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.

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.

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.

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.

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.

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.

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.

Two Isostructural Multi-metal Borates: Syntheses, Crystal Structures and Characterizations of M_3LiNa_4Be_4B_(10)O_(24)F(M = Sr, Cd)

Two new isostructural multi-metal beryllium borates, m^3 Li Na4Be4B10O24F（M = Sr（1）, Cd（2））, have been synthesized by spontaneous crystallization. The structures were verified by single-crystal X-ray crystallography. The compounds crystallize in the trigonal space group R 3, with a = b = 9.4645（1） A, c = 38.842（8） A, V = 3013.2（6） A3, Z = 6, F（000） = 2568, Dc = 3.005 g/cm^3, Mr = 908.9, R = 0.0327, w R = 0.0678, μ = 8.160 mm-1 for Sr3 Li Na4Be4B10O24F and a = b = 9.3019（8） A, c = 37.782（7） A, V = 2831.12（9） A3, Z = 6, F（000） = 2748, Dc = 3.459 g/cm^3, Mr = 983.24, R = 0.0158, w R = 0.0455, μ = 3.586 mm-1 for Cd3 Li Na4Be4B10O24F. The structures are characterized by an infinite two-dimensional [Be8B16O40F2]∞ double layer bridged by [B12O24] groups like a sandwich structure, while the cations reside in tunnels along different directions. UV-vis-IR diffuse reflectance spectroscopy demonstrates that their cut-off edges are below 200 nm. Thermal analysis shows that they melt incongruently and their melting points are around 740-770 ℃.

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.

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.

An SCF－MS－Xα Study of the Electronic Structures of Binuclear and Trinuclear Gold（Ⅰ） Compounds

The SCF-Xα-SW molecular orbital calculations were carried out on the modelcompounds of binuclear and trinuclear gold(Ⅰ)using starting potential of Au atom and the Watson sphere.The energy level order of the frontier orbital of a binuclear gold model compound is in agreement with the experimental result.The calculated ionization potential of the binuclear model compound is consistent well with the photoelectron spectrum of Au (Me)(PMe_3).The metal-metal interactions are discussed.The calculated electronic absorption spectra of binuclear and trinuclear gold(Ⅰ)are basically in agreement with experimental results.

Crystal structures and decomposing of B–P compounds under pressure

We have systematically studied the structures, electronic properties, and lattice dynamics of B–P compounds at high pressures. BP and B_6 P are found to be thermodynamically stable below 100 GPa, and other stoichiometries are decomposable under pressure. The predicted structures of F-43 m BP and R-3 m B_6 P are in good agreement with the experimental results by comparing the powder diffraction file(PDF) standard cards with our simulated x-ray diffractions. The bonding properties of BP and B_6 P have also been analyzed by electronic localization functions, charge density difference, and Bader charge analysis. Our results show that BP and B_6 P decompose into B and P under high pressure, which is proven to be dominated by the volumes of them. Furthermore, the infrared and Raman spectra of F-43 m and R-3 m are investigated at selected pressures and will provide useful information for future experimental studies about B–P compounds.

A Semi-automatic Method Based on Statistic for Mandarin Semantic Structures Extraction in Specific Domains

This paper proposed a new method of semi-automatic extraction for semantic structures from unlabelled corpora in specific domains. The approach is statistical in nature. The extracted structures can be used for shallow parsing and semantic labeling. By iteratively extracting new words and clustering words, we get an inital semantic lexicon that groups words of the same semantic meaning together as a class. After that, a bootstrapping algorithm is adopted to extract semantic structures. Then the semantic structures are used to extract new

The structures of eye and surrounding tissues of Longman's beaked whale,Indopacetus pacificus

Observations were made on one eye from a Longman’s beaked whale Indopacetus pacificus, which was probably one of the least known extant cetaceans. The whale died shortly after swimming aground on the coast in the Nishikata Beach, Sendai-shi, Kagoshima-ken Prefecture, Japan, on July 26, 2002. It was a mature female with body length 6.45 m. This paper documented the basic structural characteristics of her visual organ of the whale in order to better understand this animal.

Crystal Structures and Antimicrobial Activity of Two Phosphorus Compounds

One phosphorus heterocycle compound 1, C13H13N2OPS, was synthesized by the reaction of Lawesson＇s reagent （LR） with o-phenylene diamine. The crystal belongs to the orthorhombic system, space group P212121 with a = 5.5274（11）, b = 8.1603（16）, c = 28.830（6） A, V = 1300.4（4） A^3, Z = 4, Mr= 276.28, Dc = 1.411 g/cm^3, F（000） = 576,μ = 0.360 mm^-1, R = 0.0259 and wR = 0.0652 for 1414 observed reflections with I 〉 2σ（I）. While compound 2, C14H17N2O2PS, was obtained as a ring-cleavage product of compound 1. This crystal is of monoclinic system, space group P21/c with a = 9.5619（19）, b = 21.879（4）, c = 7.3618（15） A, β= 103.03（3）°, V=1500.4（5） A^3, Z = 4, Mr= 308.33, Dc = 1.365 g/cm^3, F（000） = 648,μ = 0.325 mm^-1, R = 0.0383 and wR =0.0742 for 2283 observed reflections with I 〉 2σ（I）. Phosphorus atom in each compound bonds with sulfur and carbon atoms using sp^3 hybrid orbitals, and crystals of these two compounds are formed and stabilized by intermolecular hydrogen bonds and Van der Waals＇ forces. The special structure of compound 1 leads to its good antimicrobial activity against staphylococcus aureus.

Nanostructures on Surface of SrTio₃Single Crystals Treated by Plasma

Modification of a surface of strontium titanate single crystals as pure as doped with Mn (Ni) or Nd (Sm) ions after plasma treatment was studied by combination of scanning electron microscopy and atomic force microscopy techniques. Valence shift method for characteristic X ray lines was used for study of stoichiometry violation and oxidation state of ions on the crystals surface after plasma treatment. One-and two-level ordered systems of unit crystallites sized of about 10-7 – 10-10 m were discovered on samples surface after plasma treatment with energy density of about 5 - 20 (40) J.cm-2. Oxidation state of Ti ions and stoichiometry of the surface changed essentially on background of high stability of strontium ions valence.

The Problem of Quasiperiodic Photonic Structures Solved by Considering the Cut of 2D Periodic Structure

The physical objective of solving for eigen-modes of a 1D quasiperiodic structure in photonics has been achieved. This was achieved thru considering this structure as a 1D projection or cut of a 2D periodic structure. And the problem is solved in a manner similar to 2D periodic photonic structures. A mechanical analogy (quasiperiodic orbits) helps to bring conceptual clarity.