Systematic investigation of the material basis, effectiveness and safety of Thesium chinense Turcz. and its preparation Bairui Granules against lung inflammation.

BACKGROUND: Thesium chinense Turcz. (Named as Bai Rui Cao in Chinese) and its preparations (e.g., Bairui Granules) have been used to treat inflammatory diseases, such as acute mastitis, lobar pneumonia, tonsillitis, coronavirus disease 2019 (COVID-19), and upper respiratory tract infection. However, the material basis, pharmacological efficiency, and safety have not been illustrated. METHODS: Anti-inflammatory activity-guided isolation of constituents has been performed using multiple column chromatography, and their structures were elucidated by NMR spectroscopy and ECD calculations. The inhibitory effects on lung inflammation and safety of the crude ethanol extract (CE), Bairui Granules (BG), and the purified active constituents were evaluated using lipopolysaccharide (LPS)-stimulated acute lung inflammation (ALI) mice model or normal mice. RESULTS: Seven new compounds (1-7) and fifty-six known compounds (8-63) were isolated from T. chinense, and fifty-four were reported from this plant for the first time. The new flavonoid glycosides 1-2, new fatty acids 4-5, new alkaloid 7 as well as the known constituents including flavonoid aglycones 8-11, lignans 46-54, alkaloids 34 and 45, coumarins 57, phenylpropionic acids 27, and simple aromatic compounds 39, 44 and 58 exhibited anti-inflammatory activity. Network pharmacology analysis indicated that anti-inflammation of T. chinense was attributed to flavonoids and alkaloids by regulating inflammation-related proteins (e.g., TNF, NF-κB, TGF-ß). Furthermore, constituents of T. chinense including kaempferol-3-O-glucorhamnoside (KN, also named as Bairuisu I, 19), astragalin (AG, Bairuisu II, 12), and kaempferol (KF, Bairuisu III, 8), as well as CE and BG could alleviate lung inflammation caused by LPS in mice by preventing neutrophils infiltration and the expression of the genes for pro-inflammatory cytokines NLRP3, caspase-1, IL-1ß, and COX-2. After a 28-day subacute toxicity test, BG at doses of 4.875 g/kg and 9.750 g/kg (equivalent to onefold and twofold the clinically recommended dose) and CE at a dose of 11.138 g/kg (equivalent to fourfold the clinical dose of BG) were found to be safe and non-toxic. CONCLUSIONS: The discovery of sixty-three constituents comprehensively illustrated the material basis of T. chinense. T. chinense and Bairui Granules could alleviate lung inflammation by regulating inflammation-related proteins and no toxicity was observed under the twofold of clinically used doses.

Achieving Ultrahigh Electrocaloric Response in (Bi0.5Na0.5)TiO3-Based Ceramics through B-Site Defect Engineering.

Lead-free electrocaloric (EC) ferroelectrics are considered ideal for the next generation of environmentally friendly solid-state refrigeration materials. However, their inferior performance compared to lead-based materials significantly restricts their potential application. According to phase-field simulations, it is predicted that the pinning effect of a moderate number of defects can effectively enhance the reversible polarization response associated with the entropy change. Herein, sodium-bismuth titanate (BNT) ceramics with high spontaneous polarization are selected to construct B-site defects by introducing Li+ and Nb5+. Under an electric field of 6 kV mm-1, ultrahigh EC temperature changes of ΔTpos = 1.77 and ΔTneg = 1.49 K are achieved at 65 °C by direct measurement (ΔTneg > 1 K over 55-120 °C). Furthermore, ΔTneg remains above 0.70 K in the temperature range from 25 to 130 °C, exhibiting immense potential for practical applications. This study offers a promising direction for optimizing the EC response in defect systems.

Herb induced liver injury by Xianling Gubao Tablets: A case assessed for causality using updated RUCAM and integrated evidence chain.

