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.

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.

Lignin‐derived carbon with pyridine N‐B doping and a nanosandwich structure for high and stable lithium storage

Biomass‐derived carbon is a promising electrode material in energy storage devices.However,how to improve its low capacity and stability,and slow diffusion kinetics during lithium storage remains a challenge.In this research,we propose a“self‐assembly‐template”method to prepare B,N codoped porous carbon(BN‐C)with a nanosandwich structure and abundant pyridinic N‐B species.The nanosandwich structure can increase powder density and cycle stability by constructing a stable solid electrolyte interphase film,shortening the Li^(+) diffusion pathway,and accommodating volume expansion during repeated charging/discharging.The abundant pyridinic N‐B species can simultaneously promote the adsorption/desorption of Li^(+)/PF_(6)^(−) and reduce the diffusion barrier.The BN‐C electrode showed a high lithium‐ion storage capacity of above 1140 mAh g^(−1) at 0.05 A g^(−1) and superior stability(96.5% retained after 2000 cycles).Moreover,owing to the synergistic effect of the nanosandwich structure and pyridinic N‐B species,the assembled symmetrical BN‐C//BN‐C full cell shows a high energy density of 234.7Wh kg^(−1),high power density of 39.38 kW kg−1,and excellent cycling stability,superior to most of the other cells reported in the literature.As the density functional theory simulation demonstrated,pyridinic N‐B shows enhanced adsorption activity for Li^(+) and PF_(6)^(−),which promotes an increase in the capacity of the anode and cathode,respectively.Meanwhile,the relatively lower diffusion barrier of pyridinic N‐B promotes Li^(+) migration,resulting in good rate performance.Therefore,this study provides a new approach for the synergistic modulation of a nanostructure and an active site simultaneously to fabricate the carbon electrode material in energy storage devices.

Structures and electrochemical hydrogen storage performance of Si added A_2B_7-type alloy electrodes

In order to ameliorate the electrochemical hydrogen storage performance of La-Mg-Ni system A2B7-type electrode alloys, a small amount of Si was added. The La0.8Mg0.2Ni3.3Co0.2Six （x=0-0.2） electrode alloys were prepared by casting and annealing. The effects of adding Si on the structure and electrochemical hydrogen storage characteristics of the alloys were investigated systematically. The results indicate that the as-cast and annealed alloys hold multiple structures, involving two major phases of （La, Mg）2Ni7 with a Ce2Ni7-type hexagonal structure and LaNi5 with a CaCu5-type hexagonal structure as well as one residual phase LaNi3. The addition of Si results in a decrease in （La, Mg）2Ni7 phase and an increase in LaNi5 phase without changing the phase structure of the alloys. What is more, it brings on an obvious effect on electrochemical hydrogen storage characteristics of the alloys. The discharge capacities of the as-cast and annealed alloys decline with the increase of Si content, but their cycle stabilities clearly grow under the same condition. Furthermore, the measurements of the high rate discharge ability, the limiting current density, hydrogen diffusion coefficient as well as electrochemical impedance spectra all indicate that the electrochemical kinetic properties of the electrode alloys first increase and then decrease with the rising of Si content.

基于s和B样条曲线的传输机构分段轨迹规划

为了改善Pecvd设备在运输石墨舟过程中遇到的振动、过量损耗等问题,提出一种分段式作业轨迹规划方法。分别采用自适应的s曲线以及B样条曲线对传输机构的两段作业轨迹进行轨迹规划,并对较复杂的B样条曲线轨迹采用自适应遗传算法进行优化;同时采用模糊PID控制方法,将机构控制误差限制在合理范围之内。通过石墨舟传输机构模型轨迹仿真实验,验证了所提出的分段轨迹规划方法可使机构运动平稳;实际样机实验验证了该方法控制信号误差在5%以内。实验结果表明,所提出的轨迹规划方法在效率、误差控制方面均符合生产需求,可用于实际生产。

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.

