Three-dimensional atomic structure and local chemical order of medium- and high-entropy nanoalloys.

Medium- and high-entropy alloys (M/HEAs) mix several principal elements with near-equiatomic composition and represent a model-shift strategy for designing previously unknown materials in metallurgy1-8, catalysis9-14 and other fields15-18. One of the core hypotheses of M/HEAs is lattice distortion5,19,20, which has been investigated by different numerical and experimental techniques21-26. However, determining the three-dimensional (3D) lattice distortion in M/HEAs remains a challenge. Moreover, the presumed random elemental mixing in M/HEAs has been questioned by X-ray and neutron studies27, atomistic simulations28-30, energy dispersive spectroscopy31,32 and electron diffraction33,34, which suggest the existence of local chemical order in M/HEAs. However, direct experimental observation of the 3D local chemical order has been difficult because energy dispersive spectroscopy integrates the composition of atomic columns along the zone axes7,32,34 and diffuse electron reflections may originate from planar defects instead of local chemical order35. Here we determine the 3D atomic positions of M/HEA nanoparticles using atomic electron tomography36 and quantitatively characterize the local lattice distortion, strain tensor, twin boundaries, dislocation cores and chemical short-range order (CSRO). We find that the high-entropy alloys have larger local lattice distortion and more heterogeneous strain than the medium-entropy alloys and that strain is correlated to CSRO. We also observe CSRO-mediated twinning in the medium-entropy alloys, that is, twinning occurs in energetically unfavoured CSRO regions but not in energetically favoured CSRO ones, which represents, to our knowledge, the first experimental observation of correlating local chemical order with structural defects in any material. We expect that this work will not only expand our fundamental understanding of this important class of materials but also provide the foundation for tailoring M/HEA properties through engineering lattice distortion and local chemical order.

Programmable heating and quenching for efficient thermochemical synthesis.

Conventional thermochemical syntheses by continuous heating under near-equilibrium conditions face critical challenges in improving the synthesis rate, selectivity, catalyst stability and energy efficiency, owing to the lack of temporal control over the reaction temperature and time, and thus the reaction pathways1-3. As an alternative, we present a non-equilibrium, continuous synthesis technique that uses pulsed heating and quenching (for example, 0.02 s on, 1.08 s off) using a programmable electric current to rapidly switch the reaction between high (for example, up to 2,400 K) and low temperatures. The rapid quenching ensures high selectivity and good catalyst stability, as well as lowers the average temperature to reduce the energy cost. Using CH4 pyrolysis as a model reaction, our programmable heating and quenching technique leads to high selectivity to value-added C2 products (>75% versus <35% by the conventional non-catalytic method and versus <60% by most conventional methods using optimized catalysts). Our technique can be extended to a range of thermochemical reactions, such as NH3 synthesis, for which we achieve a stable and high synthesis rate of about 6,000 µmol gFe-1 h-1 at ambient pressure for >100 h using a non-optimized catalyst. This study establishes a new model towards highly efficient non-equilibrium thermochemical synthesis.

Determining the three-dimensional atomic structure of an amorphous solid.

Amorphous solids such as glass, plastics and amorphous thin films are ubiquitous in our daily life and have broad applications ranging from telecommunications to electronics and solar cells1-4. However, owing to the lack of long-range order, the three-dimensional (3D) atomic structure of amorphous solids has so far eluded direct experimental determination5-15. Here we develop an atomic electron tomography reconstruction method to experimentally determine the 3D atomic positions of an amorphous solid. Using a multi-component glass-forming alloy as proof of principle, we quantitatively characterize the short- and medium-range order of the 3D atomic arrangement. We observe that, although the 3D atomic packing of the short-range order is geometrically disordered, some short-range-order structures connect with each other to form crystal-like superclusters and give rise to medium-range order. We identify four types of crystal-like medium-range order-face-centred cubic, hexagonal close-packed, body-centred cubic and simple cubic-coexisting in the amorphous sample, showing translational but not orientational order. These observations provide direct experimental evidence to support the general framework of the efficient cluster packing model for metallic glasses10,12-14,16. We expect that this work will pave the way for the determination of the 3D structure of a wide range of amorphous solids, which could transform our fundamental understanding of non-crystalline materials and related phenomena.

Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models.

Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia. SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes. Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role of SSX1 in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis.

ZSWIM4 regulates embryonic patterning and BMP signaling by promoting nuclear Smad1 degradation.

