Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.

基于“微生物-肠-脑轴”探讨补肾通腑方对APP/PS1小鼠肠道菌群及LPS/TLR4/NF-κB通路的影响

目的探讨补肾通腑方调控肠道菌群,改善阿尔茨海默病(Alzheimer’s disease,AD)模型小鼠学习记忆能力的作用机制。方法以APP/PS1小鼠为研究对象,给予补肾通腑方治疗8周,采用Morris水迷宫法观察小鼠空间学习记忆能力变化;16S rDNA检测小鼠肠道菌群丰度、多样性变化;HE染色观察海马病理形态学变化;免疫荧光检测海马区小胶质细胞活化情况;Western blot检测TLR4、NF-κB、IL-6等炎症因子表达。结果与模型组相比,补肾通腑方可以缩短AD模型小鼠逃避潜伏期、游泳路径,增加跨越平台次数(P<0.05),提升肠道菌群多样性,调节肠道菌群丰度,促进海马神经元细胞损伤修复,降低iNOS/Iba1共表达,提高Arg1/Iba1共表达(P<0.01),促进小胶质细胞从M1型向M2型转化,下调TLR4、NF-κB、IL-6等促炎因子的表达。结论补肾通腑方改善AD模型小鼠学习记忆能力的作用机制可能与调节肠道菌群介导的LPS/TLR4/NF-κB通路,从而抑制促炎型小胶质细胞活化、减轻中枢神经系统炎症、改善海马区神经元细胞损伤有关。

Dietary polyphenols reduced the allergenicity ofβ-lactoglobulin via non-covalent interactions:a study on the structure-allergenicity relationship

Studies showed that complexation of polyphenols with milk allergens reduced their immunogenic potential.However,the relationship between structures of polyphenols and their hypoallergenic effects on milk allergens in association with physiological and conformational changes of the complexes remain unclear.In this study,polyphenols from eight botanical sources were extracted to prepare non-covalent complexes withβ-lactoglobulin(β-LG),a major allergen in milk.The dominant phenolic compounds bound toβ-LG with a diminished allergenicity were identified to investigate their respective role on the structural and allergenic properties ofβ-LG.Extracts from Vaccinium fruits and black soybeans were found to have great inhibitory effects on the IgE-and IgG-binding abilities ofβ-LG.Among the fourteen structure-related phenolic compounds,flavonoids and tannins with larger MWs and multi-hydroxyl substituents,notably rutin,EGCG,and ellagitannins were more potent to elicit changes on the conformational structures ofβ-LG to decrease the allergenicity of complexedβ-LG.Correlation analysis further demonstrated that a destabilized secondary structure and protein depolymerization caused by polyphenol-binding were closely related to the allergenicity property of formed complexes.This study provides insights into the understanding of structure-allergenicity relationship ofβ-LG-polyphenol interactions and would benefit the development of polyphenol-fortified matrices with hypoallergenic potential.

Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice

In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.

Allozyme Diversity and Population Genetic Structure of Three Medicinal Epimedium Species from Hubei

Three Epimedium species, E. pubescens Maxim., E. sagittatum （Sieb. ＆ Zucc.） Maxim., and E. wushanense T. S. Ying, which are sympatrically distributed in the western Hubei Province, have been used in traditional Chinese medicine （TCM） for about 2,000 years. Genetic variability and population genetic structure of 11 natural populations of these Epimedium species were investigated using isoelectric focusing in thin-layer polyacrylamide slab gels. Of the 22 enzyme systems prescreened, six coding for 13 loci and 45 alleles were resolved, which were used for analyzing genetic diversity and population structure at both intraspecific and interspecific levels. The results showed that： l） high levels of genetic diversity were observed in all three species （A = 2.6-3.2, P = 69.2%-84.6%, Ho= 0.274-0.377, HE= 0.282-0.369）, which were higher than that of other herbaceous and aulmal-pollinated species with similar life-history characteristics; 2） there was significant deviation from Hardy-Weinberg Equilibrium, with one half of the loci showing heterozygote excess and the other homozygote excess, in all populations, suggesting the complicated breeding system of Epimedium species; 3） the low level of intraspecific and interspecific genetic differentiation （GST= 0.0246-0.0409 and 0.0495-0.1213, respectively） indicated a high level of gene flow among populations and close genetic relationship among the three species; and 4） UPGMA cluster analysis further showed that E. pubescens was more closely related to E. sagittatum than to E. wushanense, which was in good agreement with the morphological characters and the recent phylogenetic analysis of these species. On the basis of these results, it was concluded that the mixed breeding system, long-lived perennial life form, ancient evolutionary history, and seed dispersal by ants in Epimedium are responsible for the genetic variation and population structure of these species.

