CBP/P300溴结构域联芳基类抑制剂三维定量构效关系研究

CREB结合蛋白(CBP)和与其高度同源的P300蛋白是组蛋白乙酰化酶的两个亚型,两者通过它们的溴结构域(bromodomain,BRD)与染色质结合,目前,CBP/P300已经成为人类在肿瘤靶点领域中的研究热点。本研究基于CBP/P300溴结构域联芳基类抑制剂建立三维定量构效关系,采用比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(Co MSIA)分别建立35个已知活性抑制剂的3D-QSAR模型,以确定CBP/P300溴结构域联芳基类抑制剂分子结构与生物活性之间的定量关系。Co MFA和Co MSIA模型活性数据p IC50的预测值与实验值基本一致,说明这两个模型具有较高的预测能力和统计学意义。根据Co MFA和Co MSIA模型所提供的立体场、静电场、疏水场、氢键给体场、氢键供体场等信息提出了改善此类抑制剂活性的药物设计思路,为指导设计具有更高活性的新分子和预测更加有效的CBP/P300溴结构域抑制剂提供理论依据。     

Volumetric properties of {PEG 200 (or 300) (1) + water (2)} mixtures at several temperatures and correlation with the Jouyban–Acree model

Molar volumes and excess molar volumes were investigated from density values for {PEG 200 (1) + water (2)} and {PEG 300 (1) + water (2)} binary mixtures at temperatures from 278.15 to 313.15 K. Both systems exhibit negative excess volumes probably due to increased interactions such as hydrogen bonding and/or large differences in molar volumes of components. Volume thermal expansion coefficients were also calculated for both binary mixtures and pure solvents. The Jouyban–Acree model was used for density and molar volume correlations of the studied mixtures at different temperatures. The mean relative deviations between experimental and calculated density data were 0.02% and 0.04%, for aqueous mixtures of PEG 200 and PEG 300, respectively; whereas the corresponding values for molar volume data were 1.76% and 2.72%.     

Local structure and redox state of copper in tellurite glasses

The local glass structure of tellurite glasses containing CuO with the nominal composition x(CuO) · (1−x)(TeO₂), where x=0.10, 0.20, 0.30, 0.40, and 0.50, as well as the valence state of the copper ions have been investigated by X-ray photoelectron spectroscopy (XPS) and magnetization measurements. The Te 3d core level spectra for all glass samples show symmetrical peaks (Te 3d_5/2 and Te 3d_3/2) at essentially the same binding energies as measured for TeO₂ indicating that the chemical environment of the Te atoms in the glasses does not vary significantly with the addition of CuO. The O 1s spectra, however, show slight asymmetry for all glass samples which results from two contributions, one from the presence of oxygen atoms in the Te-O-Te environment (bridging oxygen BO) and the other from oxygen atoms in an Te-O-Cu environment (non-bridging oxygen NBO). The ratio of NBO to total oxygen was found to increase with CuO content and to be in good agreement with calculated values for the TeO₄ trigonal bipyramid structure. Moreover, the appearance of a satellite peak in the Cu 2p spectra provides definitive evidence for the presence of Cu²⁺ ions in these glass samples where the asymmetry and broadening of the Cu 2p_3/2 and Cu 2p_1/2 peaks are indicative of the presence of both Cu²⁺ and Cu⁺ ions. The relative concentration Cu²⁺ determined from XPS is in good qualitative agreement with the determinations of Cu²⁺ from magnetic susceptibility measurements on the same glass samples. Furthermore the susceptibility data follow a Curie-Weiss temperature-dependent behavior (χ=C/(T−θ)) with negative Curie temperatures indicating that the predominant magnetic interactions between the Cu²⁺-Cu²⁺ exchange pairs are antiferromagnetic in nature.     

Silica gel with continuous macropores prepared from water glass in the presence of poly(acrylic acid)

Monolithic silica gel with macropores was prepared in the solution of water glass and polyacrylic acid (HPAA) by freezing transitional structures of phase separation. In the system, phase separation proceeds between silica polymers and HPAA, so that the porous morphology varies from closed macropores to particle aggregates through bicontinuous morphology, where both macropores and silica skeleton are three-dimensionally interconnected, with increasing HPAA/silica ratio. In addition, we can control the macropore size in bicontinuous morphology by varying the concentration of both silica and HPAA, or by changing the molecular weight of HPAA. The pore size distribution is quite sharp indicating the presence of pores with the same size all through the monolithic samples.     

A novel process utilizing subcritical water to recycle soda-lime-silicate glass

Colored soda-lime-silicate glass was successfully converted into silica by a novel process of hydrothermal treatment in subcritical condition followed by leaching in nitric acid. This method may provide a new non-toxic and low-energy consuming process for the recycling of inorganic wastes.     

