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Metalloenzymes catalyze a variety of reactions using a limited number of natural amino acids and metallocofactors. Therefore, the environment beyond the primary coordination sphere must play an important role in both conferring and tuning their phenomenal catalytic properties, enabling active sites with otherwise similar primary coordination environments to perform a diverse array of biological functions. However, since the interactions beyond the primary coordination sphere are numerous and weak, it has been difficult to pinpoint structural features responsible for the tuning of activities of native enzymes. Designing artificial metalloenzymes (ArMs) offers an excellent basis to elucidate the roles of these interactions and to further develop practical biological catalysts. In this review, we highlight how the secondary coordination spheres of ArMs influence metal binding and catalysis, with particular focus on the use of native protein scaffolds as templates for the design of ArMs by either rational design aided by computational modeling, directed evolution, or a combination of both approaches. In describing successes in designing heme, nonheme Fe, and Cu metalloenzymes, heteronuclear metalloenzymes containing heme, and those ArMs containing other metal centers (including those with non-native metal ions and metallocofactors), we have summarized insights gained on how careful controls of the interactions in the secondary coordination sphere, including hydrophobic and hydrogen bonding interactions, allow the generation and tuning of these respective systems to approach, rival, and, in a few cases, exceed those of native enzymes. We have also provided an outlook on the remaining challenges in the field and future directions that will allow for a deeper understanding of the secondary coordination sphere a deeper understanding of the secondary coordintion sphere to be gained, and in turn to guide the design of a broader and more efficient variety of ArMs.

Reducing health inequality and ensuring national health equity have become issues of great concern to all countries in the world. This paper based on the ordered Probit model and concentrated index decomposition method, analysed the influencing factors and evolution trend of health inequality among the elderly with high age in China from 2005 to 2017. The study found that in 2005-2017, the self-rated health distribution of the elderly with high age in China showed an obvious inverted "U" shape, with the proportion of general and relatively healthy being the largest, while the proportion of unhealthy and very healthy was lower. Lifestyle, family income, and age were the main important factors to expand health inequality. Therefore, encouraging the elderly with high age to develop good living habits and narrowing the income gap of the elderly are conducive to solving the health inequality of the elderly with high age and achieving the goals of active ageing and healthy ageing.

The aim of this study is to investigate the role of calcium-sensing receptor (CaSR) in the expression of inflammatory mediators of lipopolysaccharide (LPS)-treated human dental pulp cells (hDPCs). The expression profile of CaSR in LPS-simulated hDPCs was detected using immunofluorescence, real time quantitative PCR (RT-qPCR), and Western blot analyses. Then, its regulatory effects on the expression of specific inflammatory mediators such as interleukin (IL)-1β, IL-6, cyclooxygenase 2 (COX2)-derived prostaglandin E2 (PGE

Immune checkpoint blockade (ICB) therapy, represented by programmed cell death protein 1 (PD-1) and its ligand (PD-L1) monoclonal antibodies (mAbs), has shown an obvious benefit for melanoma immunotherapy, but the overall response rate is still low. To find an effective combination therapy strategy, we successfully produced small size silver nanoparticles coated with sucrose (S-AgNPs) as potent adjuvants. The antitumor effects of S-AgNPs were tested in vitro and comparatively investigated in immunodeficient and immunocompetent mice with melanoma. Fluorescence-activated cell sorting and immunofluorescent staining analysis were conducted to identify the tumor microenvironments. The expression of PD-L1 in tumors was tested by multiple methods. The combination therapy and potential toxicity of S-AgNPs and PD-1 mAbs were assessed in melanoma-bearing mice. In our findings, S-AgNPs presented potent antitumor effects, good druggability and low systemic toxicity. Functionally, we found that S-AgNPs exhibited better antitumor effects in immunocompetent mice. Mechanistically, we showed that S-AgNPs suppress tumor cell proliferation by inducing cellular apoptosis and promote cytotoxic CD8