The Tension Cosmology, Largest Cosmic Structures and Explosions of Supernovae from SST

Here, using the Scale-Symmetric Theory (SST) we explain the cosmological tension and the origin of the largest cosmic structures. We show that a change in value of strong coupling constant for cold baryonic matter leads to the disagreement in the galaxy clustering amplitude, quantified by the parameter S8. Within the same model we described the Hubble tension. We described also the mechanism that transforms the gravitational collapse into an explosion—it concerns the dynamics of virtual fields that lead to dark energy. Our calculations concern the Type Ia supernovae and the core-collapse supernovae. We calculated the quantized masses of the progenitors of supernovae, emitted total energy during explosion, and we calculated how much of the released energy was transferred to neutrinos. Value of the speed of sound in the strongly interacting matter measured at the LHC confirms that presented here model is correct. Our calculations show that the Universe is cyclic.

A welding document management software package based on a Client/Server structure

According to specifications for Welding Procedure Qualification of ASME IX Section and Chinese code, JB 4708 2000, a software package for managing welding documents has been rebuilt. Consequently, the new software package can be used in a Limited Area Network (LAN) with 4 different levels of authorities for different users. Therefore, the welding documents, including DWPS (Design for Welding Procedure Specifications), PQRs (Procedure Qualification Records) and WPS (Welding Procedure Specifications) can be shared within a company. At the same time, the system provides users various functions such as browsing, copying, editing, searching and printing records, and helps users to make decision of whether a new PQR test is necessary or not according to the codes above as well. Furthermore, super users can also browse the history of record modification and retrieve the records when needed.

Dinuclear Copper(Ⅱ) Complex with a New Polycarboxylate Ligand:Syntheses,Characterization and Crystal Structure

A dinuclear copper（Ⅱ） complex,[Cu2（HL）2（H2O）6] 1（H3L = 2,4,6-tri（3-carboxy-phenylthio）-1,3,5-triazine）,was synthesized hydrothermally and characterized by single-crystal X-ray diffraction,IR and thermal analysis.Single-crystal X-ray diffraction reveals that complex 1 is a dinuclear copper（Ⅱ） complex,which is further extended to a 3D network by weak interactions such as O…H-O hydrogen bonds and noncovalent S...S interactions.The crystal of compound 1 belongs to monoclinic,space group C2/c,with a = 50.15（2）,b = 6.789（3）,c =15.667（8） ,β = 90.588（9）o,V = 5334（4） 3,Z = 4,C48H38Cu2N6O18S6,Mr = 1306.28,Dc = 1.627 g/cm3,F（000） = 2664,Rint = 0.0631,T = 293（2） K,μ = 1.112 mm-1,the final R = 0.0661 and wR = 0.1850 for 3782 observed reflections with I 2σ（I）.

