Bimetal Oxides Anchored on Carbon Nanotubes/Nanosheets as High-Efficiency and Durable Bifunctional Oxygen Catalyst for Advanced Zn-Air Battery: Experiments and DFT Calculations.

To meet increasing requirement for innovative energy storage and conversion technology, it is urgent to prepare effective, affordable, and long-term stable oxygen electrocatalysts to replace precious metal-based counterparts. Herein, a two-step pyrolysis strategy is developed for controlled synthesis of Fe2O3 and Mn3O4 anchored on carbon nanotubes/nanosheets (Fe2O3-Mn3O4-CNTs/NSs). The typical catalyst has a high half-wave potential (E1/2 = 0.87 V) for oxygen reduction reaction (ORR), accompanied with a smaller overpotential (η10 = 290 mV) for oxygen evolution reaction (OER), showing substantial improvement in the ORR and OER performances. As well, density functional theory calculations are performed to illustrate the catalytic mechanism, where the in situ generated Fe2O3 directly correlates to the reduced energy barrier, rather than Mn3O4. The Fe2O3-Mn3O4-CNTs/NSs-based Zn-air battery exhibits a high-power density (153 mW cm-2) and satisfyingly long durability (1650 charge/discharge cycles/550 h). This work provides a new reference for preparation of highly reversible oxygen conversion catalysts.

Lignan glucosides from Gentiana macrophylla with potential anti-arthritis and hepatoprotective activities.

Ten lignans, including six previously undescribed phenolic ester glycosyl lignans (1-6), were isolated from a well-known traditional Chinese medicine, Qin-Jiao, which is the dry root of Gentiana macrophylla Pall. (Gentianaceae). Their structures were determined by spectroscopic and chemical methods, especially 2D NMR techniques. Quantum chemical calculations of theoretical ECD spectra allowed the determination of their absolute configurations. Refer to its traditional applications for the treatment of rheumatic arthralgia and hepatopathy, these compounds were evaluated on a TNF-α induced MH7A human synoviocyte inflammation model and a D-GalN induced AML12 hepatocyte injury model. Compounds 1, 2, 5, and 6 significantly reduced the release of proinflammatory cytokine IL-1ß in MH7A cells at 15 µM and they also could strongly protect AML12 cells against D-GalN injury at 30 µM. Flow cytometry and Western blot analysis showed that compound 5 ameliorated D-GalN induced AML12 cell apoptosis by upregulating the expression of anti-apoptotic Bcl-2 protein and down-regulating the expression of pro-apoptotic Bax protein.

Can the Blended Application of Controlled-Release and Common Urea Effectively Replace the Common Urea in a Wheat-Maize Rotation System? A Case Study Based on a Long-Term Experiment.

The one-time application of blended urea (BU), combining controlled-release urea (CRU) and uncoated urea, has proven to be a promising nitrogen (N) management strategy. However, the long-term sustainability of blending urea remains largely unexplored. To assess whether a single application of blended urea could effectively replace split uncoated urea applications, a long-term field experiment was conducted in the North China Plain (NCP). The results indicated that, when compared to common urea (CU) at the optimal N rate (180 kg N ha-1), BU achieved comparable grain yields, N uptake and NUE (61% vs. 62). BU exhibited a 12% higher 0-20 cm soil organic nitrogen stock and a 9% higher soil organic carbon (C) stock. Additionally, BU reduced life-cycle reactive N (Nr) losses and the N footprint by 10%, and lowered greenhouse gas (GHG) emissions and the C footprint by 7%. From an economic analysis perspective, BU demonstrated comparable private profitability and a 3% greater ecosystem economic benefit. Therefore, BU under the optimal N rate has the potential to substitute split applications of common urea in the long-term and can be regarded as a sustainable N management strategy for wheat and maize production in the NCP.

Structure of a fungal 1,3-ß-glucan synthase.