Industrial funding eases the pressure on universities to raise research funding and actively contribute to university–industry (U–I) collaboration. However, whether industrial funding facilitates university technology transfer remains an open question, and we lack an understanding of the mechanisms that moderate this linkage. This study presents a framework and empirical analysis of the relationship between industrial funding and university technology transfer. Moreover, we examined the role of intellectual property rights (IPR) enforcement in moderating the focal relationship. We constructed a unique database by linking university- and province-level data, applying negative binomial regression analysis, finding that higher industrial funding has a positive effect on the promotion of U–I technology transfer. Furthermore, the results show that IPR enforcement significantly moderates the focal relationship. Our study highlights the role of industrial funding and offers implications for policymakers focusing on strengthening IPR enforcement in developing countries.

A series of quinoxaline-based compounds 1–4 have been synthesized by a palladium-catalyzed cross-coupling reaction and their photophysical properties have been extensively studied. Compounds 1–4 show deep blue light emission both in solution (λem ≤ 425 nm, Commission Internationale de L’Eclairage y (CIEy) ≤ 0.03) and in the solid state. Moreover, compounds 1–3 show a non-typical aggregation-induced enhanced emission (AIEE), which would be effective deep blue light-emitting materials. The DFT calculation indicated that the HOMO energy levels of compounds 1–3 are distributed throughout the molecule, and the LUMO energy levels are mainly concentrated on the quinoxaline group. However, the HOMO of compound 4 is mainly on the benzene ring at 2,3 position, and the LUMO is distributed both of the quinoxaline and the benzaldehyde group at the 6,7 position.

Ionic polymer-metal composites (IPMC), one of the most popular materials in the field of artificial muscle research, have attracted much attention because of their high flexibility, low drive voltage (10 V), high force density, large deformation, and so forth. However, the results show that the serious electrode fatigue crack and water loss of traditional IPMC greatly decrease its fatigue life and limit the practical application. In this study, we developed a novel liquid metal composite electrode. A layer of eutectic gallium-indium alloy (EGaIn) liquid metal was applied to the surface of the platinum electrode of the IPMC using a mask. Because of the good self-healing performance of the liquid metal, it is expected to solve the above problems of resistance increase and water loss caused by cracks. It turns out that the prepared EGaIn/Pt-IPMC exhibits a driving force up to 120 mN and maximum fatigue life of about 25,000 s at a driving voltage of 3 V. Compared with the best work reported, the fatigue strength of EGaIn/Pt-IPMC was increased by about 210%, and the maximum driving force of EGaIn/Pt-IPMC prepared by a single-layer basement membrane was between the IPMC prepared by 4-6 layer basement membrane. The electromechanical properties were significantly improved, and it is expected to realize a series of bionic applications.

As an indispensable part of wearable devices and mechanical arms, stretchable conductors have received extensive attention in recent years. The design of a high-dynamic-stability, stretchable conductor is the key technology to ensure the normal transmission of electrical signals and electrical energy of wearable devices under large mechanical deformation, which has always been an important research topic domestically and abroad. In this paper, a stretchable conductor with a linear bunch structure is designed and prepared by combining numerical modeling and simulation with 3D printing technology. The stretchable conductor consists of a 3D-printed bunch-structured equiwall elastic insulating resin tube and internally filled free-deformable liquid metal. This conductor has a very high conductivity exceeding 104 S cm−1, good stretchability with an elongation at break exceeding 50%, and great tensile stability, with a relative change in resistance of only about 1% at 50% tensile strain. Finally, this paper demonstrates it as a headphone cable (transmitting electrical signals) and a mobile phone charging wire (transmitting electrical energy), which proves its good mechanical and electrical properties and shows good application potential.