基于B/S架构的远程会诊质控系统的设计与应用

目的研发远程会诊质控系统,在区域内实现远程会诊质控、管理、监管、考评、统计和持续改进的信息化。方法2020年,组建多学科团队,运用智力激励法和专题小组讨论法,基于B/S架构研发远程会诊质控系统,与既有远程会诊信息系统完全嵌合兼容,满足远程会诊全流程质量管理的功能需求。结果针对远程会诊质控工作要求,系统设计研发了质控管理、质控考评、实时监管、统计分析4个子模块,可满足远程会诊全流程质量管理的功能需求。结论该质控系统创新了远程会诊信息化质量管理模式,在区域内实现了远程会诊全流程的信息化管理,取得了较好的质量管理成效,有效促进区域内远程会诊工作的推进和发展。

Spatial distribution characteristics of bacterial community structure and gene abundance in sediments of the Bohai Sea

This study investigated differences in the community structure and environmental responses of the bacterial community in sediments of the Bohai Sea.Illumina high-throughput sequencing technology and real-time PCR were used to assay the bacterial 16S rRNA genes in the surface sediments of 13 sampling stations in the Bohai Sea.The results showed that sediments at the majority of the 13 sampling stations were contaminated by heavy metal mercury.The main phyla of bacteria recorded included Proteobacteria(52.92%),Bacteroidetes(11.76%),Planctomycetes(7.39%),Acidobacteria(6.53%)and Chloroflexi(4.97%).The genus with the highest relative abundance was Desulfobulbus(4.99%),which was the dominant genus at most sampling stations,followed by Lutimonas and Halioglobus.The main factors influencing bacterial community structure were total organic carbon,followed by depth and total phosphorus.The content of lead,cadmium,chromium,copper and zinc had a consistent effect on community structure.Arsenic showed a negative correlation with bacterial community structure in most samples,while the impact of mercury on community structure was not significant.The bacterial community in sediment samples from the Bohai Sea was rich in diversity and displayed an increase in diversity from high to low latitudes.The data indicated that the Bohai Sea had abundant microbial resources and was rich in bacteria with the potential to metabolize many types of pollutants.

Study on soil-pile-structure-TMD interaction system by shaking table model test

The success of the tuned mass damper (TMD) in reducing wind-induced structural vibrations has been well established. However, from most of the recent numerical studies, it appears that for a structure situated on very soft soil, soil-structure interaction (SSI) could render a damper on the structure totally ineffective. In order to experimentally verify the SSI effect on the seismic performance of TMD, a series of shaking table model tests have been conducted and the results are presented in this paper. It has been shown that the TMD is not as effective in controlling the seismic responses of structures built on soft soil sites due to the SSI effect. Some test results also show that a TMD device might have a negative impact if the SSI effect is neglected and the structure is built on a soft soil site. For structures constructed on a soil foundation, this research verifies that the SSI effect must be carefully understood before a TMD control system is designed to determine if the control is necessary and if the SSI effect must be considered when choosing the optimal parameters of the TMD device.

Study on S wave velocity structure beneath part stations in Shanxi Province

Based on S wave records of deep teleseisms on Digital Seismic Network of Shanxi Province, shear wave velocity structures beneath 6 stations were obtained by means of S wave waveform fitting. The result shows that the crust is thick in the studied region, reaching 40 km in thickness under 4 stations. The crust all alternatives high velocity layer with low velocity one. There appear varied velocity structures for different stations, and the stations around the same tectonic region exhibit similar structure characteristics. Combined with dominant depth distribution of many small-moderate earthquakes, the correlation between seismogenic layers and crustal structures of high and low velocity layers has been discussed.

Isolation, Crystal Structure and Antitussive Activity of 9S,9aS-neotuberostemonine