Objective: A typical case of Xianling Gubao (XLGB) Tablets-induced liver injury was systematically studied in the clinic and the laboratory. Methods: A patient with herb-induced liver injury (HILI) and a history of taking XLGB Tablets before disease onset was engaged as the study subject, and the case was diagnosed according to the updated Roussel Uclaf Causality Assessment Method (RUCAM) and the integrated evidence chain (iEC) method recommended by the Guidelines for Diagnosis and Treatment of Herb-induced Liver Injury (HILI Guidelines). Results: Clinical history, biochemical indexes and imaging tests were used to exclude the influence of fundamental diseases and confusing liver diseases such as viral, alcoholic and autoimmune liver diseases on the diagnosis. Based on an investigation of the patient's medication history, she was suspected to have HILI caused by XLGB Tablets, as the patient was only taking an oral preparation of XLGB Tablets, and the influence of other drugs on the diagnosis was excluded. This patient with alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and a calculated R of 6 was diagnosed with possible acute drug-induced hepatocellular injury. The relationship was considered "highly probable" (score of 9) using the updated RUCAM of 2016. Moreover, the fingerprint similarity between the preparation taken by the patient and a commercially available preparation was 0.99, suggesting that the patient was consuming XLGB Tablets rather than another drug. LC-MS technology and the Agilent Fake TCM-Drugs database were used to investigate the drug, and no chemical additions were found. Examination of the drug for pesticide residues, heavy metals, aflatoxins and other exogenous substances indicated compliance with the content limits of the Chinese Pharmacopoeia. Conclusion: In summary, the final diagnosis of XLGB-induced liver injury reached the clinical diagnosis of HILI and was acute severe hepatocellular injury type by the updated RUCAM and iEC. Therefore, this study provides scientific evidence regarding the causality evaluation of compound preparations of traditional Chinese medicines-induced liver injury.

Detecting Visible to Near-Infrared II Light via CsPbBr3 Nanocrystals/Y6 Heterojunctions.

In the endeavor to develop advanced photodetectors (PDs) with superior performance, all-inorganic perovskites, recognized for their outstanding photoelectric properties, have emerged as highly promising materials. Due to their unique electronic structure and band characteristics, the majority of all-inorganic perovskite materials are not sensitive to near-infrared (NIR) light. Here, we demonstrate the fabrication of a high-performance broadband PD comprising CsPbBr3 perovskite NCs/Y6 planar heterojunctions. The incorporation of Y6 not only facilitates charge transfer from CsPbBr3 NCs to Y6 for enhancing photodetection performance under visible illumination but also broadens the absorption spectrum range of the whole device toward the NIR regime. As a result, the heterojunction PD exhibits a photo-to-dark-current ratio above 105, a dynamic range of 149.5 dB, and an impressive lowest detection limit of incident power density of 1.6 nW/cm2 under 505 nm illumination. In the NIR regime, where photon energy is below the bandgap of CsPbBr3, electron-hole pairs can still be produced in the Y6 layer even when illuminated at 1120 nm. Consequently, photodetection is uniquely possible in PDs that incorporate heterojunctions when the illumination wavelength is longer than 565 nm. At 850 nm, the heterojunction device is capable of detecting light with power densities as low as 1.3 µW/cm2 corresponding to a LDR of 99.8 dB. The exceptional performance is attributed to the creation of a heterojunction between CsPbBr3 NCs and Y6. These findings propose a novel approach for developing broadband PDs based on perovskite NC materials.

Comparative analysis of POD genes and their expression under multiple hormones in Pyrus bretschenedri.

