eIF3d: A driver of noncanonical cap-dependent translation of specific mRNAs and a trigger of biological/pathological processes.

Eukaryotic initiation factor 3d (eIF3d), a known RNA-binding subunit of the eIF3 complex, is a 66 to 68-kDa protein with an RNA-binding motif and a cap-binding domain. Compared with other eIF3 subunits, eIF3d is relatively understudied. However, recent progress in studying eIF3d has revealed a number of intriguing findings on its role in maintaining eIF3 complex integrity, global protein synthesis, and in biological and pathological processes. It has also been reported that eIF3d has noncanonical functions in regulating translation of a subset of mRNAs by binding to 5'-UTRs or interacting with other proteins independent of the eIF3 complex and additional functions in regulating protein stability. The noncanonical regulation of mRNA translation or protein stability may contribute to the role of eIF3d in biological processes such as metabolic stress adaptation and in disease onset and progression including severe acute respiratory syndrome coronavirus 2 infection, tumorigenesis, and acquired immune deficiency syndrome. In this review, we critically evaluate the recent studies on these aspects of eIF3d and assess prospects in understanding the function of eIF3d in regulating protein synthesis and in biological and pathological processes.

Artesunate protects against ocular fibrosis by suppressing fibroblast activation and inducing mitochondria-dependent ferroptosis.

Artesunate, a derivative from extracts of Artemisia annua, has recently been reported to alleviate fibrosis recently. Here, in this study, we sought to determine the anti-fibrosis effect of artesunate in rabbit glaucoma filtration surgery (GFS) model and illuminate underlying mechanisms. Our results showed that artesunate subconjunctival injection alleviated bleb fibrosis by inhibiting fibroblast activation and inducing ferroptosis. Further mechanistic investigation in primary human ocular fibroblasts (OFs) showed that artesunate abrogated fibroblast activation by inhibiting TGF-ß1/SMAD2/3 and PI3K/Akt pathways and scavenged OFs by inducing mitochondria-dependent ferroptosis. Mitochondrial dysfunction, mitochondrial fission, and iron-dependent mitochondrial lipid peroxidation were observed in artesunate-treated OFs. Besides, mitochondria-localized antioxidants inhibited artesunate-induced cell death, suggesting a critical role of mitochondria in artesunate-induced ferroptosis. Our study also found that expression of mitochondrial GPX4 but no other forms of GPX4 was decreased after artesunate treatment and that mitochondrial GPX4 overexpression rescued artesunate-induced lipid peroxidation and ferroptosis. Other cellular ferroptosis defense mechanisms, including cellular FSP1 and Nrf2, were also inhibited by artesunate. In conclusion, our study demonstrated that artesunate protects against fibrosis through abrogation of fibroblast activation and induction of mitochondria-dependent ferroptosis in OFs, which may offer a potential treatment for ocular fibrosis.

Comparison of Anti-Icing, Antifouling, and Anticorrosion Performances of the Superhydrophobic and Lubricant-Infused Coatings Based on a Hollow-Structured Kapok Fiber.

The superhydrophobic surface and slippery liquid-infused porous surface (SLIPS)/lubricant-infused surface (LIS) have attracted increasing attention owing to their multifunctionality. However, their practical applications face several problems such as complex and inefficient preparation technology, loss of lubricant, and fragile microstructures. Therefore, new strategies for preparing microstructures must be developed for constructing superhydrophobic and lubricant-infused coatings. Herein, a low-cost and high-efficiency method for developing superhydrophobic and lubricant-infused coatings based on in situ grown TiO2 on the surface of a hollow kapok fiber (KF) is reported. The anti-icing, antifouling, and anticorrosion performance of the superhydrophobic and lubricant-infused coatings are compared. The superhydrophobic coating reduces the formation and accumulation of ice. The lubricant-infused coating exhibits an extremely low ice adhesion strength and durable anti-icing properties. The superhydrophobic and lubricant-infused coatings show the outstanding antifouling property of diatom; the superhydrophobic surface exhibits superior stability over LIS without an external force field. The lubricant-infused coating shows excellent corrosion resistance and durability when immersed in a 3.5% NaCl solution. The superhydrophobic coating loses its protection as a result of the corrosion media permeating the metal substrate via the electrolytic cell and coating interface, and the lubricant-infused coating provides lasting corrosion resistance because of the lubricant filling into the interface. Although the superhydrophobic coating is fragile and the lubricant-infused coating will lose lubricant, this simple and convenient approach can be repeated to keep the coatings active. This study provides new inspiration for the fabrication of superhydrophobic surfaces and LIS based on natural products.