Aims This study aims to outline the ‘true’ natural history of ascending thoracic aortic aneurysm (ATAA) based on a cohort of patients not undergoing surgical intervention. Methods and results The outcomes, risk factors, and growth rates of 964 unoperated ATAA patients were investigated, over a median follow-up of 7.9 (maximum of 34) years. The primary endpoint was adverse aortic events (AAE), including dissection, rupture, and aortic death. At aortic sizes of 3.5–3.9, 4.0–4.4, 4.5–4.9, 5.0–5.4, 5.5–5.9, and ≥6.0 cm, the average yearly risk of AAE was 0.2%, 0.2%, 0.3%, 1.4%, 2.0%, and 3.5%, respectively (P < 0.001), and the 10-year survival free from AAE was 97.8%, 98.2%, 97.3%, 84.6%, 80.4%, and 70.9%, respectively (P < 0.001). The risk of AAE was relatively flat until 5 cm of aortic size, at which it began to increase rapidly (P for non-linearity Conclusion An aortic size of 5 cm, rather than 5.5 cm, may be a more appropriate intervention criterion for prophylactic ATAA repair. Aortic growth may not be an applicable indicator for intervention.

Combination therapy of zoledronic acid (ZOL) plus aromatase inhibitor (AI) was found to reduce bone metastasis risk and improve overall survival for treatment-naïve postmenopausal women (PMW) with hormone receptor–positive (HR+) early breast cancer (EBC), when compared with AI alone. The objective of this study was to evaluate the cost-effectiveness of adding ZOL to AI in treating PMW with HR+ EBC in China. A 5-state Markov model was constructed to evaluate the cost-effectiveness of adding ZOL to AI for PMW-EBC (HR+) over a lifetime horizon from the perspective of Chinese healthcare provider. Data used were obtained from previous reports and public data. The primary outcomes of this study were direct medical cost, life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed to examine the robustness of the presented model. Over a lifetime horizon, adding ZOL to AI was projected to yield a gain of 1.286 LYs and 1.099 QALYs compared with AI monotherapy, which yielded ICER $11 140.75 per QALY with an incremental cost of $12 247.36. The one-way sensitivity analysis indicated that the cost of ZOL was the most influential factor in our study. The probability that adding ZOL to AI was cost-effective at a threshold of $30 425 per QALY in China was 91.1%. ZOL is likely to be cost-effective in reducing bone metastasis risk and improving overall survival for PMW-EBC (HR+) in China.

Little is known about B-lymphoblastic leukemia (B-ALL) that lacks expression of terminal deoxynucleotidyl transferase (TdT). To address this, we performed the largest study to date of TdT-negative B-ALL using data from St. Jude Total XV and XVI clinical trials. Compared to TdT-positive B-ALL (n = 896), TdT-negative B-ALL (n = 21) was associated with younger age (median, 1.4 versus 6.8 years, P

Bacterial infections are often polymicrobial.Pseudomonas aeruginosaandStaphylococcus aureuscause chronic co-infections, which are more problematic than mono-species infections. We found that the production ofS. aureusmembrane-bound pigment staphyloxanthin (STX), was induced by theP. aeruginosaexoproduct, 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). The induction phenotype was conserved inP. aeruginosaandS. aureusclinical isolates examined. When subjected to hydrogen peroxide or human neutrophils,P. aeruginosasurvival was significantly higher when mixed with wild-type (WT)S. aureus, compared to a mutant deficient in STX production orP. aeruginosaalone. In a murine wound model, co-infection with WTS. aureus, but not the STX-deficient mutant, enhancedP. aeruginosaburden and disease compared to mono-infection. In conclusion, we discovered a novel role forP. aeruginosaHQNO mediating polymicrobial interactions withS. aureusby inducing STX production, which consequently promotes resistance of both pathogens to innate immune effectors. These results further our understanding of how different bacterial species cooperatively cause co-infections.