BACKGROUND: Class III peroxidase (POD) enzymes play vital roles in plant development, hormone signaling, and stress responses. Despite extensive research on POD families in various plant species, the knowledge regarding the POD family in Chinese pear (Pyrus bretschenedri) is notably limited. RESULTS: We systematically characterized 113 POD family genes, designated as PbPOD1 to PbPOD113 based on their chromosomal locations. Phylogenetic analysis categorized these genes into seven distinct subfamilies (I to VII). The segmental duplication events were identified as a prevalent mechanism driving the expansion of the POD gene family. Microsynteny analysis, involving comparisons with Pyrus bretschenedri, Fragaria vesca, Prunus avium, Prunus mume and Prunus persica, highlighted the conservation of duplicated POD regions and their persistence through purifying selection during the evolutionary process. The expression patterns of PbPOD genes were performed across various plant organs and diverse fruit development stages using transcriptomic data. Furthermore, we identified stress-related cis-acting elements within the promoters of PbPOD genes, underscoring their involvement in hormonal and environmental stress responses. Notably, qRT-PCR analyses revealed distinctive expression patterns of PbPOD genes in response to melatonin (MEL), salicylic acid (SA), abscisic acid (ABA), and methyl jasmonate (MeJA), reflecting their responsiveness to abiotic stress and their role in fruit growth and development. CONCLUSIONS: In this study, we investigated the potential functions and evolutionary dynamics of PbPOD genes in Pyrus bretschenedri, positioning them as promising candidates for further research and valuable indicators for enhancing fruit quality through molecular breeding strategies.

Diastereo-divergent synthesis of chiral hindered ethers via a synergistic calcium(II)/gold(I) catalyzed cascade hydration/1,4-addition reaction.

Hindered ethers are ubiquitous in natural products and bioactive molecules. However, developing an efficient method for the stereocontrolled synthesis of all stereoisomers of chiral hindered ethers is highly desirable but challenging. Here we show a strategy that utilizes in situ-generated water as a nucleophile in an asymmetric cascade reaction involving two highly reactive intermediates, 3-furyl methyl cations and ortho-quinone methides (o-QMs), to synthesize chiral hindered ethers. The Ca(II)/Au(I) synergistic catalytic system enables the control of diastereoselectivity and enantioselectivity by selecting suitable chiral phosphine ligands in this cascade hydration/1,4-addition reaction, affording all four stereoisomers of a diverse range of chiral tetra-aryl substituted ethers with high diastereoselectivities (up to >20/1) and enantioselectivities (up to 95% ee). This work provides an example of chiral Ca(II)/Au(I) bimetallic catalytic system controlling two stereogenic centers via a cascade reaction in a single operation.

Brain Metastasis from EGFR-Mutated Non-Small Cell Lung Cancer: Secretion of IL11 from Astrocytes Up-Regulates PDL1 and Promotes Immune Escape.

Patients who have non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are more prone to brain metastasis (BM) and poor prognosis. Previous studies showed that the tumor microenvironment of BM in these patients is immunosuppressed, as indicated by reduced T-cell abundance and activity, although the mechanism of this immunosuppression requires further study. This study shows that reactive astrocytes play a critical role in promoting the immune escape of BM from EGFR-mutated NSCLC by increasing the apoptosis of CD8+ T lymphocytes. The increased secretion of interleukin 11(IL11) by astrocytes promotes the expression of PDL1 in BM, and this is responsible for the increased apoptosis of T lymphocytes. IL11 functions as a ligand of EGFR, and this binding activates EGFR and downstream signaling to increase the expression of PDL1, culminating in the immune escape of tumor cells. IL11 also promotes immune escape by binding to its intrinsic receptor (IL11Rα/glycoprotein 130 [gp130]). Additional in vivo studies show that the targeted inhibition of gp130 and EGFR suppresses the growth of BM and prolongs the survival time of mice. These results suggest a novel therapeutic strategy for treatment of NSCLC patients with EGFR mutations.

Genome-wide identification and expression analysis of TIFY genes under MeJA, cold and PEG-induced drought stress treatment in Dendrobium huoshanense.