Considering climate change impact on the global potential geographical distribution of the invasive Argentine ant and little fire ant.

The Argentine ant (Linepithema humile) and the little fire ant (Wasmannia auropunctata) are among the top 100 invasive alien species globally, causing significant ecological and economic harm. Therefore, it is crucial to study their potential geographic distribution worldwide. This study aimed to predict their global distribution under current and future climate conditions. We used distribution data from various sources, including CABI, GBIF, and PIAKey, and key climate variables selected from 19 environmental factors to model their potential geographic distribution using MaxEnt. The AUC values were 0.925 and 0.937 for L. humile and W. auropunctata, respectively, indicating good predictive performance. Suitable areas for L. humile were mainly in southern North America, northern South America, Europe, central Asia, southern Oceania, and parts of Africa, while W. auropunctata suitable areas were mostly in southern North America, most of South America, a small part of Europe, southern Asia, central Africa, and some parts of Oceania. Under climate change scenario, suitable areas for L. humile increased, while highly suitable areas for W. auropunctata decreased. The top four countries with the largest areas of overlapping suitable habitat under current climate were Brazil, China, Australia, and Argentina, while under future SSP585 climate scenario, the top four countries were Brazil, China, Indonesia, and Argentina. Some countries, such as Estonia and Finland, will see an overlapping adaptation area under climate change. In conclusion, this study provides insight into controlling the spread and harm of L. humile and W. auropunctata.

Loading of Single Atoms of Iron, Cobalt, or Nickel to Enhance the Electrocatalytic Hydrogen Evolution Reaction of Two-Dimensional Titanium Carbide.

The rational design of advanced electrocatalysts at the molecular or atomic level is important for improving the performance of hydrogen evolution reactions (HERs) and replacing precious metal catalysts. In this study, we describe the fabrication of electrocatalysts based on Fe, Co, or Ni single atoms supported on titanium carbide (TiC) using the molten salt method, i.e., TiC-FeSA, TiC-CoSA, or TiC-NiSA, to enhance HER performance. The introduction of uniformly distributed transition-metal single atoms successfully reduces the overpotential of HERs. Overpotentials of TiC-FeSA at 10 mA cm-2 are 123.4 mV with 61.1 mV dec-1 Tafel slope under acidic conditions and 184.2 mV with 85.1 mV dec-1 Tafel slope under alkaline conditions, which are superior to TiC-NiSA and TiC-CoSA. TiC samples loaded with transition-metal single atoms exhibit high catalytic activity and long stability under acidic and basic conditions. Density functional theory calculations indicate that the introduction of transition-metal single atoms effectively reduces the HER barrier of TiC-based electrocatalysts.

A Functional Switch Between Asperfumene and Fusicoccadiene Synthase and Entrance to Asperfumene Biosynthesis through a Vicinal Deprotonation-Reprotonation Process.

The diterpene synthase AfAS was identified from Aspergillus fumigatiaffinis. Its amino acid sequence and - according to a structural model - active site architecture are highly similar to those of the fusicocca-2,10(14)-diene synthase PaFS, but AfAS produces a structurally much more complex diterpene with a novel 6-5-5-5 tetracyclic skeleton called asperfumene. The cyclisation mechanism of AfAS was elucidated through isotopic labelling experiments and DFT calculations. The reaction cascade proceeds in its initial steps through similar intermediates as for the PaFS cascade, but then diverges through an unusual vicinal deprotonation-reprotonation process that triggers a skeletal rearrangement at the entrance to the steps leading to the unique asperfumene skeleton. The structural model revealed only one major difference between the active sites: The PaFS residue F65 is substituted by I65 in AfAS. Intriguingly, site-directed mutagenesis experiments with both diterpene synthases revealed that position 65 serves as a bidirectional functional switch for the biosynthesis of tetracyclic asperfumene versus structurally less complex diterpenes.

Translation initiation factor eIF3a regulates glucose metabolism and cell proliferation via promoting small GTPase Rheb synthesis and AMPK activation.