The dorsoventral gradient of BMP signaling plays an essential role in embryonic patterning. Zinc Finger SWIM-Type Containing 4 (zswim4) is expressed in the Spemann-Mangold organizer at the onset of Xenopus gastrulation and is then enriched in the developing neuroectoderm at the mid-gastrula stages. Knockdown or knockout of zswim4 causes ventralization. Overexpression of zswim4 decreases, whereas knockdown of zswim4 increases the expression levels of ventrolateral mesoderm marker genes. Mechanistically, ZSWIM4 attenuates the BMP signal by reducing the protein stability of SMAD1 in the nucleus. Stable isotope labeling by amino acids in cell culture (SILAC) identifies Elongin B (ELOB) and Elongin C (ELOC) as the interaction partners of ZSWIM4. Accordingly, ZSWIM4 forms a complex with the Cul2-RING ubiquitin ligase and ELOB and ELOC, promoting the ubiquitination and degradation of SMAD1 in the nucleus. Our study identifies a novel mechanism that restricts BMP signaling in the nucleus.

A general method for rapid synthesis of refractory carbides by low-pressure carbothermal shock reduction.

Refractory carbides are attractive candidates for support materials in heterogeneous catalysis because of their high thermal, chemical, and mechanical stability. However, the industrial applications of refractory carbides, especially silicon carbide (SiC), are greatly hampered by their low surface area and harsh synthetic conditions, typically have a very limited surface area (<200 m2 g-1), and are prepared in a high-temperature environment (>1,400 °C) that lasts for several or even tens of hours. Based on Le Chatelier's principle, we theoretically proposed and experimentally verified that a low-pressure carbothermal reduction (CR) strategy was capable of synthesizing high-surface area SiC (569.9 m2 g-1) at a lower temperature and a faster rate (∼1,300 °C, 50 Pa, 30 s). Such high-surface area SiC possesses excellent thermal stability and antioxidant capacity since it maintained stability under a water-saturated airflow at 650 °C for 100 h. Furthermore, we demonstrated the feasibility of our strategy for scale-up production of high-surface area SiC (460.6 m2 g-1), with a yield larger than 12 g in one experiment, by virtue of an industrial viable vacuum sintering furnace. Importantly, our strategy is  also applicable to the rapid synthesis of refractory metal carbides (NbC, Mo2C, TaC, WC) and even their emerging high-entropy carbides (VNbMoTaWC5, TiVNbTaWC5). Therefore, our low-pressure CR method provides an alternative strategy, not merely limited to temperature and time items, to regulate the synthesis and facilitate the upcoming industrial applications of carbide-based advanced functional materials.

Integrative Omics Reveals Rapidly Evolving Regulatory Sequences Driving Primate Brain Evolution.

Although the continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here, we performed large-scale comparative genomic, transcriptomic, and epigenomic analyses to investigate the evolutionary alterations acquired by brain genes and provide comprehensive listings of innovatory genetic elements along the evolutionary path from ancestral primates to human. The regulatory sequences associated with brain-expressed genes experienced rapid change, particularly in the ancestor of the Simiiformes. Extensive comparisons of single-cell and bulk transcriptomic data between primate and nonprimate brains revealed that these regulatory sequences may drive the high expression of certain genes in primate brains. Employing in utero electroporation into mouse embryonic cortex, we show that the primate-specific brain-biased gene BMP7 was recruited, probably in the ancestor of the Simiiformes, to regulate neuronal proliferation in the primate ventricular zone. Our study provides a comprehensive listing of genes and regulatory changes along the brain evolution lineage of ancestral primates leading to human. These data should be invaluable for future functional studies that will deepen our understanding not only of the genetic basis of human brain evolution but also of inherited disease.

Kindlin2 regulates neural crest specification via integrin-independent regulation of the FGF signaling pathway.

The focal adhesion protein Kindlin2 is essential for integrin activation, a process that is fundamental to cell-extracellular matrix adhesion. Kindlin 2 (Fermt2) is widely expressed in mouse embryos, and its absence causes lethality at the peri-implantation stage due to the failure to trigger integrin activation. The function of kindlin2 during embryogenesis has not yet been fully elucidated as a result of this early embryonic lethality. Here, we showed that kindlin2 is essential for neural crest (NC) formation in Xenopus embryos. Loss-of-function assays performed with kindlin2-specific morpholino antisense oligos (MOs) or with CRISPR/Cas9 techniques in Xenopus embryos severely inhibit the specification of the NC. Moreover, integrin-binding-deficient mutants of Kindlin2 rescued the phenotype caused by loss of kindlin2, suggesting that the function of kindlin2 during NC specification is independent of integrins. Mechanistically, we found that Kindlin2 regulates the fibroblast growth factor (FGF) pathway, and promotes the stability of FGF receptor 1. Our study reveals a novel function of Kindlin2 in regulating the FGF signaling pathway and provides mechanistic insights into the function of Kindlin2 during NC specification.