Wenhui Mai,1,2,&ast; Yiwei Liu,1,3,&ast; Qiaoyi Meng,1,3 Jianping Xu,1,4 Jinyan Wu1,3,5 1Center for Science Experiments, Hainan Medical University, Haikou, Hainan Province, People’s Republic of China; 2Laboratory Department, Haikou Maternal and Child Health Hospital, Haikou, Hainan Province, People’s Republic of China; 3Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan Province, People’s Republic of China; 4Department of Biology, McMaster University, Hamilton, Ontario, Canada; 5Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianping Xu; Jinyan Wu, Email jpxu@mcmaster.ca; hy0303003@hainmc.edu.cnPurpose: To investigate the bacterial species and antimicrobial susceptibility of respiratory specimens of children with pneumonia in Hainan, China.Methods: A total of 5017 specimens, including 4986 sputum samples, 19 bronchoalveolar lavage fluid samples and 12 tracheal tube tip samples from hospitalized children with pneumonia from April 1, 2021 to March 31, 2022 were studied. All the bacterial isolates were identified and confirmed with the VITEK 2 system. Antimicrobial susceptibility of all isolates was determined using the Kirby-Bauer method or the VITEK 2 Compact automatic system, following the breakpoints recommended by the Clinical and Laboratory Standards Institute.Results: A total of 996 bacterial isolates were collected and classified into 24 species. The top 10 most frequent species were Haemophilus influenzae (356 isolates, 35.7%), Streptococcus pneumoniae (128, 12.9%), Moraxella catarrhalis (114, 11.5%), Escherichia coli (89, 8.9%), Staphylococcus aureus (89, 8.9%), Klebsiella pneumoniae (82, 8.2%), Acinetobacter baumannii (31, 3.1%), Pseudomonas aeruginosa (28, 2.8%), Enterobacter cloacae (18, 1.8%), and Streptococcus agalactiae (13, 1.3%). 70.5% strains had the resistant (R) and/or intermediate (I) phenotypes to at least one of the tested drugs, with a large proportion (54.6%) showing resistance to two or more commonly used antibiotics. In addition, 60.5% (69/114) of M. catarrhalis strains and 42.9% (153/356) of H. influenzae strains produced β-lactamases while 19.1% (17/89) E. coli and 6.1% (5/82) K. pneumoniae strains produced extended-spectrum β-lactamases.Conclusion: A diversity of pathogenic bacteria were isolated from the respiratory tract of children with pneumonia in Hainan, China. High-frequency resistance to first-line antimicrobial drugs was observed in Gram-negative and Gram-positive bacteria, including 544 isolates resistant to at least two antibiotics. Rapid identification and susceptibility testing should be implemented for children with bacterial pneumonia in Hainan before drug treatment is recommended.Keywords: pneumonia, bacteria, antimicrobial resistance, children, multidrug-resistant bacteria