Eukaryotic translation initiation factor 3 subunit A (eIF3a), the largest subunit of the eIF3 complex, has been shown to be overexpressed in malignant cancer cells, potentially making it a proto-oncogene. eIF3a overexpression can drive cancer cell proliferation but contributes to better prognosis. While its contribution to prognosis was previously shown to be due to its function in suppressing synthesis of DNA damage repair proteins, it remains unclear how eIF3a regulates cancer cell proliferation. In this study, we show using genetic approaches that eIF3a controls cell proliferation by regulating glucose metabolism via the phosphorylation and activation of AMP-activated protein kinase alpha (AMPKα) at Thr172 in its kinase activation loop. We demonstrate that eIF3a regulates AMPK activation mainly by controlling synthesis of the small GTPase Rheb, largely independent of the well-known AMPK upstream liver kinase B1 and Ca2+/calmodulin-dependent protein kinase kinase 2, and also independent of mammalian target of rapamycin signaling and glucose levels. Our findings suggest that glucose metabolism in and proliferation of cancer cells may be translationally regulated via a novel eIF3a-Rheb-AMPK signaling axis.

Identification of Novel 5' and 3' Translation Enhancers in Umbravirus-Like Coat Protein-Deficient RNA Replicons.

Translation of plant plus-strand RNA viral genomes that lack a 5' cap frequently requires the use of cap-independent translation enhancers (CITEs) located in or near the 3' untranslated region (UTR). 3'CITEs are grouped based on secondary structure and ability to interact with different translation initiation factors or ribosomal subunits, which assemble a complex at the 3' end that is nearly always transferred to the 5' end via a long-distance kissing-loop interaction between sequences in the 3'CITE and 5' hairpins. We report here the identification of a novel 3'CITE in coat protein-deficient RNA replicons that are related to umbraviruses. Umbra-like associated RNAs (ulaRNAs), such as citrus yellow vein-associated virus (CYVaV), are a new type of subviral RNA that do not encode movement proteins, coat proteins, or silencing suppressors but can independently replicate using their encoded RNA-dependent RNA polymerase. An extended hairpin structure containing multiple internal loops in the 3' UTR of CYVaV is strongly conserved in the most closely related ulaRNAs and structurally resembles an I-shaped structure (ISS) 3'CITE. However, unlike ISS, the CYVaV structure binds to eIF4G and no long-distance interaction is discernible between the CYVaV ISS-like structure and sequences at or near the 5' end. We also report that the ∼30-nucleotide (nt) 5' terminal hairpin of CYVaV and related ulaRNAs can enhance translation of reporter constructs when associated with either the CYVaV 3'CITE or the 3'CITEs of umbravirus pea enation mosaic virus (PEMV2) and even independent of a 3'CITE. These findings introduce a new type of 3'CITE and provide the first information on translation of ulaRNAs. IMPORTANCE Umbra-like associated RNAs (ulaRNAs) are a recently discovered type of subviral RNA that use their encoded RNA-dependent RNA polymerase for replication but do not encode any coat proteins, movement proteins, or silencing suppressors yet can be found in plants in the absence of any discernible helper virus. We report the first analysis of their translation using class 2 ulaRNA citrus yellow vein-associated virus (CYVaV). CYVaV uses a novel eIF4G-binding I-shaped structure as its 3' cap-independent translation enhancer (3'CITE), which does not connect with the 5' end by a long-distance RNA:RNA interaction that is typical of 3'CITEs. ulaRNA 5' terminal hairpins can also enhance translation in association with cognate 3'CITEs or those of related ulaRNAs and, to a lesser extent, with 3'CITEs of umbraviruses, or even independent of a 3'CITE. These findings introduce a new type of 3'CITE and provide the first information on translation of ulaRNAs.

Anti-GPIb/IX autoantibodies are associated with poor response to dexamethasone combined with rituximab therapy in primary immune thrombocytopenia patients.

This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. One-hundred twenty-six ITP patients were included and retrospectively analyzed, 66.7% of anti-GPIb/IX and 65.9% of anti-GPIIb/IIIa autoantibodies. Results showed that overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at 4 weeks (OR: 73.8% vs. 47.6%, CR: 50.0% vs. 26.2%; P < 0.05) and 6 months (OR: 71.4% vs. 45.2%, CR: 42.9% vs. 25.0%; P < .05). Furthermore, patients with anti-GPIb/IX single-positivity exhibited higher resistance to DXM-RTX than patients with anti-GPIIb/IIIa single-positivity at 4 weeks (OR: 37.5% vs. 78.3%; P < .05) and 6 months (OR: 29.2% vs. 78.3%; P < .05). Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies and megakaryocytes were associated with the OR rate of patients at both 4 weeks and 6 months, and anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX (F = 9.128, P = .003). Therefore, platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX in ITP patients.

