhibitor U0126 in a concentration‑dependent manner, with peak inhibition rates of 62.6 and 56.1%, respectively. LY294002 and U0126 also reduced HUVEC proliferation with a concomitant increase in apoptotic rate. In conclusion, HSP27 phosphorylation is important in mediating the proliferation and apoptosis of HUVECs induced by high glucose, and PI3K/Akt and ERK1/2 are important signaling pathways that contribute to HSP27 phosphorylation.

To study the chemical constituents of Elephantopus tomentosus.The compounds were isolated by repeated HP20 macro porous adsorption resin column combined with Sephadex LH-20, ODS and silica gel chromatographies. The structures were identified on the basis of extensive spectroscopic data analysis and by comparison of their spectral data reported.Eighteen compounds were identified as 2-deethoxy-2beta-hydroxyphantomolin (1), 2beta-hydroxy-2-deethoxy-8-O-deacylphantomolin-8-O-tiglinate (2), 2beta-methoxy-2-deethoxyphantomolin (3), 2beta-methoxy-2-deethoxy-8-O-deacylphantomolin-8-O-tiglinate (4), molephantin (5), molephantinin (6), tricin (7), luteolin (8), quercetin (9), 3beta-friedelinol (10), 3beta-hydroxyolean-12-en-28-oic acid (11), 3, 5-di-O-caffeoyl quinic acid (12), 3,4-di-O-caffeoyl quinic acid (13), syringaresinol-4-beta-D-glucopyranoside (14), xylogranatinin (15), byzantionoside B (16), 2'-hydroxycinnamaldehyde (17), and caffeic acid ethyl ester (18).Compounds 9, 11, 14-18 were separated from Elephantopus for the first time.

The diagnosis and treatment of one case of cerebral sparganosis suggests that stereotactic positioning operation is an effective treatment, and understanding of the spectrum of parasitic diseases is helpful for the diagnosis and differential diagnosis. However, in non-epidemic area of sparganosis, the classical epidemiological route of transmission is difficult to satisfy the explanation of the current status of the disease.

Essential genes are frequently conserved among bacterial species and thus microbial and eukaryote genome comparisons can be used to compile datasets of homologous proteins and families that can be utilized to identify attractive targets for the design of antimicrobial agents and other drugs. These searches can now often be conducted using Web tools. A number of such resources that provide sequence information and comparative software as well as computational tools for convenient analysis of the data are summarized here and their step-by-step use explained.

Essential genes are frequently conserved among bacterial species and thus microbial and eukaryote genome comparisons can be used to compile datasets of homologous proteins and families that can be utilized to identify attractive targets for the design of antimicrobial agents and other drugs. These searches can now often be conducted using Web tools. A number of such resources that provide sequence information and comparative software as well as computational tools for convenient analysis of the data are summarized here and their step-by-step use explained.

The transactivation domain (TAD) of tumor suppressor p53 can bind with the nuclear coactivator binding domain (NCBD) of cyclic-AMP response element binding protein (CBP) and activate transcription. NMR experiments demonstrate that both apo-NCBD and TAD are intrinsic disordered and bound NCBD/TAD undergoes a transition to well folded. The recognition mechanism between intrinsic disordered proteins is still hotly debated. Molecular dynamics (MD) simulations in explicit solvent are used to study the recognition mechanism between intrinsic disordered TAD and NCBD. The average RMSD values between bound and corresponding apo states and Kolmogorov-Smirnov P test analysis indicate that TAD and NCBD may follow an induced fit mechanism. Quantitative analysis indicates there is also a global conformational selection. In summary, the recognition of TAD and NCBD might obey a local induced fit and global conformational selection. These conclusions are further supported by high-temperature unbinding kinetics and room temperature landscape analysis. These methods can be used to study the recognition mechanism of other intrinsic disordered proteins.

To study effective active constituents of Cayratia japonica,a genuine herbal medicine from Fujian.Such chromatographic methods as Macroporous, Sephadex LH-20, ODS and normal phase silica gel column chromatography were adopted to separate the chemical components of C. japonica.Thirteen compounds were obtained, and their structures were identified by analyzing multiple spectral data as luteolin(1), apigenin(2), triethyl citrate-(3), 3-formylindole(4), esculetin(5), bis(2-ethylhexyl)-phthalate(6), calendin(7), ethyl-trans-3,4-dihydr-oxycinnamate(8), luteolin7-O-D-glucoside(9),5-hydroxy-3,4-dimethyl-5-pentyl-2(5H-furanone(10),ethyl-3,4-dihydroxybenzoate(11), eriodictyol(12) and daucosterol(13).Among them, compounds 3-8 and 10-12 were separated from the plant for the first time.