Synthesis and Biological Evaluation of Spirocyclic Chromane Derivatives as a Potential Treatment of Prostate Cancer

As a significant co-activator involved in cell cycle and cell growth, differentiation and development, p300/CBP has shown extraordinary potential target in cancer therapy. Herein we designed new compounds from the lead compound A-485 based on molecular dynamic simulations. A series of new spirocyclic chroman derivatives was prepared, characterized and proven to be a potential treatment of prostate cancer. The most potent compound B16 inhibited the proliferation of enzalutamide-resistant 22Rv1 cells with an IC₅₀ value of 96 nM. Furthermore, compounds B16–P2 displayed favorable overall pharmacokinetic profiles, and better tumor growth inhibition than A-485 in an in vivo xenograft model.     

Acetylation of the HIV-1 Tat protein: an in vitro study

In the last few years, the understanding of lysine acetylation as a regulatory post-translational modification of proteins in cell signalling cascades has increased. It is now known that not only histones but also non-histone factors can serve as substrates of different acetyltransferase enzymes. Acetylated lysine residues in non-histone factors are often identified using radioactive labelling experiments and immunochemical analysis of synthetic peptides. In this study of the human immunodeficiency virus 1 (HIV-1) Tat protein, we demonstrate the benefits of matrix-assisted laser desorption/ionisation mass spectrometry, proteolytic digestion and Edman sequencing for the mapping of acetylation sites. We confirmed that the HIV-1 Tat protein is acetylated in vitro by the acetyltransferase p300 at a specific lysine residue at position 50 in its RNA binding region. Furthermore, we showed that the Tat cysteine-rich region is acetylated at multiple cysteine residues in the absence of enzyme. Since this non-enzymatic cysteine acetylation occurs independently from the surrounding peptide sequence, we consider the presence of cysteine residues in acetylated peptides an important factor for the interpretation of in vitro acetylation assays in general.Abbreviations aa Amino acid - AcCoA Acetyl coenzyme A - acm Acetamidomethyl - ARM Arginine-rich motif - CRR Cysteine-rich region - HAT Histone acetyltransferaseThis article is dedicated to Harald zur Hausen on the occasion of his retirement as head of the German Cancer Research Center (Deutsches Krebsforschungszentrum) with gratitude and appreciation for 20 years of leadership     

我国股指期货市场与股票市场风险传导机理研究——基于双变量CAViaR方法

本文基于日内和日度数据使用双变量CAViaR模型估计了沪深300股指期货和标的指数的风险价值,并基于沪深300股指期货市场日内交易行为角度分析了股指期货和现货市场间日内与日间风险传导作用的差异。结果发现,期货市场日内风险的自相关特征显著高于现货市场,而两个市场的日间自相关性相差甚小,期货市场向现货市场的单向风险溢出效应仅体现在日内信息的传递过程中。与现货市场相比,期货交易的杠杆性以及当日回转交易便利了日内投机、套利交易,因而期货市场日内信息传递效率更高。     

Failure to direct detect magnetic field dephasing corresponding to ERP generation

Functional magnetic resonance imaging (fMRI) has become the method of choice for mapping brain activity in human subjects and detects changes in regional blood oxygenation and volume associated with local changes in neuronal activity. While imaging based on blood oxygenation level dependent (BOLD) contrast has good spatial resolution and sensitivity, the hemodynamic signal develops relatively slowly and is only indirectly related to neuronal activity. An alternative approach termed magnetic source magnetic resonance imaging (msMRI) is based on the premise that neural activity may be mapped by magnetic resonance imaging (MRI) with greater temporal resolution by detecting the local magnetic field perturbations associated with local neuronal electric currents. We used a hybrid ms/BOLD MRI method to investigate whether msMRI could detect signal changes that occur simultaneously at the time of the production of well-defined event-related potentials, the P300 and N170, in regions that previously have been identified as generators of these electrical signals. Robust BOLD activations occurred after some seconds, but we were unable to detect any significant changes in the T2*-weighted signal in these locations that correlated temporally with the timings of the evoked response potentials (ERPs).     

Numerical investigation on radiation characteristics of discrete-frequency noise from scarf and scoop aero-intakes

Numerical studies have been carried out to investigate the detailed geometrical effects of full three-dimensional aero-intakes on the radiation of the discrete-frequency rotor-stator interaction noise. The near-field acoustic radiation characteristics and the far-field directivity patterns from the scarf and scoop aero-intakes with three different scarf/scoop angles are quantitatively analyzed and compared. The near-field predictions were obtained by solving the linearized Euler equations with computational aeroacoustic techniques consisting of high-order finite difference scheme, non-reflecting boundary conditions, overset grids and parallel computational methods. For the prediction of far-field directivity pattern, the Kirchhoff integral method was applied. By comparing the directivities of discrete-frequency noise radiating from the scarf and the scoop aero-intakes with that from an axisymmetric aero-intake, it is shown that the 7 dB noise reduction at downward peak radiation angle can be achieved by using the scoop aero-intake with scoop angle of 15°, and the 5 dB noise reduction by the scarf aero-intake with the scarf angle of 15°. The scattering of the radiating acoustic wave by the background mean flow around the aero-intakes shifts the peak lobe radiation angle toward ground and increases the amplitude of the acoustic pressure compared with the cases without mean flow effect. Overall, the scoop aero-intake was found to be more effective than the scarf and the axisymmetric aero-intakes in view of the lower noise radiation toward ground.