The TIFY family consists of plant-specific genes that regulates multiple plant functions, including developmental and defense responses. Here, we performed a comprehensive genomic analysis of TIFY genes in Dendrobium huoshanense. Our analysis encompassed their phylogenetic relationships, gene structures, chromosomal distributions, promoter regions, and patterns of collinearity. A total of 16 DhTIFY genes were identified, and classified into distinct clusters named JAZ, PPD, ZIM, and TIFY based on their phylogenetic relationship. These DhTIFYs exhibited an uneven distribution across 7 chromosomes. The expansion of the DhTIFY gene family appears to have been significantly influenced by whole-genome and segmental duplication events. The ratio of non-synonymous to synonymous substitutions (Ka/Ks) implies that the purifying selection has been predominant, maintaining a constrained functional diversification after duplication events. Gene structure analysis indicated that DhTIFYs exhibited significant structural variation, particularly in terms of gene organization and intron numbers. Moreover, numerous cis-acting elements related to hormone signaling, developmental processes, and stress responses were identified within the promoter regions. Subsequently, qRT-PCR experiments demonstrated that the expression of DhTIFYs is modulated in response to MeJA (Methyl jasmonate), cold, and drought treatment. Collectively, these results enhance our understanding of the functional dynamics of TIFY genes in D. huoshanense and may pinpoint potential candidates for detailed examination of the biological roles of TIFY genes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01442-9.

Electric Double Layer Oriented Eutectic Additive Design towards Stable Zn Anodes with A High Depth of Discharge.

ZnSO4-based electrolytes for aqueous zinc ion batteries (AZIBs) fail to meet practical application metrics due to hydrogen evolution reaction (HER) and dendrite growth. In this work, we rationally designed a highly polarized eutectic additive, glycerophosphorylcholine (GPC), to regulate the EDL structure for stable Zn anodes with a high depth of discharge (DOD). On one hand, GPC molecules with abundant hydroxyl groups can precisely regulate the hydrogen bond network in EDL to suppress HER. On the other hand, the enrichment of GPC at the interface is positively responsible for the negative charge density on the Zn surface, which leads to the formation of a robust ZnxPyOz-rich solid-electrolyte interphase (SEI) and terminates dendrite growth in the charge-rich sites. This EDL-oriented eutectic additive engineering enables highly reversible and selectively (002)-textured Zn anodes to operate for over 1450 h at a high DOD of 45.3%. Meanwhile, a high-capacity (185.7 mAh g-1) aqueous Zn||VS2 full cell shows remarkable cycling stability over 220 cycles with an excellent capacity retention of 90.4% even at a low current density of 0.1 A g-1 (0.5 C). This work sheds light on electrolyte design and interface engineering for high-performance aqueous batteries. This article is protected by copyright. All rights reserved.

The Effect of Inhibiting the Wingless/Integrated (WNT) Signaling Pathway on the Early Embryonic Disc Cell Culture in Chickens.

The utilization of chicken embryonic-derived pluripotent stem cell (PSC) lines is crucial in various fields, including growth and development, vaccine and protein production, and germplasm resource protection. However, the research foundation for chicken PSCs is relatively weak, and there are still challenges in establishing a stable and efficient PSC culture system. Therefore, this study aims to investigate the effects of the FGF2/ERK and WNT/ß-catenin signaling pathways, as well as different feeder layers, on the derivation and maintenance of chicken embryonic-derived PSCs. The results of this study demonstrate that the use of STO cells as feeder layers, along with the addition of FGF2, IWR-1, and XAV-939 (FIX), allows for the efficient derivation of chicken PSC-like cells. Under the FIX culture conditions, chicken PSCs express key pluripotency genes, such as POUV, SOX2, and NANOG, as well as specific proteins SSEA-1, C-KIT, and SOX2, indicating their pluripotent nature. Additionally, the embryoid body experiment confirms that these PSC-like cells can differentiate into cells of three germ layers in vitro, highlighting their potential for multilineage differentiation. Furthermore, this study reveals that chicken Eyal-Giladi and Kochav stage X blastodermal cells express genes related to the primed state of PSCs, and the FIX culture system established in this research maintains the expression of these genes in vitro. These findings contribute significantly to the understanding and optimization of chicken PSC culture conditions and provide a foundation for further exploration of the biomedical research and biotechnological applications of chicken PSCs.

New Alkalescent Electrolyte Chemistry for Zinc-Ferricyanide Flow Battery.