Processing bulk natural wood into a high-performance structural material.

Synthetic structural materials with exceptional mechanical performance suffer from either large weight and adverse environmental impact (for example, steels and alloys) or complex manufacturing processes and thus high cost (for example, polymer-based and biomimetic composites). Natural wood is a low-cost and abundant material and has been used for millennia as a structural material for building and furniture construction. However, the mechanical performance of natural wood (its strength and toughness) is unsatisfactory for many advanced engineering structures and applications. Pre-treatment with steam, heat, ammonia or cold rolling followed by densification has led to the enhanced mechanical performance of natural wood. However, the existing methods result in incomplete densification and lack dimensional stability, particularly in response to humid environments, and wood treated in these ways can expand and weaken. Here we report a simple and effective strategy to transform bulk natural wood directly into a high-performance structural material with a more than tenfold increase in strength, toughness and ballistic resistance and with greater dimensional stability. Our two-step process involves the partial removal of lignin and hemicellulose from the natural wood via a boiling process in an aqueous mixture of NaOH and Na2SO3 followed by hot-pressing, leading to the total collapse of cell walls and the complete densification of the natural wood with highly aligned cellulose nanofibres. This strategy is shown to be universally effective for various species of wood. Our processed wood has a specific strength higher than that of most structural metals and alloys, making it a low-cost, high-performance, lightweight alternative.

The Genetic Echo of the Tarim Mummies in Modern Central Asians.

The diversity of Central Asians has been shaped by multiple migrations and cultural diffusion. Although ancient DNA studies have revealed the demographic changes of the Central Asian since the Bronze Age, the contribution of the ancient populations to the modern Central Asian remains opaque. Herein, we performed high-coverage sequencing of 131 whole genomes of Indo-European-speaking Tajik and Turkic-speaking Kyrgyz populations to explore their genomic diversity and admixture history. By integrating the ancient DNA data, we revealed more details of the origins and admixture history of Central Asians. We found that the major ancestry of present-day Tajik populations can be traced back to the admixture of the Bronze Age Bactria-Margiana Archaeological Complex and Andronovo-related populations. Highland Tajik populations further received additional gene flow from the Tarim mummies, an isolated ancient North Eurasian-related population. The West Eurasian ancestry of Kyrgyz is mainly derived from Historical Era populations in Xinjiang of China. Furthermore, the recent admixture signals detected in both Tajik and Kyrgyz are ascribed to the expansions of Eastern Steppe nomadic pastoralists during the Historical Era.

Munronin V with 7/7/6 tricarbocyclic framework from Munronia henryi harms inhibits tau pathology by activating autophagy.

Munronin V (1), isolated from Munronia henryi Harms, is the first example, to the best of our knowledge, of an unprecedented 7/7/6 tricarbocyclic framework featuring an unusual A,B-seco-limonoid ring. The structures of munronin V were established from extensive spectroscopic and electronic circular dichroism (ECD) analyses. The novel A,B-seco with two seven-membered lactones was formed as a result of Baeyer-Villiger oxidation. Compound 1 activated autophagy and inhibited Tau pathology as revealed by flow cytometric analyses, confocal imaging analysis and western blotting, and this effect was mediated by transcription factor EB (TFEB). These findings suggested that 1 might have potential as a compound for combating Alzheimer's disease.

Tupaia GBP1 Interacts with STING to Initiate Autophagy and Restrict Herpes Simplex Virus Type 1 Infection.

Stimulator of IFN genes (STING) is a key molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase to activate IFN expression and autophagy in the fight against microbial infection. The regulation of STING in the activation of IFN expression has been extensively reported, whereas the regulation of STING in the initiation of autophagy is still insufficiently determined. IFN-inducible guanylate-binding proteins (GBPs) are central to the cell-autonomous immunity in defending a host against viral, bacterial, and protozoan infections. In this study using the Chinese tree shrew (Tupaia belangeri chinensis), which is genetically close to primates, we found that Tupaia GBP1 (tGBP1) combines with Tupaia STING (tSTING), promotes autophagy, and moderately inhibits HSV type 1 (HSV-1) infection. The antiviral effects of tGBP1 are IFN independent. Mechanistically, tGBP1 interacted with tSTING, Tupaia sequestosome 1, and Tupaia microtubule associated protein 1 L chain 3, forming a complex which promotes autophagy in response to HSV-1 infection. This function of tGBP1 against HSV-1 infection was lost in tSTING knockout cells. Overexpression of either tSTING or its mutant tSTING-ΔCTT that can only activate autophagy rescued the anti-HSV-1 activity of tGBP1 in tSTING knockout cells. Our study not only elucidated the underlying mechanism of tGBP1 antiviral activity against HSV-1 infection, but also uncovered the regulation of tSTING in the initiation of autophagy in response to HSV-1 infection.