1,3-ß-Glucan serves as the primary component of the fungal cell wall and is produced by 1,3-ß-glucan synthase located in the plasma membrane. This synthase is a molecular target for antifungal drugs such as echinocandins and the triterpenoid ibrexafungerp. In this study, we present the cryo-electron microscopy structure of Saccharomyces cerevisiae 1,3-ß-glucan synthase (Fks1) at 2.47-Å resolution. The structure reveals a central catalytic region adopting a cellulose synthase fold with a cytosolic conserved GT-A-type glycosyltransferase domain and a closed transmembrane channel responsible for glucan transportation. Two extracellular disulfide bonds are found to be crucial for Fks1 enzymatic activity. Through structural comparative analysis with cellulose synthases and structure-guided mutagenesis studies, we gain previously unknown insights into the molecular mechanisms of fungal 1,3-ß-glucan synthase.

Structure, catalysis, chitin transport, and selective inhibition of chitin synthase.

Chitin is one of the most abundant natural biopolymers and serves as a critical structural component of extracellular matrices, including fungal cell walls and insect exoskeletons. As a linear polymer of ß-(1,4)-linked N-acetylglucosamine, chitin is synthesized by chitin synthases, which are recognized as targets for antifungal and anti-insect drugs. In this study, we determine seven different cryo-electron microscopy structures of a Saccharomyces cerevisiae chitin synthase in the absence and presence of glycosyl donor, acceptor, product, or peptidyl nucleoside inhibitors. Combined with functional analyses, these structures show how the donor and acceptor substrates bind in the active site, how substrate hydrolysis drives self-priming, how a chitin-conducting transmembrane channel opens, and how peptidyl nucleoside inhibitors inhibit chitin synthase. Our work provides a structural basis for understanding the function and inhibition of chitin synthase.

Optimizing Agronomic, Environmental, Health and Economic Performances in Summer Maize Production through Fertilizer Nitrogen Management Strategies.

Although nitrogen (N) fertilizer application plays an essential role in improving crop productivity, an inappropriate management can result in negative impacts on environment and human health. To break this dilemma, a 12-year field experiment (2008-2019) with five N application rates was conducted on the North China Plain (NCP) to evaluate the integrated impacts of optimizing N management (Opt. N, 160 kg N ha-1 on average) on agronomic, environmental, health, and economic performances of summer maize production. Over the 12-year study, the Opt. N treatment achieved the maximal average grain yield (10.6 Mg ha-1) and grain protein yield (793 kg ha-1) among five N treatments. The life cycle assessment methodology was applied to determine the negative impacts on environmental and human health, and both of them increased with the N rate. Compared with the farmers' conventional N rate (250 kg N ha-1), the Opt. N treatment reduced acidification, eutrophication, global warming, and energy depletion potentials by 29%, 42%, 35%, and 18%, respectively, and reduced the health impact by 32% per Mg of grain yield or grain protein yield produced. Both the Opt. N and Opt. N*50-70% treatments resulted in high private profitability (2038 USD ha-1), ecosystem economic benefit (1811 USD ha-1), and integrated compensation benefit (17,548 USD ha-1). This study demonstrates the potential benefits of long-term optimizing of N management to maintain high maize yields and grain quality, to reduce various environmental impacts and health impacts, and to enhance economic benefits. These benefits can be further enhanced when Opt. N was combined with advanced agronomic management practices. The results also suggest that reducing the optimal N rate from 160 to 145 kg N ha-1 is achievable to further reduce the negative impacts while maintaining high crop productivity. In conclusion, optimizing the N management is essential to promote sustainable summer maize production on the NCP.

Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase.

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.

[Countertraction method for reduction of irreducible subcoracoid dislocation of the shoulder joint with Hill-Sacks lesion].