Alkaline zinc-ferricyanide flow batteries are efficiency and economical as energy storage solutions. However, they suffer from low energy density and short calendar life. The strongly alkaline conditions (3 mol L-1 OH-) reduce the solubility of ferri/ferro-cyanide (normally only 0.4 mol L-1 at 25 oC) and induce the formation of zinc dendrites at the anode. Here, we report a new zinc-ferricyanide flow battery based on a mild alkalescent (pH 12) electrolyte. Using a chelating agent to rearrange ferri/ferro-cyanide ion-solvent interactions and improve salt dissociation, we increased the solubility of ferri/ferro-cyanide to 1.7 mol L-1 and prevented zinc dendrites. Our battery has an energy density of ~74 Wh L-1 at 60 oC and remains stable for 1800 cycles (1800 hours) at 0 oC and for >1400 cycles (2300 hours) at 25 oC. An alkalescent zinc-ferricyanide cell stack built using this alkalescent electrolyte stably delivers 608 W of power for ~40 days.

Unraveling a Stable 16-Ring Aluminophosphate DNL-11 through Three-Dimensional Electron Diffraction for Atmospheric Water Harvesting.

Sorption-based atmospheric water harvesting (AWH) is a promising solution for addressing water scarcity. Developing cost-effective and stable water adsorbents with high water uptake capacity and a low-temperature regeneration requirement is a crucially important procedure. In this Communication, we present a novel and stable aluminophosphate (AlPO) molecular sieve (MS) named DNL-11 with 16-ring channels synthesized by using an affordable and commercialized organic structure directing agent (OSDA), whose crystallographic structure is elucidated by three-dimensional electron diffraction (3D ED). DNL-11 exhibits a significant water uptake capacity (189 mg/g) at a very low vapor pressure (5% relative humidity at 30 °C). In addition, most of the adsorbed water can be effortlessly removed by purging N2 at 25 °C under ambient pressure conditions. This may expand the possibility of AWH under extreme drought conditions.

Glymphatic System Dysfunction Underlying Schizophrenia Is Associated With Cognitive Impairment.

BACKGROUND AND HYPOTHESIS: Despite the well-documented structural and functional brain changes in schizophrenia, the potential role of glymphatic dysfunction remains largely unexplored. This study investigates the glymphatic system's function in schizophrenia, utilizing diffusion tensor imaging (DTI) to analyze water diffusion along the perivascular space (ALPS), and examines its correlation with clinical symptoms. STUDY DESIGN: A cohort consisting of 43 people with schizophrenia and 108 healthy controls was examined. We quantified water diffusion metrics along the x-, y-, and z-axis in both projection and association fibers to derive the DTI-ALPS index, a proxy for glymphatic activity. The differences in the ALPS index between groups were analyzed using a 2-way ANCOVA controlling for age and sex, while partial correlations assessed the association between the ALPS index and clinical variables. STUDY RESULTS: People with schizophrenia showed a significantly reduced DTI-ALPS index across the whole brain and within both hemispheres (F = 9.001, P = .011; F = 10.024, P = .011; F = 5.927, P = .044; false discovery rate corrected), indicating potential glymphatic dysfunction in schizophrenia. The group by cognitive performance interaction effects on the ALPS index were not observed. Moreover, a lower ALPS index was associated with poorer cognitive performance on specific neuropsychological tests in people with schizophrenia. CONCLUSION: Our study highlights a lower ALPS index in schizophrenia, correlated with more pronounced cognitive impairments. This suggests that glymphatic dysfunction may contribute to the pathophysiology of schizophrenia, offering new insights into its underlying mechanisms.

Rationally Engineering pH Adaptation of Acid-Induced Arginine Decarboxylase from Escherichia coli to Alkaline Environments to Efficiently Biosynthesize Putrescine.

