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.

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.

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.

A study on deep structure using teleseismic receiver function in Western Yunnan

s Western Yunnan is located at the boundary of collision or underthrusting zone of Eurasian plate and is influenced by many times tectonic movements. With very complex geological environment and tectonic background, it is one of the seismically active areas. In the paper, the teleseismic records were selected from 16 national, local and mo-bile stations, including 4 very-wide-band mobile stations of PASSCAL. And nearly 2 000 receiver functions were extracted. Two measuring lines are 650 km and 450 km, respectively and across some major tectonic units in Western Yunnan. It is indicated that Nujiang might be a seam characterized by underthrusting. The western and eastern boundaries of Sichuan-Yunnan rhombus block, i.e., Honghe and Xiaojiang faults, might be an erection seam or collision belt. Panxi tectonic zone still has the characteristics of continental rift valley, that is, the surface is hollow and the upper mantle is upwarping. The tectonic situation in Western Yunnan is of certain regulation with the interlacing distribution of orogenic zone and seam. The crustal thickness decreases gradually from the north to the south and the S wave velocity is globally lower here.

Analysis of the Structure of Shakespeare's Sonnets

The sonnet is a kind of lyrics with restrict forms which cannot depart from the contents. Shakespeare's sonnets are like a valuable flower blossoming in the England poetry garden during the age of Renaissance and a bright pearl sparkling in the world's poetry treasury. This paper will analyze his sonnets from the perspective of the structure and then interpret the meanings behind those words, which can demonstrate the importance of the connection between the forms and the contents.

Effect of C/S Ratio on Morphology and Structure of Hydrothermally Synthesized Calcium Silicate Hydrate

The samples of the C-S-H series were synthesized by hydrothermal reaction of fumed silica, CaO and deionized water at initial C/S ratios between 1.0-1.7. Phase composition and structural and morphology characteristics of C-S-H samples were analyzed by XRD, IR and SEM. The experimental results showed that the d-spacing of （002）, （110） and （020） decreased, the d-spacing of （200） increased, and the d-spacing of （310） varied randomly, the polymerization of silica tetrahedra of C-S-H decreased, and morphology of C-S-H samples varied from sheet shapes to long reticular fibers as C/S ratio increased.

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.

A study on deep structure using teleseismic receiver function in Western Yunnan

s Western Yunnan is located at the boundary of collision or underthrusting zone of Eurasian plate and is influenced by many times tectonic movements. With very complex geological environment and tectonic background, it is one of the seismically active areas. In the paper, the teleseismic records were selected from 16 national, local and mo-bile stations, including 4 very-wide-band mobile stations of PASSCAL. And nearly 2 000 receiver functions were extracted. Two measuring lines are 650 km and 450 km, respectively and across some major tectonic units in Western Yunnan. It is indicated that Nujiang might be a seam characterized by underthrusting. The western and eastern boundaries of Sichuan-Yunnan rhombus block, i.e., Honghe and Xiaojiang faults, might be an erection seam or collision belt. Panxi tectonic zone still has the characteristics of continental rift valley, that is, the surface is hollow and the upper mantle is upwarping. The tectonic situation in Western Yunnan is of certain regulation with the interlacing distribution of orogenic zone and seam. The crustal thickness decreases gradually from the north to the south and the S wave velocity is globally lower here.

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.

The quadratic-form identity for constructing Hamiltonian structures of the Guo hierarchy

The trace identity is extended to the quadratic-form identity. The Hamiltonian structures of the multi-component Guo hierarchy, integrable coupling of Guo hierarchy and （2＋l）-dimensional Guo hierarchy are obtained by the quadraticform identity. The method can be used to produce the Hamiltonian structures of the other integrable couplings or multi-component hierarchies.

Structure and function of the contactin-associated protein family in myelinated axons and their relationship with nerve diseases

The contactin-associated protein （Caspr） family participates in nerve excitation and conduction, and neurotransmitter release in myelinated axons. We analyzed the structures and functions of the Caspr family- CNTNAP1 （Casprl）, CNTNAP2 （Caspr2）, CNTNAP3 （Caspr3）, CNTNAP4 （Caspr4） and CNTNAP5 （Caspr5）, Casprl-5 is not only involved in the formation of myelinated axons, but also participates in maintaining the stability of adjacent connections. Casprl participates in the formation, differentiation, and proliferation of neurons and astrocytes, and in motor control and cognitive function. We also analyzed the relationship between the Caspr family and neurodegenerative diseases, multiple sclerosis, and autoimmune encephalitis. However, the effects of Caspr on disease course and prognosis remain poorly understood. The effects of Caspr on disease diagnosis and treatment need further investigation.

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.

S-wave velocity structure inferred from receiver function inversion in Tengchong volcanic area

Tengchong volcanic area is located near the impinging and underthrust margin of India and Eurasia plates. The volcanic activity is closely related to the tectonic environment. The deep structure characteristics are inferred from the receiver function inversion with the teleseismic records in the paper. The results show that the low velocity zone is influenced by the NE-trending Dayingjiang fault. The S-wave low velocity structure occurs obviously in the southern part of the fault, but unobviously in its northern part. There are low velocity zones in the shallow po-sition, which coincides with the seismicity. It also demonstrates that the low velocity zone is directly related to the thermal activity in the volcanic area. Therefore, we consider that the volcano may be alive again.

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.

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.

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.

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.

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.