Tuning element distribution, structure and properties by composition in high-entropy alloys.

High-entropy alloys are a class of materials that contain five or more elements in near-equiatomic proportions1,2. Their unconventional compositions and chemical structures hold promise for achieving unprecedented combinations of mechanical properties3-8. Rational design of such alloys hinges on an understanding of the composition-structure-property relationships in a near-infinite compositional space9,10. Here we use atomic-resolution chemical mapping to reveal the element distribution of the widely studied face-centred cubic CrMnFeCoNi Cantor alloy2 and of a new face-centred cubic alloy, CrFeCoNiPd. In the Cantor alloy, the distribution of the five constituent elements is relatively random and uniform. By contrast, in the CrFeCoNiPd alloy, in which the palladium atoms have a markedly different atomic size and electronegativity from the other elements, the homogeneity decreases considerably; all five elements tend to show greater aggregation, with a wavelength of incipient concentration waves11,12 as small as 1 to 3 nanometres. The resulting nanoscale alternating tensile and compressive strain fields lead to considerable resistance to dislocation glide. In situ transmission electron microscopy during straining experiments reveals massive dislocation cross-slip from the early stage of plastic deformation, resulting in strong dislocation interactions between multiple slip systems. These deformation mechanisms in the CrFeCoNiPd alloy, which differ markedly from those in the Cantor alloy and other face-centred cubic high-entropy alloys, are promoted by pronounced fluctuations in composition and an increase in stacking-fault energy, leading to higher yield strength without compromising strain hardening and tensile ductility. Mapping atomic-scale element distributions opens opportunities for understanding chemical structures and thus providing a basis for tuning composition and atomic configurations to obtain outstanding mechanical properties.

Premature transcription termination at the expanded GAA repeats and aberrant alternative polyadenylation contributes to the Frataxin transcriptional deficit in Friedreich's ataxia.

Frataxin deficiency in Friedreich's ataxia results from transcriptional downregulation of the FXN gene caused by expansion of the intronic trinucleotide guanine-adenine-adenine (GAA) repeats. We used multiple transcriptomic approaches to determine the molecular mechanism of transcription inhibition caused by long GAAs. We uncovered that transcription of FXN in patient cells is prematurely terminated upstream of the expanded repeats leading to the formation of a novel, truncated and stable RNA. This FXN early terminated transcript (FXN-ett) undergoes alternative, non-productive splicing and does not contribute to the synthesis of functional frataxin. The level the FXN-ett RNA directly correlates with the length of the longer of the two expanded GAA tracts. Targeting GAAs with antisense oligonucleotides or excision of the repeats eliminates the transcription impediment, diminishes expression of the aberrant FXN-ett, while increasing levels of FXN mRNA and frataxin. Non-productive transcription may represent a common phenomenon and attractive therapeutic target in diseases caused by repeat-mediated transcription aberrations.

Targeting 3' and 5' untranslated regions with antisense oligonucleotides to stabilize frataxin mRNA and increase protein expression.

Friedreich's ataxia (FRDA) is a severe multisystem disease caused by transcriptional repression induced by expanded GAA repeats located in intron 1 of the Frataxin (FXN) gene encoding frataxin. FRDA results from decreased levels of frataxin; thus, stabilization of the FXN mRNA already present in patient cells represents an attractive and unexplored therapeutic avenue. In this work, we pursued a novel approach based on oligonucleotide-mediated targeting of FXN mRNA ends to extend its half-life and availability as a template for translation. We demonstrated that oligonucleotides designed to bind to FXN 5' or 3' noncoding regions can increase FXN mRNA and protein levels. Simultaneous delivery of oligonucleotides targeting both ends increases efficacy of the treatment. The approach was confirmed in several FRDA fibroblast and induced pluripotent stem cell-derived neuronal progenitor lines. RNA sequencing and single-cell expression analyses confirmed oligonucleotide-mediated FXN mRNA upregulation. Mechanistically, a significant elongation of the FXN mRNA half-life without any changes in chromatin status at the FXN gene was observed upon treatment with end-targeting oligonucleotides, indicating that transcript stabilization is responsible for frataxin upregulation. These results identify a novel approach toward upregulation of steady-state mRNA levels via oligonucleotide-mediated end targeting that may be of significance to any condition resulting from transcription downregulation.