Acid-induced arginine decarboxylase AdiA is a typical homo-oligomeric protein biosynthesizing alkaline nylon monomer putrescine. However, upon loss of the AdiA decamer oligomeric state at neutral and alkaline conditions the activity also diminishes, obstructing the whole-cell biosynthesis of alkaline putrescine. Here, a structure cohesion strategy is proposed to change the pH adaptation of AdiA to alkaline environments based on the rational engineering of meridional and latitudinal oligomerization interfaces. After integrating substitutions of E467K at the latitudinal interface and H736E at the meridional channel interface, the structural stability of AdiA decamer and its substrate transport efficiency at neutral and alkaline conditions are improved. Finally, E467K_H736E is well adapted to neutral and alkaline environments (pH 7.0-9.0), and its enzymatic activity is 35-fold higher than that of wild AdiA at pH 8.0. Using E467K_H736E in the putrescine synthesis pathway, the titer of putrescine is up to 128.9 g·L-1 with a conversion of 0.94 mol·mol-1 in whole-cell catalysis. Additionally, the neutral pH adaptation of lysine decarboxylase, with a decamer structure similar to AdiA, is also improved using this cohesion strategy, providing an option for pH-adaptation engineering of other oligomeric decarboxylases.

Ethnic disparities in the prevalence of diabetes and its association with sleep disorder among older adults in rural southwest China.

OBJECTIVES: This study aimed to examine ethnic disparities in the prevalence of diabetes and its association with sleep disorders among the older adults Han and ethnic minority (Bai, Ha Ni, and Dai) population in rural southwest China. METHODS: A cross-sectional survey of 5,642 was conducted among the rural southwest population aged ≥60 years, consisting of a structured interview and measurement of fasting blood glucose, height, weight, and waist circumference. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. RESULTS: The overall prevalence of diabetes and sleep disorder was 10.2% and 40.1%, respectively. Bai participants had the highest prevalence of diabetes (15.9%) and obesity (9.9%)(P < 0.01), while Ha Ni participants had the lowest prevalence of diabetes (5.1%) and obesity (3.4%)(P < 0.01). The highest prevalence of sleep disorder (48.4%) was recorded in Bai participants, while Dai participants had the lowest prevalence of sleep disorder (25.6%)(P < 0.01). In all four studied ethnicities, females had a higher prevalence of sleep disorder than males (P < 0.01), and the prevalence of sleep disorder increased with age (P < 0.01). The results of multivariate logistic regression analysis indicated older adults with sleep disorder had a risk of developing diabetes (P < 0.05). Moreover, the higher educational level, family history of diabetes, and obesity were the main risk factors for diabetes in participants (P < 0.01). CONCLUSION: There are stark ethnic disparities in the prevalence of diabetes and sleep disorders in southwest China. Future diabetes prevention and control strategies should be tailored to address ethnicity, and improving sleep quality may reduce the prevalence of diabetes.

Correction: Combined use of principal component analysis/multiple linear regression analysis and artificial neural network to assess the impact of meteorological parameters on fluctuation of selected PM2.5-bound elements.

[This corrects the article DOI: 10.1371/journal.pone.0287187.].

High-Quality Solution-Processed Quasi-2D Perovskite for Low-Threshold Lasers.

Spin-coated quasi-two-dimensional halide perovskite films, which exhibit superior optoelectronic properties and environmental stability, have recently been extensively studied for lasers. Crystallinity is of great importance for the laser performance. Although some parameters related to the spin-coating process have been studied, the in-depth understanding and effective control of the acceleration rate on two-dimensional perovskite crystallization during spin-coating are still unknown. Here we investigate the effect of solvent evaporation on the microstructure of the final perovskite films during the spin-coating process. The crystallization quality of the film can be significantly improved by controlling solvent evaporation. As a result, the prepared quasi-2D perovskite film exhibits a stimulated emission threshold (pump: 343 nm, 6 kHz, 290 fs) of 550 nm as low as 16.2 µJ/cm2. Transient absorption characterization shows that the radiative biexciton recombination time is reduced from 738.5 to 438.3 ps, benefiting from the improved crystallinity. The faster biexciton recombination significantly enhanced the photoluminescence efficiency, which is critical for population inversion. This work could contribute to the development of low-threshold lasers.

In situ structural insights into the excitation-contraction coupling mechanism of skeletal muscle.