The title compound 9S,9aS-neotuberostemonine （1） was isolated from the 95%ethanol extract of the roots of Stemona tuberosa. The crystal structure of 1, C22H33NO4, wasdetermined by single-crystal X-ray diffraction analysis. The crystal belongs to orthorhombicsystem, space group P212121, with a-9.0115（11）, b = 10.612（4）, c = 22.074（3） A, V= 2110.9（8）S^3, Z= 4, Mr= 375.49, Dc= 1.182 g/cm3, λ= 0.71079 A,μ= 0.080 cm^-1, F（000） = 816, S = 1.019,R = 0.0579 and wR = 0.1358. A total of 3109 unique reflections were collected, of which 2902were observed （I〉 2σ（I））. The absolute configuration of 1 could be assigned by referring to theconserved configuration of the methyl groups at C（13） and C（20）. In the solid state, the moleculeswere linked into a chain along the a-axis through weak hydrogen bond C（ll）-H（11A）…O（2）.Compound 1 shows significant inhibition of cough by 24%, 44% and 65% at doses of 50, 100 and150 mg/kg, respectively.

基于B/S和SOA架构的LIMS系统设计与研究

为提升水质检测业务的专业化、智能化、系统化、自动化水平,针对新发展阶段下水利高质量发展对水质信息管理的需求,研究并开发基于B/S系统架构和SOA设计架构的新型综合性水质信息管理系统(LIMS),运用仪器谱图识别及数据提取、PHP与MySQL融合、仪器谱图与原始记录自动关联等技术,在一定程度上提高水质数据的电子化无纸化获取、处理、传输及应用等方面的管理水平,实现水质检测业务流程与资源的动态关联和闭环追溯,提升水质监测评价工作的管理效率和质量管理能力。基于B/S和SOA架构的LIMS在前沿高新技术中的应用研究,为水质检测和管理的各项活动提供智能、高效的数据支持平台,也为水利行业信息系统管理建设及水域功能监测监管提供技术支撑。

Bionic structure of shark's gill jet orifice based on artificial muscle

Based on the biological prototype characteristics of shark’s gill jet orifice,the flexible driving characteristics of ionic exchange polymer metal composites(IPMC)artificial muscle materials and the use of sleeve flexible connector,the IPMC linear driving unit simulation model is built and the IPMC material-driving dynamic control structure of bionic gill unit is developed.Meanwhile,through the stress analysis of bionic gill plate and the motion simulation of bionic gill unit,it is verified that various dynamic control and active control of the jet orifice under the condition of different mainstream field velocities will be taken by using IPMC material-driving.Moreover,the large-deflection deformation of bionic gill plate under dynamic pressure and the comparative analysis with that of a rigid gill plate is studied,leading to the achievement of approximate revised modifier from real value to theoretical value of the displacement control of IPMC.

Determining relative block structure rating for rock erodibility evaluation in the case of non-orthogonal joint sets

The most commonly used method for assessing the hydraulic erodibility of rock is Annandale's method.This method is based on a correlation between the erosive force of flowing water and the capacity of rock resistance. This capacity is evaluated using Kirsten's index, which was initially developed to evaluate the excavatability of earth materials. For rocky material, this index is determined according to certain geomechanical factors related to intact rock and rock mass, such as compressive strength of intact rock, rock block size, discontinuity shear strength and relative block structure. To quantify the relative block structure, Kirsten(1982) developed a mathematical expression that accounts for the shape and orientation of the blocks relative to the direction of flow. Kirsten's initial concept for assessing the relative block structure considers that the geological formation is mainly fractured by two joint sets forming an orthogonally fractured system. An adjusted concept is proposed to determine the relative block structure when the fractured system is non-orthogonal where the angle between the planes of the two joint sets is greater or less than 90°. An analysis of the proposed relative block structure rating shows that considering a non-orthogonally fractured system has a significant effect on Kirsten's index and, as a consequence, on the assessment of the hydraulic erodibility of rock.

