FBXO6 regulates the antiviral immune responses via mediating alveolar macrophages survival.

Inducing early apoptosis in alveolar macrophages is one of the strategies influenza A virus (IAV) evolved to subvert host immunity. Correspondingly, the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 is reported to interact with virus polymerase basic protein 1-frame 2 (PB1-F2) accessory protein to counteract virus-induced apoptosis. Herein, we report that one of the F-box proteins, FBXO6, promotes proteasomal degradation of NLRX1, and thus facilitates IAV-induced alveolar macrophages apoptosis and modulates both macrophage survival and type I interferon (IFN) signaling. We observed that FBXO6-deficient mice infected with IAV exhibited decreased pulmonary viral replication, alleviated inflammatory-associated pulmonary dysfunction, and less mortality. Analysis of the lungs of IAV-infected mice revealed markedly reduced leukocyte recruitment but enhanced production of type I IFN in Fbxo6-/- mice. Furthermore, increased type I IFN production and decreased viral replication were recapitulated in FBXO6 knockdown macrophages and associated with reduced apoptosis. Through gain- and loss-of-function studies, we found lung resident macrophages but not bone marrow-derived macrophages play a key role in the differences FBXO6 signaling pathway brings in the antiviral immune response. In further investigation, we identified that FBXO6 interacted with and promoted the proteasomal degradation of NLRX1. Together, our results demonstrate that FBXO6 negatively regulates immunity against IAV infection by enhancing the degradation of NLRX1 and thus impairs the survival of alveolar macrophages and antiviral immunity of the host.

Neutrophil membrane-coated nanoparticles for enhanced nanosecond pulsed electric field treatment of pancreatic cancer.

OBJECTIVE: Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Poor prognosis and low survival rates have driven the development of novel therapeutic strategies. Nanosecond pulsed electric field has emerged as a novel, minimal invasive and non-thermal treatment for solid tumors. It is of great significance to study the combination therapy of nsPEF and other treatment strategies for pancreatic cancer. METHODS: We developed neutrophil membrane-wrapped liposomal nanoparticles loaded with gemcitabine (NE/Lip-GEM) and investigated their use as a complementary agent for nsPEF treatment. RESULTS: Our results showed that neutrophil-mediated delivery of liposomal-gemcitabine (NE/Lip-GEM) efficiently inhibited the growth of pancreatic tumors in mice whose has been treated with incomplete nsPEF ablation. CONCLUSIONS: The combination of nsPEF and NE/Lip-GEM may be a promising synergistic strategy for pancreatic cancer therapy.

Promoting Electrocatalytic Oxygen Reactions Using Advanced Heterostructures for Rechargeable Zinc-Air Battery Applications.

In order to facilitate electrochemical oxygen reactions in electrically rechargeable zinc-air batteries (ZABs), there is a need to develop innovative approaches for efficient oxygen electrocatalysts. Due to their reliability, high energy density, material abundance, and ecofriendliness, rechargeable ZABs hold promise as next-generation energy storage and conversion devices. However, the large-scale application of ZABs is currently hindered by the slow kinetics of the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER). However, the development of heterostructure-based electrocatalysts has the potential to surpass the limitations imposed by the intrinsic properties of a single material. This Account begins with an explanation of the configurations of ZABs and the fundamentals of the oxygen electrochemistry of the air electrode. Then, we summarize recent progress with respect to the variety of heterostructures that exploit bifunctional electrocatalytic reactions and overview their impact on ZAB performance. The range of heterointerfacial engineering strategies for improving the ORR/OER and ZAB performance includes tailoring the surface chemistry, dimensionality of catalysts, interfacial charge transfer, mass and charge transport, and morphology. We highlight the multicomponent design approaches that take these features into account to create advanced highly active bifunctional catalysts. Finally, we discuss the challenges and future perspectives on this important topic that aim to enhance the bifunctional activity and performance of zinc-air batteries.

Real-world effectiveness of molnupiravir, azvudine and paxlovid against mortality and viral clearance among hospitalized patients with COVID-19 infection during the omicron wave in China: A retrospective cohort study.