The rabbit (Oryctolagus cuniculus) is an important experimental animal for studying human diseases, such as hypercholesterolemia and atherosclerosis. Despite this, genetic information and RNA expression profiling of laboratory rabbits are lacking. Here, we characterized the whole-genome variants of three breeds of the most popular experimental rabbits, New Zealand White (NZW), Japanese White (JW) and Watanabe heritable hyperlipidemic (WHHL) rabbits. Although the genetic diversity of WHHL rabbits was relatively low, they accumulated a large proportion of high-frequency deleterious mutations due to the small population size. Some of the deleterious mutations were associated with the pathophysiology of WHHL rabbits in addition to the LDLR deficiency. Furthermore, we conducted transcriptome sequencing of different organs of both WHHL and cholesterol-rich diet (Chol)-fed NZW rabbits. We found that gene expression profiles of the two rabbit models were essentially similar in the aorta, even though they exhibited different types of hypercholesterolemia. In contrast, Chol-fed rabbits, but not WHHL rabbits, exhibited pronounced inflammatory responses and abnormal lipid metabolism in the liver. These results provide valuable insights into identifying therapeutic targets of hypercholesterolemia and atherosclerosis with rabbit models.

Purpose: Linear Boltzmann transport equation (LBTE) is as accurate as the Monte Carlo method for dose calculation. This work is to develop an asymptotic-preserving (AP) scheme to accelerate the LBTE, i.e., to achieve the same accuracy with significantly reduced number of spatial grids. Methods: In this proof-of-concept study, two-dimensional LBTE is solved by the discrete ordinate method. The Level-Symmetric (LQn) quadrature set is employed for angular discretization of LBTE. The Henyey-Greenstein scattering function is used for simulating the anisotropic scattering. For the AP scheme, the anisotropic scattering kernel is discretized as a scattering matrix and its difference with the analytical form is minimized with some constraints that are introduced to preserve the diffusive limit. Since LBTE is linear, the solution on each grid is approximated by linear combination of characteristic solutions and a special solution. A four-point cell-centered scheme is used to establish the linear system of the final solution with unknowns and a finite difference scheme connects the unknowns at four edge centers of the cell to solve this system. Results: First, compared with the exact analytical solution, the discrete L2 norm of the numerical error of the proposed method is less than 0.03 percents when the order of quadrature set is larger than 6 (i.e., more than 48 angles), even when the spatial grid is reduced to 8 by 8. Second, when using fewer spatial grids, the proposed method is more accurate than the conventional Source Iteration method. Conclusion: The AP scheme is developed for accelerating LBTE, and the accurate results can be achieved with significantly reduced number of spatial grids. The authors were partially supported by the NSFC (#11405105), the 973 Program (#2015CB856000), and the Shanghai Pujiang Talent Program (#14PJ1404500).

The circadian rhythm (CR) of arterial blood pressure (ABP) in Alzheimer disease (AD) patients was examined in a case-control clinical study.This study was constructed using the case-control method and investigates non-hypertensive AD patients, compared with normotensive controls from a primary care setting. Twenty-four-hour ABP was measured with an automatic oscillometric device and recorded every 30 min throughout the day and night. Extreme dipper, dipper, non-dipper and reverse-dipper patterns were defined as those individuals with20%, 10-20%,10% and no fall in nocturnal ABP relative to daytime values.There were significant differences in ABP dipper status between cases and controls (cases - 16.15%, 60.00%, 17.70% and 6.15% vs controls - 3.19%, 31.9 2%, 42.02% and 22.88% for reverse dipper, non-dipper, dipper and extreme dipper, respectively, df = 3, χ(2) = 56.76, p0.001). Compared with normal controls, AD patients had significantly higher 24-h mean blood pressure, 24-h mean systolic blood pressure (SBP), night mean SBP, night mean pulse pressure (PP) and 24-h mean PP. There were no significant differences in 24-h mean diastolic blood pressure (DBP), daytime mean DBP or night-time mean DBP, and no significant differences in daytime mean SBP.The circadian rhythm of ABP in AD patents differed from normal controls, perhaps from higher night SBP in AD patents.

A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α–mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α–mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α–induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α–dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells. Cancer Res; 73(1); 307–18. ©2012 AACR.