Ganoapplins A and B with an unprecedented 6/6/6/5/6-fused pentacyclic skeleton from Ganoderma inhibit Tau pathology through activating autophagy.

Ganoapplins A and B (1 and 2) with a 6/6/6/5/6-fused pentacyclic skeleton containing an aromatic E ring, were obtained from Ganoderma applanatum. Their structures were established through extensive spectroscopic analyses, quantum chemical calculations, including calculated chemical shifts with DP4 + analysis and electronic circular dichroism (ECD). A plausible biosynthetic pathway for 1 and 2 was proposed. Furthermore, their roles in activating autophagy were investigated and the cellular assays showed that 1 and 2 can inhibit tau pathology by inducing autophagy, suggesting their potential against Alzheimer's disease (AD).

High-throughput, combinatorial synthesis of multimetallic nanoclusters.

Multimetallic nanoclusters (MMNCs) offer unique and tailorable surface chemistries that hold great potential for numerous catalytic applications. The efficient exploration of this vast chemical space necessitates an accelerated discovery pipeline that supersedes traditional "trial-and-error" experimentation while guaranteeing uniform microstructures despite compositional complexity. Herein, we report the high-throughput synthesis of an extensive series of ultrafine and homogeneous alloy MMNCs, achieved by 1) a flexible compositional design by formulation in the precursor solution phase and 2) the ultrafast synthesis of alloy MMNCs using thermal shock heating (i.e., ∼1,650 K, ∼500 ms). This approach is remarkably facile and easily accessible compared to conventional vapor-phase deposition, and the particle size and structural uniformity enable comparative studies across compositionally different MMNCs. Rapid electrochemical screening is demonstrated by using a scanning droplet cell, enabling us to discover two promising electrocatalysts, which we subsequently validated using a rotating disk setup. This demonstrated high-throughput material discovery pipeline presents a paradigm for facile and accelerated exploration of MMNCs for a broad range of applications.

New Monoterpenoid Indole Alkaloids from Tabernaemontana crassa Inhibit ß-Amyloid42 Production and Phospho-Tau (Thr217).

Eleven monoterpenoid indole alkaloids, including three new ones, tabercrassines A-C (1-3), were isolated from the seeds of Tabernaemontana crassa. Tabercrassine A (1) is an ibogan-ibogan-type bisindole alkaloid which is formed by the polymerization of two classic ibogan-type monomers through a C3 unit aliphatic chain. Their structures were established by extensive analysis of HRESIMS, NMR, and ECD spectra. Cellular assays showed that alkaloids 1-3 all reduce Aß42 production and inhibit phospho-tau (Thr217), a new biomarker of Alzheimer's disease [AD] associated with BACE1-, NCSTN-, GSK3ß-, and CDK5-mediated pathways, suggesting these alkaloids' potential against AD.

Sabatier Relations in Electrocatalysts Based on High-entropy Alloys with Wide-distributed d-band Centers for Li-O2 Batteries.

Li-O2 battery (LOB) is a promising "beyond Li-ion" technology with ultrahigh theoretical energy density (3457 Wh kg-1 ), while currently impeded by the sluggish cathodic kinetics of the reversible gas-solid reaction between O2 and Li2 O2 . Despite many catalysts are developed for accelerating the conversion process, the lack of design guidance for achieving high performance makes catalysts exploring aleatory. The Sabatier principle is an acknowledged theory connecting the scaling relationship with heterogeneous catalytic activity, providing a tradeoff strategy for the topmost performance. Herein, a series of catalysts with wide-distributed d-band centers (i.e., wide range of adsorption strength) are elaborately constructed via high-entropy strategy, enabling an in-depth study of the Sabatier relations in electrocatalysts for LOBs. A volcano-type correlation of d-band center and catalytic activity emerges. Both theoretical and experimental results indicate that a moderate d-band center with appropriate adsorption strength propels the catalysts up to the top. As a demonstration of concept, the LOB using FeCoNiMnPtIr as catalyst provides an exceptional energy conversion efficiency of over 80 %, and works steadily for 2000 h with a high fixed specific capacity of 4000 mAh g-1 . This work certifies the applicability of Sabatier principle as a guidance for designing advanced heterogeneous catalysts assembled in LOBs.