OBJECTIVES: In this retrospective cohort study, we aimed to assess clinical effectiveness and viral clearance following the use of molnupiravir, azvudine and paxlovid in hospitalized patients with COVID-19 in China dominated by the omicron BA.5.2 and BF.7 subvariant of SARS-CoV-2. METHODS: Enrolled patients were assigned to the molnupiravir group or the azvudine group or the paxlovid group or the control group (not taking any antiviral drugs). The primary outcome of the cohort study was viral clearance and viral burden rebound after treatment and the secondary outcome was 28-day all-cause mortality. The four groups were propensity score-matched (1:1). We plotted viral load trends for each antiviral drug intervention using locally weighted regression (LOWESS) smoothed data. Multivariate logistic regression (stepwise algorithm) models were used to determine any risk factors for 28-day mortality. RESULTS: Of the 1537 patients receiving any treatment, 886 (57.6 %) received molnupiravir, 390 (25.4 %) received azvudine, 94 (6.1 %) received paxlovid, and 167 (10.9 %) did not use any antiviral drugs. Our data analysis showed that age (OR = 1.05, 95 % CI: 1.03-1.07, P < 0.001), Charlson comorbidty index (OR = 1.32, 95 % CI: 1.18-1.48, P < 0.001), severity of COVID-19 (P < 0.001), gamma globulin (OR = 2.04, 95 % CI: 1.03-3.99, P = 0.039) and corticosteroids use (OR = 2.3, 95 % CI: 1.19-4.69, P = 0.017) were independent prognostic factors for 28-day mortality in COVID-19 patients. After propensity score matching (PSM), the paxlovid recipients (OR = 0.22, 95 % CI: 0.05-0.83, P = 0.036) or azvudine recipients (OR = 0.27, 95 % CI: 0.07-0.91, P = 0.046) had lower 28-day mortality compared to their matched controls. Viral rebound occurred in the control group around days 9-16, while no viral rebound was found in any of the three oral antiviral groups. We found that molnupiravir group performed comparably in terms of the rate of nucleic acid conversion negative compared with the paxlovid group, while azvudine group performed slightly worse compared with the paxlovid group or molnupiravir group. CONCLUSIONS: In our retrospective cohort of hospitalized patients with COVID-19 during the wave of omicron strain, the molnupiravir, paxlovid and azvudine recipients showed a faster and more stable decrease in viral load and rare virus rebound in response to antiviral treatments when compared to the controls. The study supported that initiation treatment with paxlovid and azvudine was associated with significantly lower risk of all-cause death within 28 days.

Inflammatory Microenvironment-Responsive Hydrogels Enclosed with Quorum Sensing Inhibitor for Treating Post-Traumatic Osteomyelitis.

Non-antibiotic strategies are desperately needed to treat post-traumatic osteomyelitis (PTO) due to the emergence of superbugs, complex inflammatory microenvironments, and greatly enriched biofilms. Previously, growing evidence indicated that quorum sensing (QS), a chemical communication signal among bacterial cells, can accelerate resistance under evolutionary pressure. This study aims to develop a medical dressing to treat PTO by inhibiting QS and regulating the inflammatory microenvironment, which includes severe oxidative stress and acid abscesses, through a reactive oxygen species (ROS)-responsive bond between N1- (4-borobenzoyl)-N3-(4-borobenzoyl)-the N1, the N1, N3, N3-tetramethylpropane-1,3-diamine (TSPBA) and polyvinyl alcohol (PVA), and the amino side chain of hyperbranched polylysine (HBPL). Physically enclosed QS inhibitors subsequently exerted the antibacterial effects. This hydrogel can scavenge hydrogen peroxide (H2O2), superoxide anion free radical (·O2 -), hydroxyl radicals (·OH) and 2,2-di(4-tert-octylphenyl)-1-picryl-hydrazyl (DPPH) to reduce oxidative stress and inhibit "bacteria-to-bacteria communication", thus clearing planktonic bacteria and biofilms, accelerating bacterial plasmolysis, reducing bacterial virulence and interfering with membrane transport. After in vivo treatment with hydrogel, nearly all bacteria are eliminated, inflammation is effectively inhibited, and osteogenesis and bone repair are promoted to facilitate recovery from PTO. The work demonstrates the clinical translational potential of the hydrogel in the treatment of drug-resistant bacteria induced PTO.

Ru doping and interface engineering synergistically boost the electrocatalytic performance of a WP/WP2 nanosheet array for an efficient hydrogen evolution reaction.

The surface electronic structure and morphology of catalysts have a crucial impact on the electrocatalytic hydrogen evolution reaction performance. This work reports on the fabrication of a Ru-doped WP/WP2 heterojunction nanosheet array electrode via a one-step phosphating treatment of a Ru-doped WO3 precursor. Benefitting from the large electrochemical active surface of nanosheet arrays, rich WP/WP2 heterojunction interface, and trace Ru atom doping, the catalyst has a fairly low overpotential of 58.0 mV at 10 mA cm-2 and a Tafel slope of 50.71 mV dec-1 in acid solution toward the electrocatalytic HER. Further, theoretical calculations unveil that Ru atom doping and interface effect synergistically optimized the electronic structure of the catalyst and hence weakened the adsorption capacity of the catalyst surface toward hydrogen (H), which lowered the Gibbs free energy (ΔGH*) and consequently effectively improved the HER performance. This work may open new avenues for developing advanced nanoarray electrodes with efficient electrochemical energy conversion.