Objective To study effective active constituents of Cayratia japonica,a genuine herbal medicine from Fujian. Method Such chromatographic methods as Macroporous, Sephadex LH-20, ODS and normal phase silica gel column chromatography were adopted to separate the chemical components of C. japonica. Result Thirteen compounds were obtained, and their structures were identified by analyzing multiple spectral data as luteolin(1), apigenin(2), triethyl citrate-(3), 3-formylindole(4), esculetin(5), bis(2-ethylhexyl)-phthalate(6), calendin(7), ethyl-trans-3,4-dihydr-oxycinnamate(8), luteolin7-O-D-glucoside(9),5-hydroxy-3,4-dimethyl-5-pentyl-2(5H-furanone(10),ethyl-3,4-dihydroxybenzoate(11), eriodictyol(12) and daucosterol(13). Conclusion Among them, compounds 3-8 and 10-12 were separated from the plant for the first time.

HIV-1 integrase (HIVIN) plays a key role in the replication of the HIV-1 virus and represents an attractive target for anti-HIV drug design. Experimental observation suggests that pyrimidone analogues have potent anti-HIV activity. Then, we modeled an HIVIN catalytic core domain based on the crystal structure of the prototype foamy virus (PFV) integrase. Molecular docking and molecular dynamics simulations were used to investigate the interaction mechanism between pyrimidone analogues and the HIVIN catalytic core domain. MD results suggest that the most active molecule (6K) has more stable hydrogen bonds and hydrophobic contacts than the FDA approved anti-HIV drug Raltegravir. Furthermore, the analogues and Raltegravir might have similar binding modes with HIVIN. Finally, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to construct three dimensional quantitative structure–activity (3D-QSAR) models. Eleven test set compounds which are not included in the training set were used to evaluate these models. The results suggest that these models are robust and have good prediction abilities.

Amyloid fibrils are found in many fatal neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, type II diabetes, and prion disease. The VEALYL short peptide from insulin has been confirmed to aggregate amyloid-like fibrils. However, the aggregation mechanism of amyloid fibril is poorly understood. Here, we utilized molecular dynamics simulation to analyse the stability of VEALYL hexamer. The statistical results indicate that hydrophobic residues play key roles in stabilizing VEALYL hexamer. Single point and two linkage mutants confirmed that Val1, Leu4, and Tyr5 of VEALYL are key residues. The consistency of the results for the VEALYL oligomer suggests that the intermediate states might be trimer (3-0) and pentamer(3-2). These results can help us to obtain an insight into the aggregation mechanism of amyloid fibril. These methods can be used to study the stability of amyloid fibril from other short peptides.

X86 emulation is an effectively method to solve the problem of software compatible between X86 and RISC processors, such as ARM, PowerPC, Alpha and so on. Dynamic Binary Translation (DBT) in X86 emulation translates the X86 binary codes to RISC binary code dynamically so that the software based on X86 platform could execute undifferentiated on RISC platform. However, the DBT based on software is one of the performance bottlenecks nowadays. In this case, this paper discusses a new method for DBT with hardware/software co-design. A hardware unit is designed to accelerate the DBT system, including Instruction Decoder, RISC Code Table, Translation Cache and Cache Query Unit. Instruction Decoder analyses the meaning of X86 binary codes and then looks up RISC Code Table to obtain the corresponding RISC binary codes. Translation Cache stores the recently translated RISC binary codes to reduce the repeated instruction translation. Cache Query Unit is used to determine whether cache hit or not. Finally, we achieve the hardware unit using Verilog HDL. Experiment showed that the co-design DBT system could work accurately.

A novel 3D terrain matching method based on 3D Zernike moments is presented in this paper. In the method, 3D Zernike moments which are one-to-one correspondence with the 3D terrain are proposed to represent the reference DEM and recovered DEM (REM) from real-time data to convert 3D terrain matching to 3D Zernike moments feature vectors matching. The matching is divided into coarse and fine matching two steps. In the coarse matching, the matching window glides to 5 pixels as step size, lower order 3D Zernike moments are adopted as the 3D terrain feature. Fine matching is at coarse matching foundation to process, namely we only make fine matching to three superior coarse matching positions and their nearby regions, the matching window glides to 1 pixels as step size, higher order 3D Zernike moments are adopted as the 3D terrain feature. The similar degree of two pieces of terrain is measured by the Camberra distance of the 3D Zernike moments of them, the more small Camberra distance is, the more alike two pieces of terrain is, vice versa. The proposed matching method is based on surface feature, comparing with based on point feature and line feature, it possesses higher successful matching probability and higher location accuracy and stronger robust to noise. The theories and experiments prove above conclusions.