老年急性进展性脑梗死患者血清磷脂酶A2、S100钙结合蛋白B水平与颈动脉斑块的联系

目的探讨老年急性进展性脑梗死患者血清磷脂酶A2(PLA2)、S100钙结合蛋白B(S100B)和颈动脉斑块的关系。方法将2021年1月至2022年6月收治的120例老年急性进展性脑梗死患者纳入观察组,同期将115例非进展性脑梗死患者为非进展组,100例健康人员为健康组。将观察组分为无斑块组34例、斑块稳定组45例和斑块不稳定组41例。分析血清PLA2、S100B水平与颈动脉斑块的关系。ROC分析二者对颈动脉斑块的预测价值。随访1年,以复发和死亡为终点事件分析生存率。结果斑块稳定组、斑块不稳定组血清PLA2、S100B高于无斑块组,差异有统计学意义(P<0.05)。血清PLA2、S100B与颈动脉斑块呈正相关。ROC显示二者联合预测的价值更高(P<0.05)。结论血清PLA2、S100B在老年急性进展性脑梗死患者水平升高,与颈动脉斑块关系密切。

B位掺杂提升CsSnI_(3)钙钛矿结构和电荷稳定性的第一性原理研究

全无机CsSnI_(3)钙钛矿拥有理想的带隙宽度(1.3 eV),光电转化效率理论峰值达到33%.目前CsSnI_(3)太阳能电池的发展受制于的CsSnI_(3)的结构不稳定性和Sn^(2+)易被氧化为Sn^(4+)的问题.研究基于第一性原理,详细探讨了一系列金属元素对CsSnI_(3)进行B位掺杂改性的方案,旨在提升CsSnI_(3)结构稳定性,并抑制CsSnI_(3)中Sn^(2+)被氧化为Sn^(4+)的问题.计算结果表明,在CsSnI_(3)钙钛矿B位掺杂三价金属Sb、Bi能够阻碍CsSnI_(3)相变生成Cs_(2)SnI_6,并且抑制Sn^(2+)的氧化;尤其在晶格中存在锡空位缺陷时,Sb、Bi掺杂对于Sn^(4+)形成的抑制效果更为显著.同时,低浓度的Sb、Bi掺杂不会改变CsSnI_(3)的直接带隙特性,且带隙宽度变化较小,因此能够在维持CsSnI_(3)优良光电活性的基础上进一步提高结构和电荷的稳定性.研究结果为实现高效且稳定的CsSnI_(3)钙钛矿太阳能电池提供了重要的理论指导.

基于B/S架构的防汛防旱抢险数字化管理系统研究

针对传统的防汛防旱抢险管理方式难以实现高效、精准、及时响应的问题,研究了一种基于B/S架构的防汛防旱抢险数字化管理系统。分析了该系统的技术特性,探讨了系统的框架体系、通用业务组件、应用管理平台和开发功能结构等。

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.

温阳益髓方联合富血小板血浆治疗早中期膝骨关节炎的疗效及对血清S100B、CTX-Ⅱ水平的影响

目的 分析温阳益髓方联合富血小板血浆(PRP)治疗早中期膝骨关节炎(KOA)的疗效及对血清S100B、Ⅱ型胶原C端肽(CTX-Ⅱ)水平的影响。方法 选取2021年4月至2023年1月该院收治的150例早中期KOA患者作为研究对象,根据随机数字表法将其分为观察组和对照组,各75例。对照组给予PRP治疗,观察组在对照组基础上联合温阳益髓方治疗。对比两组临床疗效、不良反应总发生率、复发率,治疗前、治疗1个月后Lysholm膝关节功能量表(LKS)评分,血清S100B、CTX-Ⅱ水平,以及治疗前、治疗1周、1个月后视觉模拟评分法(VAS)评分。结果 观察组总有效率高于对照组,复发率低于对照组,差异均有统计学意义(P<0.05)。治疗1个月后两组LKS评分高于治疗前,且观察组LKS评分高于对照组,差异均有统计学意义(P<0.05)。重复测量方差分析显示,两组治疗期间VAS评分变化有交互效应(F=20.132,P=0.030),故进一步做单独交应分析,对照组和观察组治疗1周、1个月后的VAS评分均低于治疗前,且治疗1个月后的VAS评分低于治疗1周后,差异均有统计学意义(P<0.05)。多变量方差分析结果显示,治疗1周、1个月后观察组VAS评分低于对照组,差异均有统计学意义(P<0.05)。治疗1个月后两组血清S100B、CTX-Ⅱ水平低于治疗前,且观察组低于对照组,差异均有统计学意义(P<0.05)。两组不良反应总发生率比较,差异无统计学意义(P>0.05)。结论 温阳益髓方联合PRP治疗早中期KOA患者的临床效果显著,可有效缓解疼痛症状,改善血清S100B、CTX-Ⅱ水平,促进膝关节功能康复,降低疾病复发率,值得临床推广。

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.