In Situ Observation on Dislocation-Controlled Sublimation of Mg Nanoparticles.

Sublimation is an important endothermic phase transition in which the atoms break away from their neighbors in the crystal lattice and are removed into the gas phase. Such debonding process may be significantly influenced by dislocations, the crystal defect that changes the bonding environment of local atoms. By performing systematic defects characterization and in situ transmission electron microscopy (TEM) tests on a core--shell MgO-Mg system, which enables us to "modulate" the internal dislocation density, we investigated the role of dislocations on materials' sublimation with particular focus on the sublimation kinetics and mechanism. It was observed that the sublimation rate increases significantly with dislocation density. As the density of screw dislocations is high, the intersection of screw dislocation spirals creates a large number of monatomic ledges, resulting in a "liquid-like" motion of solid-gas interface, which significantly deviates from the theoretically predicted sublimation plane. Our calculation based on density functional theory demonstrated that the remarkable change of sublimation rate with dislocation density is due to the dramatic reduction in binding energy of the monatomic ledges. This study provides direct observation to improve our understanding on this fundamental phase transition as well as to shed light on tuning materials' sublimation by "engineering" dislocation density in applications.

Composition and Interface Engineering of Alloyed MoS2 x Se2(1- x ) Nanotubes for Enhanced Hydrogen Evolution Reaction Activity.

Hierarchical MoS2 x Se2(1- x ) nanotubes assembled from several-layered nanosheets featuring tunable chalcogen compositions, expanded interlayer spacing and carbon modification, are synthesized for enhanced electrocatalytic hydrogen evolution reaction (HER). The chalcogen compositions of the MoS2 x Se2(1- x ) nanotubes are controllable by adjusting the selenization temperature and duration while the expanded (002) interlayer spacing varies from 0.98 to 0.68 nm. It is found that the MoS2 x Se2(1- x ) (x = 0.54) nanotubes with expanded interlayer spacing of 0.98 nm exhibit the highest electrocatalytic HER activity with a low onset potential of 101 mV and a Tafel slope of 55 mV dec(-1) . The improved electrocatalytic performance is attributed to the chalcogen composition tuning and the interlayer distance expansion to achieve benefitting hydrogen adsorption energy. The present work suggests a potential way to design advanced HER electrocatalysts through modulating their compositions and interlayer distances.

Effect of Bismuth Oxide on the Microstructure and Electrical Conductivity of Yttria Stabilized Zirconia.

Bismuth oxide (Bi2O3)-doped yttria-stabilized zirconia (YSZ) were prepared via the solid state reaction method. X-ray diffraction and electron diffraction spectroscopy results indicate that doping with 2 mol% Bi2O3 and adding 10 mol% yttria result in a stable zirconia cubic phase. Adding Bi2O3 as a dopant increases the density of zirconia to above 96%, while reducing its normal sintering temperature by approximately 250°C. Moreover, electrical impedance analyses show that adding Bi2O3 enhances the conductivity of zirconia, improving its capability as a solid electrolyte for intermediate or even lower temperatures.

Highly mesoporous single-crystalline zeolite beta synthesized using a nonsurfactant cationic polymer as a dual-function template.

Mesoporous zeolites are useful solid catalysts for conversion of bulky molecules because they offer fast mass transfer along with size and shape selectivity. We report here the successful synthesis of mesoporous aluminosilicate zeolite Beta from a commercial cationic polymer that acts as a dual-function template to generate zeolitic micropores and mesopores simultaneously. This is the first demonstration of a single nonsurfactant polymer acting as such a template. Using high-resolution electron microscopy and tomography, we discovered that the resulting material (Beta-MS) has abundant and highly interconnected mesopores. More importantly, we demonstrated using a three-dimensional electron diffraction technique that each Beta-MS particle is a single crystal, whereas most previously reported mesoporous zeolites are comprised of nanosized zeolitic grains with random orientations. The use of nonsurfactant templates is essential to gaining single-crystalline mesoporous zeolites. The single-crystalline nature endows Beta-MS with better hydrothermal stability compared with surfactant-derived mesoporous zeolite Beta. Beta-MS also exhibited remarkably higher catalytic activity than did conventional zeolite Beta in acid-catalyzed reactions involving large molecules.