pLink, software for data analysis of cross-linked proteins coupled with mass spectrometry, estimates false discovery rate and enables analysis of protein complexes without extensive purification. We have developed pLink, software for data analysis of cross-linked proteins coupled with mass-spectrometry analysis. pLink reliably estimates false discovery rate in cross-link identification and is compatible with multiple homo- or hetero-bifunctional cross-linkers. We validated the program with proteins of known structures, and we further tested it on protein complexes, crude immunoprecipitates and whole-cell lysates. We show that it is a robust tool for protein-structure and protein-protein–interaction studies.

Three new furostanol saponins (FSs) were recently isolated from the dried bulbs of Allium macrostemon and were shown to have antiplatelet effects. This study investigated the inhibitory capabilities of these compounds on adenosine diphosphate (ADP)-induced human platelet activation. FS-1, when compared with the other 2, had a potent inhibitory effect on ADP-induced platelet aggregation and on the expression of P-selectin and integrin β-3. FS-1 also inhibited Ca mobilization and significantly decreased phosphorylated AKT expression in ADP-activated platelets. The suppression by FS-1 of ADP-induced platelet activation and aggregation shown in this study indicate its potential for therapeutic applications.

MicroRNAs are endogenous 23–25 nt RNAs that play important gene-regulatory roles in animals and plants. Recently, miR369-3 was found to upregulate translation of TNFα mRNA in quiescent (G0) mammalian cell lines. Knock down and immunofluorescence experiments suggest that microRNA-protein complexes (with FXR1 and AGO2) are necessary for the translation upregulation. However the molecular mechanism of microRNA translation activation is poorly understood. In this study we constructed the microRNA-mRNA-AGO2-FXR1 quadruple complex by bioinformatics and molecular modeling, followed with all atom molecular dynamics simulations in explicit solvent to investigate the interaction mechanisms for the complex. A combined analysis of experimental and computational data suggests that AGO2-FXR1 complex relocalize microRNA:mRNA duplex to polysomes in G0. The two strands of dsRNA are then separated upon binding of AGO2 and FXR1. Finally, polysomes may improve the translation efficiency of mRNA. The mutation research confirms the stability of microRNA-mRNA-FXR1 and illustrates importance of key residue of Ile304. This possible mechanism can shed more light on the microRNA-dependent upregulation of translation.

Among the seven natural resveratrol analogs separated and identified from Pholidota yunnanensis R(OLFE), we found phoyunbene B (PYB, trans-3,4'-dihydroxy-2',3',5-trimethoxystilbene) was more effective in inhibiting the growth of HepG2 hepatocellular carcinoma cells than resveratrol. The inhibitory effect of PYB in HepG2 cells was due to its induction of G2/M cell cycle arrest and apoptosis. Induction of G2/M phase cell cycle arrest by PYB was associated with its up-regulation of Cyclin B1, while its induction of apoptosis was accompanied with its down-regulation of Bcl-2 and up-regulation of Bax. Our in vitro invasion/migration assays also showed that PYB could inhibit the invasion of hepatocellular carcinoma cells.

System emulation provides a new solution for software migrating on heterogeneous platform. As one of the important components of system emulation, memory emulation directly affects the performance of system. This paper presents a universal emulation model of IA-32 memory management with Software MMU, virtual TLB and virtual MMIO. And an IA-32 memory management emulator prototype is implemented successfully on the Alpha platform which achieves about 10% of the host machine's performance presently. Compared to Bochs, the performance of our emulator has increased by about 17 percent.

isolation, structure determination and retinoid X receptor transcriptional activities of two new xanthone glycosides, pruniflorosides A and B (I), a new benzophenone glycoside, prunifloroside C (II) and a new xanthone, pruniflorone S (III)

Diaryltriazine (DATA) and diarylpyrimidine (DAPY) were two category inhibitors with highly potent activity for wild type (wt) and four principal mutant types (L100I, K103N, Y181C and Y188L) of HIV-1 reverse transcriptase (RT). We had revealed the drug-resistant mechanism of DATA analogue inhibitors with molecular dynamics simulation and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. In this work, we investigated the drug-resistant mechanism of DAPY analogue inhibitors. It was found that DAPY analogue inhibitors form more hydrogen bonds and hydrophobic contacts with wild type and mutants of HIV-1 RT than DATA inhibitors. This could explain that DAPY analogue inhibitors are more potent than DATA for the wild type and mutants of HIV-1 RT. Then, 3D-QSAR models were constructed for these inhibitors of wild type and four principal mutant types HIV-1 RT and evaluated by test set compounds. These combined models can be used to design new chemical entities and make quantitative prediction of the bioactivities for HIV-1 RT inhibitors before resorting to in vitro and in vivo experiment.