Comparative Analysis of Population Genetic Structure in Bemisia tabaci(Gennadius) Biotypes B and Q Based on ISSR Marker

Bemisia tabaci （Gennadius） biotypes B and Q are two invasive biotypes in the species complex. The comparison of the population genetic structure of the two biotypes is of significance to show their invasive mechanism and to their control. The intersimple sequence repeats （ISSR） marker was used to analyze the 16 B-biotype populations and 4 Q-biotype populations worldwide with a Trialeurodes vaporariorum population in Shanxi Province, China, and a B. tabaci non-B/Qbiotype population in Zhejiang Province, China, was used as control populations. The analysis of genetic diversity showed that the diversity indexes of biotype Q including Nei＇s gene diversity index, Shannon informative index, and the percentage of polymorphic loci were higher than those of biotype B. The high genetic diversity of biotype Q might provide the genetic basis for the excellent ecological adaptation. Cluster analysis suggested that the ISSR could not be used in the phylogenetic analysis though it could easily distinguish the biotypes of B. tabaci. The difference of the population genetic structure between the biotype B and the biotype Q exists based on the ISSR marker. Meanwhile, the results suggested that the molecular marker has its limitation in the phylogenetic analysis among the biotypes of B. tabaci.

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）.

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.

EFFECT OF HEAT TREATMENT TEMPERATURE ON MICROSTRUCTURE AND PROPERTIES OF Ti-B-N FILM

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Synthesis, Crystal Structure and Properties of Ethyl 3,9-Dimethyl-7-phenyl-6H-dibenzo[b,d]pyran-6-one-8-carboxylate

ABSTRACT Ethyl 3,9-dimethyl-7-phenyl-6It-dibenzo[b,d]pyran-6-one-8-carboxylate （C24H20O4, Mr = 372.40） has been synthesized and its structure was determined by ^1H and ^1C NMR, ESI-MS, elemental analysis, and X-ray single-crystal diffraction. The crystal belongs to the monoclinic system, space group P21/n, with a = 8.3674（11）, b = 10.6683（14）, c = 11.3817（15） A, a = 95.596（2）, β = 109.866（2）, γ = 94.495（2）°, V= 944.2（2）A^3, Z= 2, Dc = 1.310 g/cm3, μ= 0.089 mm^-1, F（000） = 392, R = 0.0482 and wR = 0.1281 for 2916 observed reflections with I 〉 2σ（I）. In the crystal structure, the fused tricyclic nucleus of the title compound is not fully coplanar. Analysis of the crystal packing indicates aromatic π-π stacking interactions occurring between the fused tricyclic aromatic rings of neighboring molecules in which a maximum overlap of the x-electron systems was achieved. Fluorescence and thermal studies indicate that compound 3 has good optical properties and thermal stability.

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.

Extraction and Crystal Structure of Physalin B

The title compound of physalin B（C28H32O9）, a main active physalin of Physalis angulata L, was isolated from the whole plant of Physalis angulata L, and characterized by X-ray diffraction analysis. It crystallizes in the monoclinic system, space group P21 with C28H32O9, a = 12.4996（2）, b = 14.35620（10）, c = 14.75190（10）, V = 2607.97（5） 3, Z = 4, Dc = 1.382 mg/cm3, Mr = 542.56, F（000） = 1152, and μ = 0.870 mm-1. The final R = 0.0389 and wR = 0.1037 for 47670 observed reflections（I 〉 2σ（I））. The rigid molecule consists of eight fused rings involving two lactones. There are two C28H32O9 molecules in an symmetric unit, and the title compound is stacked into a 3D layer structure through hydrogen bonds. In the 5~20 μmol/L range, physalin B can significantly inhibit the secretion of inflammatory cytokines TNF-α and IL-6 on RAW264.7 cells. The results suggest that physalin B has anti-inflammatory activity in vitro.