Mitophagy, which selectively eliminates the dysfunctional and excess mitochondria by autophagy, is crucial for cellular homeostasis under stresses such as hypoxia. Dysregulation of mitophagy has been increasingly linked to many disorders including neurodegenerative disease and cancer. Triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype, is reported to be characterized by hypoxia. However, the role of mitophagy in hypoxic TNBC as well as the underlying molecular mechanism is largely unexplored. Here, we identified GPCPD1 (glycerophosphocholine phosphodiesterase 1), a key enzyme in choline metabolism, as an essential mediator in hypoxia-induced mitophagy. Under the hypoxic condition, we found that GPCPD1 was depalmitoylated by LYPLA1, which facilitated the relocating of GPCPD1 to the outer mitochondrial membrane (OMM). Mitochondria-localized GPCPD1 could bind to VDAC1, the substrate for PRKN/PARKIN-dependent ubiquitination, thus interfering with the oligomerization of VDAC1. The increased monomer of VDAC1 provided more anchor sites to recruit PRKN-mediated polyubiquitination, which consequently triggered mitophagy. In addition, we found that GPCPD1-mediated mitophagy exerted a promotive effect on tumor growth and metastasis in TNBC both in vitro and in vivo. We further determined that GPCPD1 could serve as an independent prognostic indicator in TNBC. In conclusion, our study provides important insights into a mechanistic understanding of hypoxia-induced mitophagy and elucidates that GPCPD1 could act as a potential target for the future development of novel therapy for TNBC patients. Abbreviations: ACTB: actin beta; 5-aza: 5-azacytidine; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; ChIP: chromatin immunoprecipitation; co-IP: co-immunoprecipitation; CQ: chloroquine; CsA: cyclosporine; DOX: doxorubicin; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; GPCPD1: glycerophosphocholine phosphodiesterase 1; HAM: hydroxylamine; HIF1A: hypoxia inducible factor 1 subunit alpha; HRE: hypoxia response element; IF: immunofluorescence; LB: lysis buffer; LC3B/MAP1LC3B: microtubule associated protein 1 light chain 3 beta; LC-MS: liquid chromatography-mass spectrometry; LYPLA1: lysophospholipase 1; LYPLA2: lysophospholipase 2; MDA231: MDA-MB-231; MDA468: MDA-MB-468; MFN1: mitofusin 1; MFN2: mitofusin 2; MKI67: marker of proliferation Ki-67; OCR: oxygen consumption rate; OMM: outer mitochondrial membrane; OS: overall survival; PalmB: palmostatin B; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; SDS: sodium dodecyl sulfate; TOMM20: translocase of outer mitochondrial membrane 20; TNBC: triple-negative breast cancer; VBIT-4: VDAC inhibitor; VDAC1: voltage dependent anion channel 1; WT: wild type.

Gastric cancer is a malignant tumor, and its early diagnosis remains challenging due to the lack of simple and sensitive detection methods and specific biomarkers. In this work, to improve the detection reliability, we developed a dual-mode detection strategy for the detection of two biomarkers associated with it. First, an N- and S-doped carbon dots-N-rich porous carbon nanoenzyme (N/S-CDs@NC) was prepared by a two-step pyrolysis of thiourea-penetrated zinc-based zeolite imidazole framework. It was then combined with the 3,3',5,5'-tetramethylbenzidine-H

Kohn-Sham density functional theory is the most widely used method for electronic structure calculations of solid-state systems. The screened-exchange functionals developed following the influential work of Scuseria and co-workers in 2003-2006 have significantly improved the accuracy of the predictions of solid-state properties. This work assesses six screened-exchange density functionals for the prediction of 60 band gaps (database BG60) and 68 lattice constants (database LC68). The band gaps are calculated with both consistently calculated lattice constants and experimental lattice constants. Results for the nonlocal screened-exchange functionals are compared with those for six widely used or recently developed local functionals. The results show that all the screened-exchange functionals have smaller mean absolute errors (MAEs) than any of the local functionals. All the functionals except HLE17 overestimate (on average) the lattice constants, and M06-SX gives the best performance among the compared functionals, with a MAE of 0.051 Å. All the functionals underestimate (on average) the band gaps, and M06-SX outperforms all other functionals, with a MAE of 0.47 eV. M06-SX also has the lowest root-mean-squared error for both LC68 and BG60. For the subdatabases of BG60, M06-SX shows better performance for ionic crystals and systems with large band gaps, while HSE12s gives better results for semiconductors and systems with small band gaps. Overall, M06-SX shows the best performance for solid-state systems, followed by N12-SX and HSE12s. The best-performing local functionals are M06-L, revM06-L, and HLE17 for band gaps and M06-L and revM06-L for lattice constants. We found that M06-SX, revM06-L, and N12-SX not only are well optimized for a broad array of chemical properties but also have very good performance for the databases in this paper, making them well-suited for applications involving heterogeneous chemistry.

Drug-induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP-induced DILI. In this study, wolfberry promoted the proliferation of activated-A. muciniphila in vitro and in vivo. For the first time, we detected that the activated-A. muciniphila but not the killed-A. muciniphila increased the expression level of Yes-associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP-induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP-induced DILI mice, which promoted the recovery of APAP-induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.