A novel furocoumarin derivative named oxyalloimperatorin (1), together with seventeen furocoumarins 2–18 were isolated from the radix of Angelica dahurica. The chemical structure of new metabolite was characterized by analysis of IR, NMR, and HR-ESI-MS spectroscopic data. Among the isolated compounds, 13, 16, and 18 (each at 20 μM) could significantly promote the gene transcriptional function of nuclear receptor RXRα. While 7–9, 13, 14, and the new structure 1 (each at 20 μM) showed significant reduction in RXRα gene transcriptional activities induced by 9-cis-retinoid acid. The findings indicated that these furocoumarin skeleton derivatives might hold beneficial effects on many intractable diseases, such as cancer and metabolic diseases, due to their potential activities on regulating the transcriptional activation function of RXRα.

Src homology-2 domain-containing protein tyrosine phosphatase (Shp2), a novel proto-oncogenic protein, is an important target in cancer therapy research. Approximately 2000 plant extracts were screened to find its natural specific inhibitors, with the ethyl acetate (EtOAc) active extract of the root of Angelica dahurica showing considerable inhibitory effects (IC(50)=21.6 mg/L). Bioguided isolation of EtOAc extract led to 13 compounds, including 10 fatty acids and derivatives. All these compounds were isolated from the plant for the first time. The inhibitory effects of these compounds on the enzyme activities of Shp2, VH1-related human protein (VHR), and hematopoietic protein tyrosine phosphatase (HePTP) were investigated. 8Z,11Z-Feptadecadienoic acid (4), 14Z,17Z-tricosadienoic acid (5), caffeic acid (9), and 2-hydroxy-3-[(1-oxododecyl) oxy]propyl-β-d-glucopyranoside (11) showed considerable selective inhibition of Shp2 activity. After treatment of HepG2 cells with the compounds, only compound 5, a polyunsaturated fatty acid, strongly induced poly (ADP-ribose) polymerase (PARP) cleavage in a dose- and time-dependent manner and increased the activities of caspase-3, caspase-8, and caspase-9 at 100 μM. Compound 5 also inhibited colony formation of HepG2 cells in a dose-dependent manner. Thus, this study reported fatty acids as specific Shp2 inhibitors and provided the molecular basis of one active compound as novel potential anticancer drug.

The integral heats of solution of nine kinds of RE(NCS)3 · nH2O (n = 6 for RE = Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Y) in aqueous glycine solution, of nine kinds of RE(NCS)3 · nH2O (n = 7 for RE = La, Pr, Nd; n = 6 for RE = Gd, Dy, Ho, Tm, Yb, Y) in aqueous alanine solution and of ten kinds of RE(NCS)3 · nH2O (n = 7 for RE = La, Pr, Nd; n = 6 for RE = Sm, Eu, Gd, Dy, Ho, Yb, Y) in aqueous serine solution have been measured calorimetrically at 298.15 ± 0.1 K. In the above measurements, the molar ratio of RE(NCS)3 · nH2O(c):amino acid(c):H2O(l) is 1:3:600. The integral heats of Dy(NCS)3 · 6H2O in more dilute aqueous solutions of glycine, alanine and serine were also measured separately. At this time, the molar ratio of Dy(NCS)3 · 6H2O(c):amino acid (c):H2O(l) was changed to 1:3:1200 and 1:3:2400. Some valuable results have been obtained and are analysed with discussion.

OBJECTIVE To study the chemical constituents of bear bile. METHOD The compounds were isolated by repeated column HP20 macroporous adsorption resin, Sephadex LH-20, ODS and silica gel as packing materials. The structures were identified on the basis of extensive spectroscopic data analysis and by comparison of their spectral data reported. RESULT Nine compounds were identified as 4',7-dihydroxyisoflavone (1), 4',7-dihydroxy-6-methoxyisoflavone (2), 4',6,7-trihydroxyisoflavone (3), 4'-methoxy-7-hydroxyisoflavone (4), tauroursodeoxycholic acid (5), taurochenodeoxycholic acid (6), ursodeoxycholic acid (7), chenodeoxycholic acid (8), cholesterol (9). CONCLUSION Compounds 1-4 were separated from bear bile for the first time.