Proteome analysis develops novel plasma proteins classifier in predicting the mortality of COVID-19.

COVID-19 has been a global concern for 3 years, however, consecutive plasma protein changes in the disease course are currently unclear. Setting the mortality within 28 days of admission as the main clinical outcome, plasma samples were collected from patients in discovery and independent validation groups at different time points during the disease course. The whole patients were divided into death and survival groups according to their clinical outcomes. Proteomics and pathway/network analyses were used to find the differentially expressed proteins and pathways. Then, we used machine learning to develop a protein classifier which can predict the clinical outcomes of the patients with COVID-19 and help identify the high-risk patients. Finally, a classifier including C-reactive protein, extracellular matrix protein 1, insulin-like growth factor-binding protein complex acid labile subunit, E3 ubiquitin-protein ligase HECW1 and phosphatidylcholine-sterol acyltransferase was determined. The prediction value of the model was verified with an independent patient cohort. This novel model can realize early prediction of 28-day mortality of patients with COVID-19, with the area under curve 0.88 in discovery group and 0.80 in validation group, superior to 4C mortality and E-CURB65 scores. In total, this work revealed a potential protein classifier which can assist in predicting the outcomes of COVID-19 patients and providing new diagnostic directions.

A tough synthetic hydrogel with excellent post-loading of drugs for promoting the healing of infected wounds in vivo.

Bacterial infection is a major obstacle to the wound healing process. The hydrogel dressings with a simpler structure and good antibacterial and wound healing performance are appealing for clinical application. Herein, a robust hydrogel was synthesized from acrylamide (AM), acrylic acid (AA) and N,N'-methylene diacrylamide (MBA) via a redox initiating polymerization. The polymerization conditions were optimized to obtain the hydrogel with minimum unreacted monomers, which were 0.25% and 0.12% for AM and AA, respectively. The hydrogel had good mechanical strength, and could effectively resist damage by external forces and maintain a good macroscopic shape. It showed large water uptake capacity, and could post load a wide range of molecules via hydrogen bonding and electrostatic interaction. Loading of antibiotic doxycycline (DOX) enabled the hydrogel with good antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria in vitro and in vivo. In a rat model of methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness skin defect wound, the DOX-loaded hydrogel showed good therapeutic effect. It could significantly promote the wound closure, increased the collagen coverage area, down-regulate the expressions of pro-inflammatory TNF-α and IL-1ß factors, and up-regulate the expressions of anti-inflammatory IL-4 factor and CD31 neovascularization factor.

Insights into the Effect of Sulfur Incorporation into Tungsten Diphosphide for Improved Hydrogen Evolution Reaction.

Exploring the highly active and stable nonprecious metal electrocatalysts is particularly important for the advancement of water electrolysis, whereas it remains a challenge to efficiently improve the intrinsic electrocatalytic activity. Herein, we reasonably constructed a self-supporting nanosheet array material with sulfur incorporated into WP2. Because of the tunability of electronic configuration and the formation of partial metal phase sulfides, the optimized catalyst exhibits a low overpotential of 115 mV at 10 mA cm-2, along with superb durability over 24 h in acidic media. Furthermore, theoretical calculations reveal that sulfur substitution effectively manipulates the local electronic configuration of WP2, which reduces the interaction between the catalyst surface and hydrogen atoms, thus improving the intrinsic activity of the hydrogen evolution reaction. This work provides valuable insight into the rational fabrication of highly efficient flexible electrode materials based on resourceful electrocatalysts for electrochemical water splitting.

Promoting the healing of infected diabetic wound by an anti-bacterial and nano-enzyme-containing hydrogel with inflammation-suppressing, ROS-scavenging, oxygen and nitric oxide-generating properties.

