CHIP-mediated hyperubiquitylation of tau promotes its self-assembly into the insoluble tau filaments

The tau protein is a highly soluble and natively unfolded protein. Under pathological conditions, tau undergoes multiple post-translational modifications (PTMs) and conformational changes to form insoluble filaments, which are the proteinaceous signatures of tauopathies. To dissect the crosstalk among tau PTMs during the aggregation process, we phosphorylated and ubiquitylated recombinant tau in vitro using GSK3β and CHIP, respectively. The resulting phospho–ub-tau contained conventional polyubiquitin chains with lysine 48 linkages, sufficient for proteasomal degradation, whereas unphosphorylated ub-tau species retained only one–three ubiquitin moieties. Mass-spectrometric analysis of in vitro reconstituted phospho–ub-tau revealed seven additional ubiquitylation sites, some of which are known to stabilize tau protofilament stacking in the human brain with tauopathy. When the ubiquitylation reaction was prolonged, phospho–ub-tau transformed into insoluble hyperubiquitylated tau species featuring fibrillar morphology and in vitro seeding activity. We developed a small-molecule inhibitor of CHIP through biophysical screening; this effectively suppressed tau ubiquitylation in vitro and delayed its aggregation in cultured cells including primary cultured neurons. Our biochemical findings point to a “multiple-hit model,” where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process, thus indicating that targeting tau ubiquitylation may be an effective strategy to alleviate the course of tauopathies.

Multiple-hit model for tau aggregation, where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process.     

Enthalpy of Adsorption and Isotherms for Adsorption of Naphthenic Acid onto Clays

The enthalpies of adsorption and the isotherms for adsorption of naphthenic acid onto Na-montmorillonite, Na-kaolinite, and Na-illite were studied by means of calorimetry and the static method at 298.15 K. The results show that the enthalpies of adsorption and saturated adsorption amounts of naphthenic acid on different clays change in the order Na-montmorillonite > Na-illite > Na-kaolinite. The interaction between naphthenic acid and clays is discussed.     

Large-volume stacking in capillary electrophoresis using pH hysteresis of the electroosmotic flow in a bare fused-silica capillary

For large-volume stacking with the electroosmotic flow pump (LVSEP) in capillary electrophoresis of anionic analytes it is required that the electroosmotic mobility (EOM) should be smaller than the magnitudes of the effective mobilities of the analytes. When a fused-silica capillary is treated with an acidic solution, the silanoate group on the silica surface is neutralized to silanol and the EOM is suppressed. Due to the slow deprotonation equilibrium of the silanol group at an intermediate pH, this reduced EOM can be retained during a number of electrophoresis runs. Using a bare fused-silica capillary preconditioned with 0.01 M HCl, successful LVSEP at pH 6.0 was achieved for weakly acidic compounds with two orders of magnitude enhancements in the concentration sensitivity. The repeatability in migration times of ten analytes stacked by LVSEP in a single day was excellent with the relative standard deviation (RSD) less than 1% (n = 6). The day-to-day repeatability was also excellent with RSD less than 3% (n = 3 x 6) when the capillary was preconditioned each day.     

DMF-甲醇体系粘度与核磁共振化学位移的同时关联

提出了一个基于局部组成概念上的核磁共振模型. 利用该模型和以前别人提出的局部组成型粘度方程, 成功地同时关联属于传递性质的粘度数据和属于波谱性质的核磁共振化学位移数据，关联所得到化学位移的平均绝对偏差小于0.0072，粘度的平均绝对偏差小于0.0006 mPa•s，结果表明提出的局部组成模型是合理的.     

Kinetics of the degradation of polystyrene in supercritical acetone

The kinetic analysis of the degradation of polystyrene (PS) in supercritical acetone has been studied using the nonisothermal weight loss technique with heating rates of 3, 5 and 7 °C/min. The weight loss data according to degradation temperature have been analyzed using the integral method based on Arrhenius form to obtain the kinetic parameters such as apparent activation energy and overall reaction order. The kinetic parameters obtained from this work were also compared with those of the thermal degradation of PS in nitrogen atmosphere. From this work, it was found that the activation energies of PS degradation in supercritical acetone were 73.3-200.7 kJ/mol and lower than those of the thermal degradation in nitrogen atmosphere.     

Copper(II) diamino acid complexes: quantum chemical computations regarding diastereomeric effects on the energy of complexation

[reaction: see text] Quantum chemical calculations were used to rationalize the observed enantiodifferentiation in the complexation of alpha-amino acids to chiral Cu(II) complexes. Apart from Cu(II)[bond]pi interactions and steric repulsions between the anchoring cholesteryl-Glu moiety and an aromatic amino acid R group, hydrogen bonding also plays a role. In fact, in the case of tryptophan, C[double bond]O...H[bond]N hydrogen bonding between the glutamate moiety and the tryptophan N[bond]H group compensates for the loss of intramolecular hydrogen-bonding and diminished Cu(II)[bond]pi interactions.     