Diaryltriazine inhibitors have highly potent and effective bioactivities for the wild type of HIV-1 reverse transcription. To design new drug of antimutant HIV-1 reverse transcriptase, the mechanism of drug resistance for four types of mutants was revealed. Molecular dynamics simulations suggest that Lys101, Leu100, Lys103, Tyr181, and Tyr188 are key residues. Different mutants of key residues may have different interaction modes and lead to different drug resistances. Then, CoMFA and CoMSIA methods were employed to construct 3D quantitative structure-activity relationship models. These models were evaluated by test set compounds. These models can be used to make quantitative prediction of their bioactivities for lead compounds before resorting to in vitro and in vivo experimentation.

The research teaching plays a important role to improve creative spirit, ability and individuality of students. It has great significance to study connotation and development of the research teaching. The research teaching based on cognitivism, humanism, constructivism and modern study theory is formed inchmeal in the education process by all world educators. It advocates that students are the subject in the teaching process. Students will get the knowledge and ability through discovering and solving the problems by themselves. The basic characteristics of the research teaching include problematic teaching content and inquiry teaching methods. In this paper, we discussed the relationship of teaching knowledge and ability training, the relationship of the classic teaching content and research teaching content and the relationship of the traditional teaching methods and modern teaching methods.

The reverse generation current under high gate voltage stress condition in LDD MOSFET has been studied. It is found that the generation current peak decreases as the stress time increases. It ascribes to the dominating oxide trapped electrons in n-MOSFET and trapped holes in p-MOSFET which reduce the effective drain bias so that lowering the maximal generation rate. The density of the effective trapped electrons in n-MOSFET and holes in p-MOSFET affecting the effective drain bias are calculated by using our model.

Tyrosine phosphatase Src-homology phosphotyrosyl phosphatase 2 (Shp2) was identified as a potential molecular target for therapeutic treatment of diabetes and obesity. However, there is still no systematic research on the enhancers for the Shp2 enzyme. The present study established a novel powerful model for the high-throughput screening of Shp2 enhancers and successfully identified a new specific Shp2 enhancer, oleanolic acid, from Chinese herbs.

To investigate the advantages, disadvantages and indications of hemilaminectomy for microsurgical resection of intraspinal tumors.We retrospectively reviewed and analyzed the clinical data of 542 cases of intraspinal tumors microsurgically resected by hemilaminectomy during the period from January 2005 to December 2008.The tumors were totally removed in 501 cases (92%). The average postoperative stay was 5.2 days. Postoperative follow-ups ranged from 6 months to 3 years (mean 9 months). The clinical symptoms of 495 cases (91%) improved. No tumor recurrence was reported in the totally removed cases. The stability of vertebral column was excellent and there was no spinal deformity in these patients.With many advantages of minimal trauma, milder postoperative reaction, shorter length of recovery and better spinal stabilization, hemilaminectomy can be used for microsurgical resection of all lateralized epidural, subdural-extramedullary and some benign intramedullary tumors.

The hairpin II of U1 snRNA can bind U1A protein with high affinity and specificity. NMR spectra suggest that the loop region of apo-RNA is largely unstructured and undergoes a transition from unstructured to well-folded upon U1Abinding. However, the mechanism that RNA folding coupled protein binding is poorly understood. To get an insight into the mechanism, we have performed explicit-solvent molecular dynamics (MD) to study the folding kinetics of bound RNA and apo-RNA. Room-temperature MD simulations suggest that the conformation of bound RNA has significant adjustment and becomes more stable upon U1A binding. Kinetic analysis of high-temperature MD simulations shows that bound RNA and apo-RNA unfold via a two-state process, respectively. Both kinetics and free energy landscape analyses indicate that bound RNA folds in the order of RNA contracting, U1A binding, and tertiary folding. The predicted Φ-values suggest that A8, C10, A11, and G16 are key bases for bound RNA folding. Mutant Arg52Gln analysis shows that electrostatic interaction and hydrogen bonds between RNA and U1A (Arg52Gln) decrease. These results are in qualitative agreement with experiments. Furthermore, this method could be used in other studies about biomolecule folding upon receptor binding.