The diabetic wound is easily to develop into a chronic wound because of the extremely serious and complex inflammatory microenvironment including biofilm formation, over-expressed reactive oxygen species (ROS), hypoxia and insufficiency of nitric oxide (NO) synthesis. In this work, a multifunctional hydrogel was designed and prepared by crosslinking hydrophilic poly(PEGMA-co-GMA-co-AAm) (PPGA) polymers with hyperbranched poly-L-lysine (HBPL)-modified manganese dioxide (MnO2) nanozymes. Pravastatin sodium, which is supposed to participate in the synthesis of NO, was further loaded to obtain the HMP hydrogel. The capabilities of this hydrogel in scavenging different types of ROS, generating O2, killing broad spectrum bacteria, and protecting cells against oxidative stress were confirmed in vitro. The transcriptome analysis revealed that HBPL inhibited bacterial quorum sensing (QS) system, downregulated virulent genes, and interfered bacterial metabolism. The HBPL-crosslinked hydrogels killed up to 94.1%-99.5% of methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (E. coli) and Pseudomonas aeruginosa even at 109 CFU/mL. HBPL modification greatly increased the stability of MnO2 nanosheets in physiological environment. The MRSA-caused infection was effectively treated by the HBPL-crosslinked HMP hydrogel in vivo, and thereby the wound closure at inflammatory phase was promoted significantly. The treatment of HMP hydrogel reduced the ROS degree and relieved the inflammatory level significantly, accompanied by the decreased neutrophil infiltration and enhanced M2-type macrophage polarization in vivo. Significantly lower levels of inflammatory factors such as interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) and chemokines-1 (CXCL-1), and higher levels of anti-inflammatory cytokines such as IL-4 and IL-10 were also confirmed. Moreover, the HMP hydrogel could promote the secretion of transforming growth factor-ß (TGF-ß) and stimulate neovascularization, and deposition of collagen with a thicker skin and epithelium structure.

The construction of a single-crystalline SbSI nanorod array-WO3 heterostructure photoanode for high PEC performance.

A novel kind of highly efficient photoanode was constructed with a SbSI/WO3 heterostructurefabricated through two hydrothermal reactions followed by an iodination reaction (WO3 → Sb2S3/WO3 → SbSI/WO3). After optimizing the solvent [carbon disulfide (CS2)] for SbI3, the SbSI(CS2)/WO3 photoanode shows high-density single-crystalline SbSI nanorods growing along the polar [001] direction on WO3 nanoplates, resulting in excellent photocurrent performance (∼2.1 mA cm-2@1.23 V vs. RHE) and an improved photostability. It is evidenced that the higher crystallinity of SbSI has a positive effect on the photostability of the constructed SbSI/WO3 photoanodes.

SnS2 Nanosheets/H-TiO2 Nanotube Arrays as a Type†II Heterojunctioned Photoanode for Photoelectrochemical Water Splitting.

Improving the separation efficiency of photogenerated electron-hole pairs and the conductivity of electrons to photoanode substrates are critical to achieve high-performance photoelectrochemical (PEC) water splitting. Here, a SnS2 /H-TiO2 /Ti heterojunction photoanode was fabricated with SnS2 nanosheets vertically grown on hydrogen-treated TiO2 (H-TiO2 ) nanotube arrays on a Ti substrate. It showed a significantly enhanced photocurrent of 4.0 mA cm-2 at 1.4 V (vs. reversible hydrogen electrode) under AM 1.5 G illumination, 70 times higher than that of SnS2 /TiO2 /Ti. Kelvin probe force microscopy measurements indicated that photogenerated electrons could be easily transported through the SnS2 /H-TiO2 interface but not through the SnS2 /TiO2 interface. Through hydrogen treatment, defects were created in H-TiO2 nanotubes to convert type I junctions to type II with SnS2 nanosheets. As a result, a high efficiency of electron-hole separation at the SnS2 /H-TiO2 interface and a high electron conductivity in H-TiO2 nanotubes were achieved and improved PEC performance. These findings show an effective route towards high-performance photoelectrodes for water splitting.

In-situ ion-exchange synthesis Ag2S modified SnS2 nanosheets toward highly photocurrent response and photocatalytic activity.

Heterojunction photocatalyst systems are deemed to be an excellent option to improve the photocatalytic behavior of a material. In this paper, Ag2S/SnS2 heterojunction photocatalysts were prepared by a simple in-situ ion exchange method from SnS2 nanosheets. The Ag2S/SnS2 composite photoanode exhibits 13.99 µA/cm2 photocurrent density at 0.7 V (vs. Ag/AgCl) in 0.5 M Na2SO4 solution and a significant increase in photocatalytic activity compared to SnS2 nanosheets. Ag2S (8 wt%)/SnS2 composite shows the highest activity (0.0440 mg/min) in the degradation of MO and good stability. The reactive species trapping experiments confirmed hole (h+) and hydroxyl radical (OH) are active groups and play key roles in the photocatalytic degradation reaction. The highly effective photoelectrochemical and phocatalytic activities of Ag2S/SnS2 heterojunctions are attributed to the efficient separation of photogenerated hole-electron pairs. This work may provide a novel concept for the rational design of high performance SnS2-based photocatalysts.