What is the context?The safety and efficacy of high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) are gradually recognized; however, there still needs to be an adequate clinical trial to predict its efficacy. Autoantibodies against platelet glycoproteins (GPs) are proven to be associated with a variety of therapeutic responses in ITP. Such as anti-GPIb/IX autoantibodies predict poor response to intravenous immunoglobulin G therapy and rhTPO therapy in ITP patients. Therefore, a retrospective study was needed to verify whether anti-GP autoantibodies can expect a response to DXM-RTX therapy in ITP patients.What is new?This study identified that anti-GPIb/IX autoantibodies were a predictive factor for poor response to DXM-RTX in ITP patients. It mainly manifested in the following aspects: (1) Overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at four weeks and six months. (2) Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies at both four weeks and six months were associated with the OR rate of patients.What is the impact?Our study suggests that ITP patients with anti-GPIb/IX positive autoantibodies respond poorly to DXM-RTX therapy. Platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX therapy in ITP patients.

The First Human Infection Case of Macacine Alphaherpesvirus 1 Virus in China.

BACKGROUND: Macacine alphaherpesvirus 1 (BV) was first reported in the 1930s and only about 60 cases have been diagnosed since then. METHODS: A 53-year-old male who worked as a veterinary surgeon, developed a fever with nausea and vomiting in April 2021 in Beijing, China. Real-time polymerase chain reaction (PCR) and metagenomics Next Generation Sequencing (mNGS) were used for diagnosis. RESULTS: BV DNA was confirmed by mNGS and PCR. The case died 51 days after onset, due to the damage to the brain and spinal cord caused by a viral infection and hypoxic-ischemic encephalopathy. The typical BV inclusion bodies in the brain were found for the first time. CONCLUSIONS: Here we reported the first human infection case of BV in China. This fatal case highlights the potential threat of BV to occupational workers and the essential role of surveillance.

Statistical inference for linear mediation models with high-dimensional mediators and application to studying stock reaction to COVID-19 pandemic.

Mediation analysis draws increasing attention in many research areas such as economics, finance and social sciences. In this paper, we propose new statistical inference procedures for high dimensional mediation models, in which both the outcome model and the mediator model are linear with high dimensional mediators. Traditional procedures for mediation analysis cannot be used to make statistical inference for high dimensional linear mediation models due to high-dimensionality of the mediators. We propose an estimation procedure for the indirect effects of the models via a partially penalized least squares method, and further establish its theoretical properties. We further develop a partially penalized Wald test on the indirect effects, and prove that the proposed test has a χ 2 limiting null distribution. We also propose an F -type test for direct effects and show that the proposed test asymptotically follows a χ 2 -distribution under null hypothesis and a noncentral χ 2 -distribution under local alternatives. Monte Carlo simulations are conducted to examine the finite sample performance of the proposed tests and compare their performance with existing ones. We further apply the newly proposed statistical inference procedures to study stock reaction to COVID-19 pandemic via an empirical analysis of studying the mediation effects of financial metrics that bridge company's sector and stock return.

Full-Chain FeCl3 Catalyzation Is Sufficient to Boost Cellulase Secretion and Cellulosic Ethanol along with Valorized Supercapacitor and Biosorbent Using Desirable Corn Stalk.