OBJECTIVE: To investigate clinical outcomes of countertraction method in treating irreducible subcoracoid dislocation of shoulder joint combined with Hill-Sacks injury. METHODS: A total of 56 patients with irreducible subcoracoid dislocation of the shoulder joint combined with Hill-Sacks injury admitted from December 2013 to June 2020 were retrospectively analyzed. Under the anesthesia of shoulder joint cavity injection, the reduction was performed by using anti-traction method (experimental group) and traditional Hippocrates method (control group), 28 cases in each group. There were 11 males and 17 females in experimental group, with an average age of (61.95±19.32) years old, 9 cases on the left side, and 19 cases on the right side. Twelve males and 16 females in control group, with an average age of (63.13±12.75) years old, 11 cases on the left side, 17 cases on the right side. The curative effects between two groups were evaluated before and after operation, including the success rate of reduction, the duration of reduction, the distance from successful reduction to injury, complications and functional rehabilitation(Constant score of shoulder joint). RESULTS: The success rates of reduction in experimental group and control group were 92.86%(26/28) and 67.86% (19/28), respectively, and the difference was statistically significant (P<0.05). The duration of simple reduction was (4.25±2.13) min and ( 6.31±1.69) min, the difference was statistically significant (P<0.05);the time from successful reduction to injury was (9.16±0.94) h and (8.94±1.31) h, respectively, with no significant difference(P>0.05). There were no complications such as vascular nerve injury and fracture in experimental group, 2 cases of axillary nerve injury and 1 case of humeral head fracture in control group. Constant scores of shoulder joint between experimental group and control group were (92.34±5.62) points and (90.91±4.73) points, respectively, with no significant difference (P>0.05). CONCLUSION: For patients with irreducible subcoracoid dislocation of the shoulder joint with Hill-Sacks injury, the countertraction method under anesthesia of the shoulder joint cavity achieved a higher success rate and few complications.

Knockdown of heat shock transcription factor 1 decreases temperature stress tolerance in Bemisia tabaci MED.

The primary function of heat shock transcription factor (HSF) in the heat shock response is to activate the transcription of genes encoding heat shock proteins (HSPs). The phloem-feeding insect Bemisia tabaci (Gennadius) is an important pest of cotton, vegetables and ornamentals that transmits several plant viruses and causes enormous agricultural losses. In this study, the gene encoding HSF (Bthsf1) was characterized in MED B. tabaci. The full-length cDNA encoded a protein of 652 amino acids with an isoelectric point of 5.55. The BtHSF1 deduced amino acid sequence showed strong similarity to HSF in other insects. Expression analyses using quantitative real-time PCR indicated that Bthsf1 was significantly up-regulated in B. tabaci adults and pupae during thermal stress. Although Bthsf1 was induced by both hot and cold stress, the amplitude of expression was greater in the former. Bthsf1 had distinct, significant differences in expression pattern during different duration of high but not low temperature stress. Oral ingestion of dsBthsf1 repressed the expression of Bthsf1 and four heat shock proteins (Bthsp90, Bthsp70-3, Bthsp20 and Bthsp19.5) in MED B. tabaci during hot and cold stress. In conclusion, our results show that Bthsf1 is differentially expressed during high and low temperature stress and regulates the transcription of multiple hsps in MED B. tabaci.

Atomic resolution Cryo-EM structure of human proteasome activator PA28γ.

The PA28 family proteasome activators play important roles in regulating proteasome activities. Though the three paralogs (PA28α, PA28ß, and PA28γ) are similar in terms of primary sequence, they show significant differences in expression pattern, cellular localization and most importantly, biological functions. While PA28αß is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28γ is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. However, why this paralog has the unique function remains elusive. Previous structural studies have mainly focused on mammalian PA28α, PA28ß and PA28αß heptamers, while structural studies on mammalian PA28γ of atomic resolution are still absent to date. In the present work, we determined the Cryo-EM structure of the human PA28γ heptamer at atomic resolution, revealing interesting unique structural features that may hint our understanding the functional mechanisms of this proteasome activator.

Six pairs of enantiomeric phthalide dimers from the rhizomes of Ligusticum chuanxiong and their absolute configurations and anti-inflammatory activities.

Six pairs of enantiomeric phthalide dimers (1-6) were isolated from the rhizomes of Ligusticum chuanxiong. Their structures and absolute configurations were elucidated by NMR spectroscopy, X-ray diffraction analyses, and electronic circular dichroism calculations. Compounds (+)-1 and (-)-1 are new phthalide dimers, featuring two classes of monomeric units (a phthalide and an unusual 2,3-seco-phthalide) with an uncommon linkage (3,6'/8,3'a). Compounds (+)-2 and (-)-3 are also novel phthalide dimers that had not been reported previously. Although (-)-2 and (+)-3 have been successfully isolated in previous studies, their absolute configurations were not unambiguously determined. As for compound 4, it was reported as a racemate in one study, and one of its enantiomers was identified in a subsequent study. Herein, all enantiomeric phthalide dimers were successfully separated, and their absolute configurations were determined. The inhibitory effects of all isolates against lipopolysaccharide-induced nitric oxide production were tested using RAW264.7 cells. The results show that compounds (+)-2, (-)-2, (+)-3, (-)-3, (+)-4, (-)-4, (+)-5, (+)-6, and (-)-6 have inhibitory activities, with compound (+)-5 being the most active (IC50 value of 4.3 ± 1.3 µM).