Nano-intermetallic AuCu3 catalyst for oxygen reduction reaction: performance and mechanism.

This paper introduces a new approach for catalyst design using the non-precious metal Cu as one of the catalytic active centers. This differs from previous studies that considered precious metals to be responsible for the catalytic reaction in precious alloys. Intermetallic AuCu3/C nanoparticles with a diameter of 3 nm were developed for the first time, with uniform dispersion and a narrow size distribution. The ca. 3 nm as-synthesised AuCu3/C showed superior catalytic performance for oxygen reduction reactions (ORR) in alkaline solutions, with comparable half-wave potential and 1.5 times mass current density of commercial Pt/C at 0.80 V (vs. reversible hydrogen electrode (RHE)). The advanced catalytic activities are mainly attributed to the synergetic effects of electro-active atomic Au and Cu on the particle surface, in which Cu helps to activate the O2 molecule and Au benefits OH(-) desorption. The excellent durability and methanol tolerance exhibited in alkaline solutions provide another advantage for AuCu3/C to be considered as a potential alternative cathode catalyst in alkaline fuel cells.

Comparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.

Cardiomyopathy is often fatal in Friedreich ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, the ISRmt has not been investigated in models with disease-relevant, partial decrease in FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion: YG8-800, KIKO-700 and FXNG127V. Few metabolites were changed in YG8-800 mice, which did not provide a signature of cardiomyopathy or ISRmt; several metabolites were altered in FXNG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FXNG127V hearts. However, these changes were surprisingly mild even at advanced age (18 months), despite a severe decrease in FXN levels to 1% of those of wild type. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Extraordinarily high activity in the hydrodesulfurization of 4,6-dimethyldibenzothiophene over Pd supported on mesoporous zeolite Y.

Design and preparation of highly active hydrodesulfurization (HDS) catalysts is very important for the removal of air pollution. Herein, we report an extraordinarily active HDS catalyst, which is synthesized by loading of Pd on mesoporous zeolite Y (Pd/HY-M). The mesoporous zeolite Y is successfully synthesized using a water glass containing N,N-dimethyl-N-octadecyl-N-(3-triethoxysilylpropyl) ammonium [(C(2)H(5)O)(3)SiC(3)H(6)N(CH(3))(2)C(18)H(37)](+) cation as a mesoscale template. Compared with mesoporous Beta and ZSM-5 supported Pd catalysts (80.0% and 73.4% for Pd/HBeta-M and Pd/HZSM-5-M, respectively) as well as commercial catalyst of γ-Al(2)O(3) supported Pd catalyst (31.4%), Pd/HY-M catalyst exhibited very high activity in HDS of 4,6-dimethyldibenzothiophene (4,6-DM-DBT, 97.3%). The higher activity of Pd/HY-M than that of Pd/HBeta-M and Pd/HZSM-5-M is assigned to the larger micropore size of zeolite Y compared to that of Beta and ZSM-5. Theoretical simulation and adsorption experimental data show that 4,6-DM-DBT has difficulty entering the micropores of ZSM-5 and Beta zeolites, but the micropores of Y zeolite are accessible.

[Study on pharmacokinetics of oridonin in mice].

OBJECTIVE: To develop a HPLC method for the determination of plasma concentration of oridonin (ORI) and study the pharmacokinetics of ORI in mice. METHOD: Blood was sampled from mice which were injected ORI by 10 mg x kg(-1) at different time intervals, and the concentration of ORI was determined by HPLC. The pharmacokinetic parameters were accessed by 3P97. RESULT: The calibration curve was linear (r = 0.998 7) within the range of 0.202-20.0 mg x L(-1) for ORI in plasma. The average recoveries were more than 93%. The within-day and between-day precisions were no more than 9%. After i.v. oridonin in mice, the plasma concentration-time course fitted well to two-compartment model. The pharmacokinetic equation was C = 16.192 5e(-0.554 6t) + 5.475 7e(-0.016 3t). The pharmacokinetic parameters were below: t1/2alpha 1.249 9 min, t1/2beta 42.638 4 min, K21 0.152 3 min(-1), K12 0.359 3 min(-1), K10 0.0592 min(-1), AUC 366.035 0 microg x min x mL(-1), CL 0.0273 L x min(-1) x kg(-1), V(c)0.461 5 L x kg(-1). CONCLUSION: The method can be used to determine the concentration and to investigate the pharmacokinetics of ORI in mice. ORI was absorbed and distributed very fast in mice. The effect of ORI was rapid. The elimination was the main process.