Cellulosic ethanol is regarded as a perfect additive for petrol fuels for global carbon neutralization. As bioethanol conversion requires strong biomass pretreatment and overpriced enzymatic hydrolysis, it is increasingly considered in the exploration of biomass processes with fewer chemicals for cost-effective biofuels and value-added bioproducts. In this study, we performed optimal liquid-hot-water pretreatment (190 °C for 10 min) co-supplied with 4% FeCl3 to achieve the near-complete biomass enzymatic saccharification of desirable corn stalk for high bioethanol production, and all the enzyme-undigestible lignocellulose residues were then examined as active biosorbents for high Cd adsorption. Furthermore, by incubating Trichoderma reesei with the desired corn stalk co-supplied with 0.05% FeCl3 for the secretion of lignocellulose-degradation enzymes in vivo, we examined five secreted enzyme activities elevated by 1.3-3.0-fold in vitro, compared to the control without FeCl3 supplementation. After further supplying 1:2 (w/w) FeCl3 into the T. reesei-undigested lignocellulose residue for the thermal-carbonization process, we generated highly porous carbon with specific electroconductivity raised by 3-12-fold for the supercapacitor. Therefore, this work demonstrates that FeCl3 can act as a universal catalyst for the full-chain enhancement of biological, biochemical, and chemical conversions of lignocellulose substrates, providing a green-like strategy for low-cost biofuels and high-value bioproducts.

A novel survivin dimerization inhibitor without a labile hydrazone linker induces spontaneous apoptosis and synergizes with docetaxel in prostate cancer cells.

Survivin, a member of the inhibitor of apoptosis protein family, exists as a homodimer and is aberrantly upregulated in a wide spectrum of cancers. It was thought to be an ideal target due to its lack of expression in most adult normal tissues and importance in cancer cell survival. However, it has been challenging to target survivin due to its "undruggable" nature. We previously attempted to target its dimerization domain with a hypothesis that inhibiting survivin dimerization would promote its degradation in proteasome, which led to identification of a lead small-molecule inhibitor, LQZ-7F. LQZ-7F consists of a flat tetracyclic aromatic core with labile hydrazone linking a 1,2,5-oxadiazole moiety. In this study, we tested the hypothesis that LQZ-7F could be developed as a prodrug because the labile hydrazone linker could be hydrolyzed, releasing the tetracyclic aromatic core. To this end, we synthesized the tetracyclic aromatic core (LQZ-7F1) using reported procedure and tested LQZ-7F1 for its biological activities. Here we show that LQZ-7F1 has a significantly improved potency with submicromolar IC50's and induces spontaneous apoptosis in prostate cancer cells. It also more effectively inhibits survivin dimerization and induces survivin degradation in a proteasome-dependent manner than LQZ-7F. We also show that the combination of LQZ-7F1 and docetaxel have strong synergism in inhibiting prostate cancer cell survival. Together, we conclude that the hydrazone linker with the oxadiazole tail is dispensable for survivin inhibition and the survivin dimerization inhibitor, LQZ-7F, may be developed as a prodrug for prostate cancer treatment and to overcome docetaxel resistance.

Investigating particle-size-induced changes in composition, physical, rheological, and bioactive properties of black tea powder.

BACKGROUND: People brew tea to drink an infusion that only contains 25% water-soluble constituents, leading to most of the insoluble materials being wasted. Tea powder could be drunk directly by mixing with water without producing any waste. Tea powder can also be used as a natural additive to improve the flavour and taste in beverages and foods. Much detailed information on the particle properties of tea powder is required with its increasing consumption. The aim of this study was to investigate the effects of particle size ranging from median diameter D50  = 4.32 to 26.59 µm on the composition, physical, rheological, and bioactive properties of black tea powder. RESULTS: The results indicate that large powder sizes had high bulk density and flowability, whereas small powder sizes possessed good swelling ability and wettability. The contents of water extract, total polyphenols, crude fibre, catechins, and thearubigins reduced with a decrease in particle size. To change the particle size and concentration could adjust the elastic modulus and the viscous modulus of the black tea powder suspension. Moreover, black tea powder with small particle size could regulate blood lipids in a hyperlipidaemic rat model by lowering triacylglycerols and elevating high-density lipoprotein cholesterol, whereas large particles presented an advantage in reducing body weight. CONCLUSION: Our investigation extended the knowledge of commercial black tea powder in composition, physical, rheological, and bioactive properties. These results lay the foundation for future exploration of the use of tea powder in the food industry. © 2022 Society of Chemical Industry.

Tobacco Necrosis Virus-AC Single Coat Protein Amino Acid Substitutions Determine Host-Specific Systemic Infections of Nicotiana benthamiana and Soybean.