Instrumental Neutron Activation Analysis of Chang'E-5 Lunar Regolith Samples.

The Chang'E-5 (CE-5) lunar samples were analyzed nondestructively for more than 40 elements by instrumental neutron activation analysis (INAA) with a strict quality assurance and quality control. Based on the INAA results, some new observations and discoveries were made. Major, minor, and trace elements in CE-5 are very different from those of the Earth and Apollo lunar samples. The rare earth element (REE) pattern indicated that the CE-5 lunar samples are mare basalts with a clear negative anomaly in Eu. Element correlations are a very interesting discovery; for example, the ratios of Ba/La and FeO/MnO in CE-5 are almost identical to those of the Apollo lunar samples. These observations and discoveries will enrich the understanding of the formation and evolution of the Moon.

Tracing the Genetic Legacy of the Tibetan Empire in the Balti.

The rise and expansion of Tibetan Empire in the 7th to 9th centuries AD affected the course of history across East Eurasia, but the genetic impact of Tibetans on surrounding populations remains undefined. We sequenced 60 genomes for four populations from Pakistan and Tajikistan to explore their demographic history. We showed that the genomes of Balti people from Baltistan comprised 22.6-26% Tibetan ancestry. We inferred a single admixture event and dated it to about 39-21 generations ago, a period that postdated the conquest of Baltistan by the ancient Tibetan Empire. The analyses of mitochondrial DNA, Y, and X chromosome data indicated that both ancient Tibetan males and females were involved in the male-biased dispersal. Given the fact that the Balti people adopted Tibetan language and culture in history, our study suggested the impact of Tibetan Empire on Baltistan involved dominant cultural and minor demic diffusion.

Functional genomics elucidates regulatory mechanisms of Parkinson's disease-associated variants.

BACKGROUND: Genome-wide association studies (GWASs) have identified multiple risk loci for Parkinson's disease (PD). However, identifying the functional (or potential causal) variants in the reported risk loci and elucidating their roles in PD pathogenesis remain major challenges. To identify the potential causal (or functional) variants in the reported PD risk loci and to elucidate their regulatory mechanisms, we report a functional genomics study of PD. METHODS: We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) (from neuronal cells and human brain tissues) data and GWAS-identified single-nucleotide polymorphisms (SNPs) in PD risk loci. We then conducted a series of experiments and analyses to validate the regulatory effects of these (i.e., functional) SNPs, including reporter gene assays, allele-specific expression (ASE), transcription factor (TF) knockdown, CRISPR-Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. RESULTS: We identified 44 SNPs (from 11 risk loci) affecting the binding of 12 TFs and we validated the regulatory effects of 15 TF binding-disrupting SNPs. In addition, we also identified the potential target genes regulated by these TF binding-disrupting SNPs through eQTL analysis. Finally, we showed that 4 eQTL genes of these TF binding-disrupting SNPs were dysregulated in PD cases compared with controls. CONCLUSION: Our study systematically reveals the gene regulatory mechanisms of PD risk variants (including widespread disruption of CTCF binding), generates the landscape of potential PD causal variants, and pinpoints promising candidate genes for further functional characterization and drug development.

Rapid Synthesis of High-Entropy Oxide Microparticles.

High-entropy nanoparticles have received notable attention due to their tunable properties and broad material space. However, these nanoparticles are not suitable for certain applications (e.g., battery electrodes), where their microparticle (submicron to micron) counterparts are more preferred. Conventional methods used for synthesizing high-entropy nanoparticles often involve various ultrafast shock processes. To increase the size thereby achieving high-entropy microparticles, longer reaction time (e.g., heating duration) is usually used, which may also lead to undesired particle overgrowth or even densified microstructures. In this work, an approach based on Joule heating for synthesizing high-entropy oxide (HEO) microparticles with uniform elemental distribution is reported. In particular, two key synthesis conditions are identified to achieve high-quality HEO microparticles: 1) the precursors need to be loosely packed to avoid densification; 2) the heating time needs to be accurately controlled to tens of seconds instead of using milliseconds (thermal shock) that leads to nanoparticles or longer heating duration that forms bulk structures. The utility of the synthesized HEO microparticles for a range of applications, including high-performance Li-ion battery anode and water oxidation catalyst. This study opens up a new door toward synthesizing high-entropy microparticles with high quality and broad material space.