Twinning-assisted dynamic adjustment of grain boundary mobility.

Grain boundary (GB) plasticity dominates the mechanical behaviours of nanocrystalline materials. Under mechanical loading, GB configuration and its local deformation geometry change dynamically with the deformation; the dynamic variation of GB deformability, however, remains largely elusive, especially regarding its relation with the frequently-observed GB-associated deformation twins in nanocrystalline materials. Attention here is focused on the GB dynamics in metallic nanocrystals, by means of well-designed in situ nanomechanical testing integrated with molecular dynamics simulations. GBs with low mobility are found to dynamically adjust their configurations and local deformation geometries via crystallographic twinning, which instantly changes the GB dynamics and enhances the GB mobility. This self-adjust twin-assisted GB dynamics is found common in a wide range of face-centred cubic nanocrystalline metals under different deformation conditions. These findings enrich our understanding of GB-mediated plasticity, especially the dynamic behaviour of GBs, and bear practical implication for developing high performance nanocrystalline materials through interface engineering.

Interlayer Coupling Dependent Discrete H → T' Phase Transition in Lithium Intercalated Bilayer Molybdenum Disulfide.

In this work, the interlayer coupling dependent lithium intercalation induced phase transition in bilayer MoS2 (BL-MoS2) was investigated using an atomic-resolution annual dark-field scanning transmission electron microscope (ADF-STEM). It was revealed that the lithiation induced H → T' phase transition in BL-MoS2 strongly depended on the interlayer twist angle; i.e., the H → T' phase transition occurred in well-stacked H phase BL-MoS2 (with a twist angle of θt = 0°) but not for θt ≠ 0° BL-MoS2. The lithiated BL-MoS2 appeared in homophase stacking, either T'/T' or H/H (locally, no phase transformation) stacking, without any heterophase stacking such as H/T' or T'/H observed. This finding indicated the H → T' phase transition occurred via a domain-by-domain mode rather than layer-by-layer. Up to 15 types of stacking orders were experimentally identified locally in lithiated bilayer T'-MoS2, and the formation mechanism was attributed to the discrete interlayer translation with a unit step of (m/6a, n/6b) (m, n = 0, 1, 2, 3), where a and b were the primitive lattice vectors of T'-MoS2. Our experimental results were further corroborated by ab initio density functional theory (DFT) calculations, where the occurrence of different stacking orders can be quantitatively correlated with the variation of intercalated lithium contents into the BL-MoS2. The present study aids in the understanding of the phase transition mechanisms in atomically thin 2D transition metal dichalcogenides (TMDCs) and will also shed light on the precisely controlled phase engineering of 2D materials for memory applications.

Pattern-Potential-Guided Growth of Textured Macromolecular Films on Graphene/High-Index Copper.

Macromolecular films are crucial functional materials widely used in the fields of mechanics, electronics, optoelectronics, and biology, due to their superior properties of chemical stability, small density, high flexibility, and solution-processing ability. Their electronic and mechanical properties, however, are typically much lower than those of crystalline materials, as the macromolecular films have no long-range structural ordering. The state-of-the-art for producing highly ordered macromolecular films is still facing a great challenge due to the complex interactions between adjacent macromolecules. Here, the growth of textured macromolecular films on a designed graphene/high-index copper (Cu) surface is demonstrated. This successful growth is driven by a patterned potential that originates from the different amounts of charge transfer between the graphene and Cu surfaces with, alternately, terraces and step edges. The textured films exhibit a remarkable improvement in remnant ferroelectric polarization and fracture strength. It is also demonstrated that this growth mechanism is universal for different macromolecules. As meter-scale graphene/high-index Cu substrates have recently become available, the results open a new regime for the production and applications of highly ordered macromolecular films with obvious merits of high production and low cost.

A CRISPR-Cas9, Cre-lox, and Flp-FRT Cascade Strategy for the Precise and Efficient Integration of Exogenous DNA into Cellular Genomes.