Synthesis of pyrimido[4,5-e][1,4]oxazepin-5-ones

Eighteen novel pyrimido[4,5-e][1,4]oxazepin-5-ones were prepared directly via the reaction of either ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate (Ia) or ethyl 4-chloro-2-m-chlorophenyl-5-pyrimidinecarboxylate (Ib) with a variety of substituted 2-(alkylamino)ethanols. A typical example was the preparation of 8,9-dihydro-9-methyl-2-phenylpyrimido[4,5-e][1,4]-oxazepin-5(7H)-one (IIa) from the reaction of Ia with 2-(methylamino)ethanol. Hydrolytic cleavage of the lactone ring in IIa with sodium hydroxide solution, followed by acidification with hydrochloric acid afforded 4-[(2-hydroxyethyl)methylamino]-2-phenyl-5-pyrimidinecarboxylic acid (IV). Reactions of IIa with concentrated ammonium hydroxide or hydrazine also caused cleavage of the lactone ring, giving the corresponding amide (V) or hydrazide (VI), respectively. Structural assignments were supported by infrared and nuclear magnetic resonance spectra.     

贮氢材料电极循环寿命的定量预测定时放电半衰期法的应用

贮氢材料电极循环寿命的定量预测定时放电半衰期法的应用韩剑文，袁满雪，周作祥，赖城明（南开大学化学系天津３０００７１）关键词：贮氢电极，循环寿命，半衰期。前文￣［１］讨论了应用定终点电位放电半衰期法来预测贮氢材料电极循环寿命的问题。本文讨论如何采用定时...     

Structural basis for inhibition of protein tyrosine phosphatases by Keggin compounds phosphomolybdate and phosphotungstate

Protein-tyrosine phosphatases (PTPs) constitute a family of receptor-like, and cytoplasmic enzymes, which catalyze the dephosphorylation of phosphotyrosine residues in a variety of receptors and signaling molecules. Together with protein tyrosine kinases (PTKs), PTPs are critically involved in regulating many cellular signaling processes. In this study, diverse compounds were screened for PTP inhibition and selectively screened for inhibitors with the end product inhibition properties. Among phosphate analogues and their derivatives for PTP inhibition, Keggin compounds phosphomolybdate (PM) and phosphotungstate (PT) strongly inhibited both PTP-1B and SHP-1, with K(i) values of 0.06-1.2 micromM in the presence of EDTA. Unlike the vanadium compounds, inhibition potencies of PM and PT were not significantly affected by EDTA. PM and PT were potent, competitive inhibitors for PTPs, but relatively poor inhibitors of Ser/Thr phosphatase. Interestingly, PM and PT did not inhibit alkaline phosphatase at all. The crystal structure of PTP-1B in complex with PM, at 2.0 A resolution, reveals that MoO(3), derived from PM by hydrolysis, binds at the active site. The molybdenium atom of the inhibitor is coordinated with six ligands: three oxo-ligands, two apical water molecules and a S atom of the catalytic cysteine residue. In support of the crystallographic finding, we observed that molybdenium oxides (MoO(3), MoO(2), and MoO(2)Cl(2)) inhibited PTP-1B with IC(50) in the range 5-15 micromM.     

芥子气模拟剂2-氯乙基乙基硫醚的光催化降解

利用连续流动微反、原位红外和GC/MS等手段考察了芥子气模拟剂2-氯乙基乙基硫醚（2-CEES）在P25 TiO2上的光催化降解反应,证实CO2和H2O是这个反应的最终产物.详细的跟踪分析表明,除了CO2和H2O外,在反应的气相混合物中可检测到C2H4、CH3CHO、CH4、CO、HCl和H2S；少量小分子的羧酸、醚和砜；微量C2H5SC2H5、C2H5S2C2H5、C2H5SC2H4Cl和CH2ClCH2Cl等中间产物;在反应后的催化剂表面可检测到C2H5S2C2H5、C2H5SC2H4OH、C4H9S2C2H5和C2H5S2C2H4OH、等物.根据这些结果提出了2-CEES光催化降解的反应机理,推断2-CEES的光催化降解涉及脱氯、C－S键断裂、有机硫化物光聚合和裂解等复杂过程最终转化为CO2和H2O.认为各种硫物种在表面的积聚引起了催化剂的缓慢失活.