Antiproliferative and Proapoptotic Effects of Phenanthrene Derivatives Isolated from Bletilla striata on A549 Lung Cancer Cells.

Lung cancer continues to be the world's leading cause of cancer death and the treatment of non-small cell lung cancer (NSCLC) has attracted much attention. The tubers of Bletilla striata are regarded as "an excellent medicine for lung diseases" and as the first choice to treat several lung diseases. In this study, seventeen phenanthrene derivatives, including two new compounds (1 and 2), were isolated from the tubers of B. striata. Most compounds showed cytotoxicity against A549 cells. An EdU proliferation assay, a cell cycle assay, a wound healing assay, a transwell migration assay, a flow cytometry assay, and a western blot assay were performed to further investigate the effect of compound 1 on A549 cells. The results showed that compound 1 inhibited cell proliferation and migration and promoted cell apoptosis in A549 cells. The mechanisms might correlate with the regulation of the Akt, MEK/ERK, and Bcl-2/Bax signaling pathways. These results suggested that the phenanthrenes of B. striata might be important and effective substances in the treatment of NSCLC.

Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity.

Hypoxia contributes to airway inflammation and remodeling in several lung diseases; however, exactly how hypoxic pulmonary epithelium regulates allergic inflammation remains to be fully characterized. Here, we report that conditional deletion of the E3 ubiquitin ligase VHL in lung epithelial cells resulted in exacerbated type 2 responses accompanied by selective increase of group 2 innate lymphoid cells (ILC2s) at steady state and following inflammation or helminth infection. Ablation of expression of the hypoxia-inducible factor 2α (HIF2α) significantly reversed VHL-mediated ILC2 activation. VHL deficiency in lung epithelial cells caused increased expression of the peptide hormone adrenomedullin (ADM), and our data suggest that HIF2α controls Adm expression. ADM directly promoted ILC2 activation both in vitro and in vivo. Our findings indicate that the hypoxic response mediated by the VHL-HIF2α axis is critical for control of pulmonary type 2 responses by increasing ADM expression in lung epithelia, causing ILC2 activation.

Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFRT790M/C797S Mutants.

A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFRT790M/C797S inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFRL858R/T790M/C797S and EGFR19Del/T790M/C797S kinases with IC50 values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. 18k also demonstrated promising EGFRT790M/C797S mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFRT790M/C797S with a close derivative 18f was solved to provide insight on the inhibitor's binding mode. Moreover, compound 18k was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.

The oblique triangle configuration of three parallel screws for femoral neck fracture fixation using computer-aided design modules.

Closed reduction and internal fixation with three cannulated compression screws is a common method for treating femoral neck fractures in young and middle-aged patients. Protocols including the inverted triangle configuration and dispersion of the screws still needed further supports. The purpose of this study was to explore a novel oblique triangle configuration (OTC) of three screws in fixing femoral neck fractures based on the morphology of the femoral neck isthmus (FNI). The computer-aided design modules were used to explore the ideal spatial configuration with largest triangle by three parallel screws. A univariate evaluation model was established based on the oval-like cross-section of the FNI. When the three screws were positioned by the OTC, Inverted Equilateral Triangle Configuration (IETC), and the Maximum Area Inverted Isosceles Triangle Configuration (MA-IITC) respectively, the proportion of area and circumference in the cross-section of FNI and the changing trend of proportion were compared under various torsion angles, eccentricity, and cross-sectional area of FNI. The area and circumference ratios of the parallel screws using the OTC method were significantly higher than in the IETC and MA-IITC groups. In the univariate evaluation model, the OTC area ratio and circumference ratio remained stable under the different femoral neck torsion angles, FNI cross-sectional area, and eccentricity. The OTC method provided an ideal spatial configuration for the FNA fixation with the largest area using three parallel screws. The position of the posterior screw was also away from the metaphyseal artery, potentially reducing the possibility of vascular injury and screw penetrating.