Syntheses and Crystal Structures of Molybdenum-Sulfur Clusters Mo_3S_4 (dtp)_3(o-CH_3OC_6H_4COO)(Py) and Mo_3S(dtp)_3(p-HOC_6H_4COO)(DMF)·EtOH

The title compounds Mo3S4(dtp)3(o-CH3OC6H4COO)(Py) 1 and Mo3S(dtp)3(p-HOC6H4COO)(DMF)稥tOH 2 (dtp = diethyldithiophosphate) were synthesized by thereactions of Mo3S4(dtp)4(CH3CN) and Mo3S4(dtp)3(CH2ClCOO)(Py) with o-methoxylbenzoic acid and p-hydroxybenzoic acid, respectively. Their crystal structures were determined by X-ray diffraction analysis. The crystal data for compound 1: Mo3S10P3C25H42O9N, monoclinic P21/n, Mr = 1201.93, Z = 4, a = 14.164(1), b = 23.065(2), c = 14.732(1) ? = 109.677(1) ? V = 4532(1) ?, D= 1.762 gcm-3, = 1.428 mm-1, F (000) = 2408, R = 0.0739, wR = 0.1528 for 3552 observed reflections (I > 2); and for compound 2: Mo3S10P3C24H48O11N, triclinic P ? Mr = 1227.96, Z = 2, = 10.2098(3), b = 14.3333(4), c = 18.1711(5) ? = 94.694(1), = 102.166(1), = 110.665(1) , V = 2396.5(1)3, Dc = 1.638 gcm-3, = 1.350mm-1, F (000) = 1184, R = 0.0445, wR = 0.1281 for 6597 observed reflections (I > 2). Intermolecular S…S interactions are observed between the molecules of compound 1 while intramolecular O…HC and intermolecular S…HC hydrogen bondings are found in the crystal packing diagram of compound 2.

3D Digital Design of Cranes' Structures Based on Hybrid Software Architecture

3D digital design for cranes’ structures based on hybrid software architecture of Client/Server and Browser/Server is introduced in this paper. Based on Pro/ENGINEER platform,3D parametric model family is built to allow generation of feasible configurations of cranes’ structures in Client/Server framework. Taking use of Visual C++,the second exploiting software kit provided by Pro/ENGINEER and ANSYS GUI/APDL modeling patterns,an integration method of 3D CAD and CAE is achieved,which includes regeneration of 3D parametric model,synchronous updating and analysis of FEA model. As in Browser/Server framework,the 3D CAD models of parts,components and the whole structure could also be displayed in the customer’s browser in VRML format.

Electronic Structures and Spectra of the Bases and Base Pairs of Nucleic Acids

The present paper covers electronic structures and spectra of the bases and the base pairs of nucleic acids calculated by using the INDO/S method. For free bases we give the energy levels of ground states and transition energies of low-lying excited states and discuss the band characters. The results indicate that the calculated spectra are in good agreement with experimental values. On the other hand, our calculations for A-T and G-C pairs are very beneficial to understanding hydrogen bond properties of these pairs.

Provenance and salt structures of gypsum formations in Pb-Zn ore-bearing Lanping basin,Southwest China

Large-scale gypsum rocks associated with world-class Pb-Zn ore formations are widely distributed in the Lanping Basin,Sowthwest China.Geochemical studies alongside field investigations were conducted in this study to determine the source and evolutionary processes of the gypsum rocks in this area.The gypsum sequences in the Lanping Basin developed in two formations:the Triassic Sanhedong Formation and the Paleogene Yunlong Formation.The gypsum hosted in the former displays a primary thick-banded structure withδ34SV-CDT values in the range of 14.5‰−14.8‰.Combined with the 87Sr/86Sr values(0.707737−0.707783)of limestone,it can be suggested that the Sanhedong Formation is of marine origin.In contrast,the gypsum from the Paleogene Yunlong Formation is characterized by the dome,bead and diapiric salt structures,wider range of both 87Sr/86Sr(0.707695−0.708629)andδ34SV-CDT values(9.6‰−17‰),thus indicating a marine source but with the input of continental materials.The initial layered salt formations were formed by chemical deposition in a basin and were later intensely deformed by collisional orogeny during the Himalaya period.As a result,variable salt structures were formed.We hereby propose an evolutionary model to elucidate the genesis of the gypsum formations in the Lanping Basin.