We describe a protocol for the precise integration of exogenous DNA into user-defined genomic loci in cultured cells. This strategy first introduces a promoter and a lox site to a specific location via a Cas9-induced double-strand break. Second, a gene of interest (GOI) is inserted into the lox site via Cre-lox recombination. Upon correct insertion, a cis-linked antibiotic resistance gene will be expressed from a promoter introduced into the genome in the first step assuring selection for correct integrants. Last, the selection cassette is excised via a Flp-FRT recombination event, leaving a precisely targeted GOI. This method is broadly applicable to any exogenous DNA to be integrated, choice of integration site, and choice of cell type. The most remarkable aspect of this versatile approach, termed "CasPi" (cascaded precise integration), is that it allows for precise genome targeting with large, frequently complex, and repetitive DNA sequences that do not integrate efficiently or at all with current genome targeting methods.

Defining Transcription Regulatory Elements in the Human Frataxin Gene: Implications for Gene Therapy.

Friedreich's ataxia (FRDA) is the most common inherited form of ataxia in humans. It is caused by severe downregulation of frataxin (FXN) expression instigated by hyperexpansion of the GAA repeats located in intron 1 of the FXN gene. Despite numerous studies focused on identifying compounds capable of stimulating FXN expression, current knowledge regarding cis-regulatory elements involved in FXN gene expression is lacking. Using a combination of episomal and genome-integrated constructs, we defined a minimal endogenous promoter sequence required to efficiently drive FXN expression in human cells. We generated 19 constructs varying in length of the DNA sequences upstream and downstream of the ATG start codon. Using transient transfection, we evaluated the capability of these constructs to drive FXN expression. These analyses allowed us to identify a region of the gene indispensable for FXN expression. Subsequently, selected constructs containing the FXN expression control regions of varying lengths were site specifically integrated into the genome of HEK293T and human-induced pluripotent stem cells (iPSCs). FXN expression was detected in iPSCs and persisted after differentiation to neuronal and cardiac cells, indicating lineage independent function of defined regulatory DNA sequences. Finally, based on these results, we generated AAV encoding miniFXN genes and demonstrated in vivo FXN expression in mice. Results of these studies identified FXN sequences necessary to express FXN in human and mouse cells and provided rationale for potential use of endogenous FXN sequence in gene therapy strategies for FRDA.

Template-free hydrothermal synthesis of MgWO4 nanoplates and their application as photocatalysts.

As a semiconductor, MgWO4 has a potential in photocatalytic applications; however, it has been overlooked in previous studies; in this study, it has been demonstrated that MgWO4 exhibits the ability to drive photocatalytic hydrogen evolution. Compared to nanoparticle structures, MgWO4 nanoplates show an increased photocatalytic ability due to their higher specific surface area. Moreover, the formation mechanism of MgWO4 nanoplates has been discussed. An oriented attachment and ripening process is proposed for the formation of the MgWO4 nanoplates. This study demonstrates that MgWO4 can be considered a valuable photocatalytic material, and future studies should be focused on how to promote its photocatalytic conversion efficiency.

Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes.

Friedreich's ataxia is caused by large homozygous, intronic expansions of GAA repeats in the frataxin (FXN) gene, resulting in severe downregulation of its expression. Pathogenic repeats are located in intron one, hence patients express unaffected FXN protein, albeit in low quantities. Although FRDA symptoms typically afflict the nervous system, hypertrophic cardiomyopathy is the predominant cause of death. Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease.

In situ atomistic observation of disconnection-mediated grain boundary migration.

Shear-coupled grain boundary (GB) migration is of general significance in the deformation of nanocrystalline and polycrystalline materials, but comprehensive understanding of the migration mechanism at the atomic scale remains largely lacking. Here, we systematically investigate the atomistic migration of Σ11(113) coherent GBs in gold bicrystals using a state-of-art in situ shear testing technique combined with molecular dynamic simulations. We show that shear-coupled GB migration can be realised by the lateral motion of layer-by-layer nucleated GB disconnections, where both single-layer and double-layer disconnections have important contributions to the GB migration through their frequent composition and decomposition. We further demonstrate that the disconnection-mediated GB migration is fully reversible in shear loading cycles. Such disconnection-mediated GB migration should represent a general deformation phenomenon in GBs with different structures in polycrystalline and nanocrystalline materials, where the triple junctions can act as effective nucleation sites of GB disconnections.