Comparison of oblique triangular configuration and inverted equilateral triangular configuration of three cannulated screws in treating unstable femoral neck fracture: A finite element analysis.

BACKGROUND: The cross-sectional area of three parallel screws might affect the stability of the internal fixation of femoral neck fractures. The screws fixed in the oblique-triangle configuration (OTC) were assumed to have a larger cross-sectional area, but the biomechanical stability has not yet been validated. In this study, finite element analyses were performed to compare the biomechanical properties of the internal fixation fixed by the OTC and the traditional Inverted Equilateral Triangle Configuration (IETC). METHOD: Pauwels type III fracture was established on the three-dimensional femoral model and three cannulated screws with the OTC and traditional IETC methods were applied. The oblique-triangle configuration with the largest area inscribed the femoral neck isthmus by the three screws was determined, the area and circumference of the cross-section formed by the OTC and IETC model were compared. Stress, strain, and displacement peaks of the two configuration models under different loads were compared. Twelve pairs of nodes on the fracture ends were selected and the displacement of the fracture ends was evaluated through the displacement between these nodes. RESULTS: The area and circumference of the cross-section formed by the OTC were larger than those in the IETC model. The degree of stress dispersion around the screw holes in the OTC model was better than that of the IETC, but the stress distribution order of the three screws in the two models was consistent. The maximum stress, strain, displacement, and displacement of the fracture end in the OTC model were smaller than those in the IETC model. The stress, strain, displacement, and fracture end displacement peaks of the two fixed models gradually increase with the increase of loads. CONCLUSION: The oblique-triangle configuration showed superior mechanical properties than the IETC in finite element analyses. This study suggests that when three screws are fixed in parallel method, the larger the cross-sectional area of the screw configuration, the better stability of the internal fixation might be obtained. Furthermore, the biomechanical properties of various spatial configurations and screw holes of the three parallel screws need to be considered before clinical practice.

A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC.

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU-MP-5 as a new-generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU-MP-5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild-type or mutant EML4-ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU-MP-5. In addition, XMU-MP-5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU-MP-5 as a novel selective ALK inhibitor with high potency and selectivity. XMU-MP-5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.

Isolation of two new genes encoding heat shock protein 70 in Bemisia tabaci and analysis during thermal stress.

The heat shock protein 70 family (HSP70) is among the most varied HSP family with respect to structure and function. The phloem-feeding insect Bemisia tabaci (Gennadius) is an important pest of cotton, vegetables and ornamentals that transmits several plant viruses and causes enormous agricultural losses. In this study, two new HSP70 genes (Bthsp70-2 and Bthsp70-3) were isolated from the MED cryptic species B. tabaci, an important phloem-feeding pest of vegetables and ornamentals. Bthsp70-2 and Bthsp70-3 encoded proteins comprised of 652 and 676 amino acids, and the deduced proteins were closely related to other HSP70s in Hemiptera. Expression analyses using real-time quantitative PCR indicated that Bthsp70-2 and Bthsp70-3 were induced in B. tabaci pupae and adults during high and low thermal stress. Bthsp70-2 and Bthsp70-3 exhibited similar, but not identical, expression patterns when exposed to different durations of high temperature stress. Oral ingestion of dsBthsp70 reduced the expression level of Bthsp70-2 and Bthsp70-3 in B. tabaci and increased the mortality of B. tabaci during heat shock. In conclusion, Bthsp70-2 and Bthsp70-3 exhibit different expression patterns during thermal stress, thus expanding the roles of HSPs in B. tabaci.

Protocol for in vivo and ex vivo assessments of glucose-stimulated insulin secretion in mouse islet ß cells.

Pancreatic islet ß cells secrete insulin in a biphasic manner when sensing high blood glucose level. This protocol describes the evaluation of different phases of insulin secretion, as well as basal, glucose-stimulated and total insulin secretion abilities, thereby enabling precise assessment of ß cell function both in vivo and ex vivo. The in vivo assay consists of intravenous tube imbedding surgery and hyperglycemic clamp. The ex vivo assay consists of islet isolation, dynamic perfusion and static immersion. For complete details on the use and execution of this protocol, please refer to Sun et al. (2021).