CCR5 is the key receptor of HIV-1 virus entry into host cells and it becomes an attractive target for antiretroviral drug design. To date, six types of CCR5 antagonist were synthesized and evaluated. To search more potent bio-active compounds, non-linear support vector machine was used to construct the relationship models for 103 oximino-piperidino-piperidine CCR5 antagonists. Then, comparative molecular field analysis and comparative molecular similarity indices analysis models were constructed after alignment with their common substructure. Twenty-one structural diverse compounds, which were not included in the support vector machine, comparative molecular field analysis, and comparative molecular similarity indices analysis models, validated these models. The results show that these models possess good predictive ability. When comparing between support vector machine and 3D-quantitative structure activity relationship models, the results obtained from these two methods are compatible. However, 3D-quantitative structure activity relationship model is significantly better than support vector machine model and previous reported pharmacophore model. These models can help us to make quantitative prediction of their bio-activities before in vitro and in vivo stages.

Background and objective During the resection of jugular foramen tumors via the basic far lateral approach, the jugular foramen tumor area as well as its adjacent structures, especially the intracranial part, can be better exposed, which avoids stripping of the petrous part of temporal bone and displacement of facial nerve, and protects the patient's hearing from damage. However, when applied in tumors developed from ventral to the brain stem and middle fossa, with extracranial tumors, this surgical approach seems to be inadequate and limited. This study was to explore the microsurgical technique and clinical value for treating giant dumbbell-shaped tumors at jugular foramen (JF) via a modified far lateral approach. Methods A retrospective analysis was performed in 16 patients with huge dumbbell-shaped tumors at JF which were removed through the modified far lateral approach (suboccipital transjugular-jugular tubercle-jugular process) between January 2001 and December 2008. The process of operation, and pre-and postoperative clinical data were included in the analysis. Results Gross total tumor removal was achieved in 14 cases, subtotal removal in 1 case, and partial removal in 1 case. Follow-up examinations in most patients demonstrated that the patient with an obvious preoperative deficit had a good recovery. During the follow-up from three months to seven years, 10 (76.9%) cases with lower cranial nerve involvement showed obvious improvement of symptom after operation, 8 (80.0%) cases with facial palsy obtained various degrees of alleviation, and 7 (77.8%) cases with hearing impairment at different levels restored hearing. Two patients developed new lower cranial nerve palsies after operation, and underwent functional rehabilitation in the three-month follow-up. Conclusions Modified far lateral approach is helpful for removing the huge tumors at JF, especially for tumors extending to the petroclival region ventral part of pontomedullary junction. It has a higher rate of total resection, preoperative cranial nerve function impairment is expected to restore, and also has the advantage of protecting the facial nerve, labyrinth and vertebral artery structure from unnecessary damage.

Amyloid fibrils are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases such as Alzheimer's disease, type II diabetes mellitus, the transmissible spongiform encephalopathies, and prion disease. The mechanism of fibril formation is still hotly debated and remains an important open question. In this study, we utilized molecular dynamics (MD) simulation to analyze the stability of hexamer for eight class peptides. The MD results suggest that VEALYL and MVGGVV-1 are the most stable ones, then SNQNNY, followed by LYQLEN, MVGGVV-2, VQIVYK, SSTSAA, and GGVVIA. The statistics result indicates that hydrophobic residues play a key role in stabilizing the zipper interface. Single point and two linkage mutants of MVGGVV-1 confirmed that both Met1 and Val2 are key hydrophobic residues. This is consistent with the statistics analysis. The stability results of oligomer for MVGGVV-1 suggest that the intermediate state should be trimer (3-0) and tetramer (2-2). These methods can be used in stabilization study of other amyloid fibril.

BACKGROUND:Kinase-inducible domain (KID) as transcriptional activator can stimulate target gene expression in signal transduction by associating with KID interacting domain (KIX). NMR spectra suggest that apo-KID is an unstructured protein. After post-translational modification by phosphorylation, KID undergoes a transition from disordered to well folded protein upon binding to KIX. However, the mechanism of folding coupled to binding is poorly understood. METHODOLOGY:To get an insight into the mechanism, we have performed ten trajectories of explicit-solvent molecular dynamics (MD) for both bound and apo phosphorylated KID (pKID). Ten MD simulations are sufficient to capture the average properties in the protein folding and unfolding. CONCLUSIONS:Room-temperature MD simulations suggest that pKID becomes more rigid and stable upon the KIX-binding. Kinetic analysis of high-temperature MD simulations shows that bound pKID and apo-pKID unfold via a three-state and a two-state process, respectively. Both kinetics and free energy landscape analyses indicate that bound pKID folds in the order of KIX access, initiation of pKID tertiary folding, folding of helix alpha(B), folding of helix alpha(A), completion of pKID tertiary folding, and finalization of pKID-KIX binding. Our data show that the folding pathways of apo-pKID are different from the bound state: the foldings of helices alpha(A) and alpha(B) are swapped. Here we also show that Asn139, Asp140 and Leu141 with large Phi-values are key residues in the folding of bound pKID. Our results are in good agreement with NMR experimental observations and provide significant insight into the general mechanisms of binding induced protein folding and other conformational adjustment in post-translational modification.