Excitation-contraction coupling (ECC) is a fundamental mechanism in control of skeletal muscle contraction and occurs at triad junctions, where dihydropyridine receptors (DHPRs) on transverse tubules sense excitation signals and then cause calcium release from the sarcoplasmic reticulum via coupling to type 1 ryanodine receptors (RyR1s), inducing the subsequent contraction of muscle filaments. However, the molecular mechanism remains unclear due to the lack of structural details. Here, we explored the architecture of triad junction by cryo-electron tomography, solved the in situ structure of RyR1 in complex with FKBP12 and calmodulin with the resolution of 16.7 Angstrom, and found the intact RyR1-DHPR supercomplex. RyR1s arrange into two rows on the terminal cisternae membrane by forming right-hand corner-to-corner contacts, and tetrads of DHPRs bind to RyR1s in an alternating manner, forming another two rows on the transverse tubule membrane. This unique arrangement is important for synergistic calcium release and provides direct evidence of physical coupling in ECC.

Multiscale reconfiguration induced highly saturated poling in lead-free piezoceramics for giant energy conversion.

The development of high-performance lead-free K0.5Na0.5NbO3-based piezoceramics for replacing commercial lead-containing counterparts is crucial for achieving environmentally sustainable society. Although the proposed new phase boundaries (NPB) can effectively improve the piezoelectricity of KNN-based ceramics, the difficulty of achieving saturated poling and the underlying multiscale structures resolution of their complex microstructures are urgent issues. Here, we employ a medium entropy strategy to design NPB and utilize texture engineering to induce crystal orientation. The developed K0.5Na0.5NbO3-based ceramics enjoys both prominent piezoelectric performance and satisfactory Curie temperature, thus exhibiting an ultrahigh energy harvesting performance as well as excellent transducer performance, which is highly competitive in both lead-free and lead-based piezoceramics. Comprehensive structural analysis have ascertained that the field-induced efficient multiscale polarization configurations irreversible transitions greatly encourages high saturated poling. This study demonstrates a strategy for designing high-performance piezoceramics and establishes a close correlation between the piezoelectricty and the underlying multiscale structures.

Flexibility of Binding Site is Essential to the Ca2+ Selectivity in EF-Hand Calcium-Binding Proteins.

High binding affinity and selectivity of metal ions are essential to the function of metalloproteins. Thus, understanding the factors that determine these binding characteristics is of major interest for both fundamental mechanistic investigations and guiding of the design of novel metalloproteins. In this work, we perform QM cluster model calculations and quantum mechanics/molecular mechanics (QM/MM) free energy simulations to understand the binding selectivity of Ca2+ and Mg2+ in the wild-type carp parvalbumin and its mutant. While a nonpolarizable MM model (CHARMM36) does not lead to the correct experimental trend, treatment of the metal binding site with the DFTB3 model in a QM/MM framework leads to relative binding free energies (ΔΔGbind) comparable with experimental data. For the wild-type (WT) protein, the calculated ΔΔGbind is ∼6.6 kcal/mol in comparison with the experimental value of 5.6 kcal/mol. The good agreement highlights the value of a QM description of the metal binding site and supports the role of electronic polarization and charge transfer to metal binding selectivity. For the D51A/E101D/F102W mutant, different binding site models lead to considerable variations in computed binding affinities. With a coordination number of seven for Ca2+, which is shown by QM/MM metadynamics simulations to be the dominant coordination number for the mutant, the calculated relative binding affinity is ∼4.8 kcal/mol, in fair agreement with the experimental value of 1.6 kcal/mol. The WT protein is observed to feature a flexible binding site that accommodates a range of coordination numbers for Ca2+, which is essential to the high binding selectivity for Ca2+ over Mg2+. In the mutant, the E101D mutation reduces the flexibility of the binding site and limits the dominant coordination number of Ca2+ to be seven, thereby leading to reduced binding selectivity against Mg2+. Our results highlight that the binding selectivity of metal ions depends on both the structural and dynamical properties of the protein binding site.