Oil/water partition coefficient (log P) is one of the key points for lead compound to be drug. In silico log P models based solely on chemical structures have become an important part of modern drug discovery. Here, we report support vector machines, radial basis function neural networks, and multiple linear regression methods to investigate the correlation between partition coefficient and physico-chemical descriptors for a large data set of compounds. The correlation coefficient r(2) between experimental and predicted log P for training and test sets by support vector machines, radial basis function neural networks, and multiple linear regression is 0.92, 0.90, and 0.88, respectively. The results show that non-linear support vector machines derives statistical models that have better prediction ability than those of radial basis function neural networks and multiple linear regression methods. This indicates that support vector machines can be used as an alternative modeling tool for quantitative structure-property/activity relationships studies.

Using the method of OES (optical emission spectrum) for measuring N2 emission spectrum, the spacial distribution of energetic electrons in multi-needle bipolar corona discharge at atmospheric pressure was investigated. According to the distribution of N2 second positive band's intensity ISPB, the outline of ionisation region was drawn accurately. The relationship between ISPB and discharge current I was obtained through the sum of ISPB. There are two ionisation regions in the multi-needle bipolar corona discharge. One is near the HV electrode and the other is near the grounded electrode. The ionisation region exists around the needlepoint within 2-3 mm. The volume of ionisation region becomes big with the applied voltage U increasing. The ionisation region of negative corona is bigger than that of positive corona. Near the HV discharge electrode, the outline of electron avalanche is similar to the configuration of electric field lines in the ionisation region, so the electron avalanche along the axis direction of needle develops farther than that along the radial direction. The electric field in the migration area is weak, and the distribution of space charges is large along the radial direction. The sum of ISPB in each ionisation region is second order linear with I, but the quadratic coefficient is very small. So the sum of ISPB is nearly linear with I, the distribution of ISPB is corresponding to the density distribution of energetic electrons. So the charged particles forming the discharge current in ionisation region are electrons. No emission spectrum of N2 can be measured in migration area, so there is no energetic electron. The energetic electrons only exist in ionisation region and the charged particles in migration area are ions.

The experiments were carried out to test whether acid-sensing ion channel 1a and 3 (ASIC1a and ASIC3) were expressed on the primarily cultured type I cells of rat carotid bodies (CBs) and whether the expression of the channels was affected by acid stimulation. The Sprague-Dawley rats of either sex (50-100 g) were used. The CBs were isolated and primarily cultured. The immunofluorescent technique was used to detect the expression of tyrosine hydroxylase (TH), a specific marker of type I cells, in order to identify the type of the cultured cells. The double-label immunofluorescent technique was used to detect the expression of ASIC1a and ASIC3 on the TH-positive type I cells. To detect the influence of acid stimulation on the expressions of ASIC1a and ASIC3, each batch of primarily cultured cells were randomly divided into pH7.3 group (control group), pH6.8 group and pH6.2 group (n=9 in each group). The cells in above three groups were treated with pH7.3, pH6.8 and pH6.2 mediums for 24 h, respectively, and then the mRNA expressions of ASIC1a and ASIC3 in type I cells were detected by semi-quantitative RT-PCR technique. The results showed that more than 93% of the primarily cultured CB cells were TH-positive, indicating that most of the cultured cells were type I cells. Furthermore, all TH-positive cells expressed ASIC1a or ASIC3. After the cells were treated with acid stimulation, the amount of ASIC1a mRNA did not change significantly (P0.05 vs control group); the amount of ASIC3 mRNA had no significant change in pH6.8 group compared with that in control group, but decreased significantly in pH6.2 group (P0.01 vs control group, P0.05 vs pH6.8 group). It is concluded that acid stimulation down-regulates the level of ASIC3 mRNA, but has no effect on the level of ASIC1a mRNA.