Plant viruses often infect several distinct host species. Sometimes, viruses can systemically infect a specific host whereas, in other cases, only local infections occur in other species. How viral and host factors interact to determine systemic infections among different hosts is largely unknown, particularly for icosahedral positive-stranded RNA viruses. The Tobacco necrosis virus-A Chinese isolate belongs to the genus Alphanecrovirus in the family Tombusviridae. In this study, we investigated variations in systemic infections of tobacco necrosis virus-AC (TNV-AC) in Nicotiana benthamiana and Glycine max (soybean) by alanine-scanning mutagenesis of the viral coat protein (CP), which is essential for systemic movement of TNV-AC. We found that three amino acids, R169, K177, and Q233, are key residues that mediate varying degrees of systemic infections of N. benthamiana and soybean. Further analysis revealed that variations in systemic trafficking of TNV-AC CP mutants in N. benthamiana and soybean are associated with virion assembly and stability. The CP amino acids K177 and Q233 are highly conserved among all TNV-A isolates and are replaced by Q and K in the TNV-D isolates. We demonstrated that systemic infectivity of either TNV-AC K177A and Q233A or K177Q and Q233K mutants are correlated with the binding affinity of the mutated CPs to the host-specific Hsc70-2 protein. These results expand our understanding of host-dependent long-distance movement of icosahedral viruses in plants.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Slippery-Liquid-Infused Electrostatic Flocking Surfaces for Marine Antifouling Application.

Most marine antifouling coatings rely on the release of toxic biocides to prevent fouling organisms from attaching, causing environmental pollution. This work proposes a biocide-free environmentally friendly marine antifouling strategy. Slippery-liquid-infused electrostatic flocking surfaces (S-EFSs) were prepared by combining electrostatic flocking and slippery liquid infusion. They exhibited complete mussel resistance after comparing adhesion to the surface of different materials in the laboratory. In addition, the unique surface morphology including lubricant was found to be crucial to their antifouling performance. Real-time polymerase chain reaction showed that different surfaces significantly affected the gene-expression levels of the mussels' foot proteins, where higher levels on S-EFSs meant that the mussels tried to secrete more proteins but they failed to adhere. Moreover, a 148-day field test showed that S-EFSs can resist not only mussels but also tubeworms, tunicates, and barnacles, and the total fouling area decreased by more than 50% compared to control samples. Notably, the maturity of electrostatic flocking technology and the simplicity of the modification steps used endow this strategy with the potential to significantly reduce the economic loss caused by marine biofouling in practical applications.

Comparative therapeutic efficacy of interferon alfa-2b and combination lopinavir/ritonavir plus interferon alfa-2b against SARS-CoV-2.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) posed an enormous threat to public health. The use of antiviral drugs in patients with this disease have triggered people's attentions. Whether interferon alfa-2b or lopinavir/ritonavir (LPV/r) plus interferon alfa-2b treatment can against SARS-CoV-2 was unknown. The objectives of this study was to evaluate the efficacy and safety of interferon alfa-2b and LPV/r plus interferon alfa-2b for SARS-CoV-2 infection in adult patients hospitalized with COVID-19. METHODS: This is a retrospective cohort study of 123 patients confirmed SARS-CoV-2 infection by PCR on nasopharyngeal swab and symptoms between Jan. 13 and Apr. 23, 2020. All patients received standard supportive care and regular clinical monitoring. Patients were assigned to standard care group (n = 12), interferon alfa-2b group (n = 44), and combination LPV/r plus interferon alfa-2b group (n = 67). The primary endpoints were duration of required oxygen support and virus clearance time. Associations between therapies and these outcomes were assessed by Cox proportional hazards regression. RESULTS: Baseline clinical characteristics were not significantly different among the three groups (P > 0.05). No significant associations were observed between LPV/r/interferon alfa-2b and faster SARS-CoV-2 RNA clearance (HR, 0.85 [95% confidence interval (CI) 0.45-1.61]; P = 0.61 in interferon alfa-2b group vs HR, 0.59 [95% CI 0.32-1.11]; P = 0.10 in LPV/r plus interferon alfa-2b group). Individual therapy groups also showed no significant association with duration of required oxygen support. There were no significant differences among the three groups in the incidence of adverse events (P > 0.05). CONCLUSIONS: In patients with confirmed SARS-CoV-2 infection, no benefit was observed from interferon alfa-2b or LPV/r plus interferon alfa-2b treatment. The findings may provide references for treatment guidelines of patients with SARS-CoV-2 infection.

Carboxypeptidase B blocks ex vivo activation of the anaphylatoxin-neutrophil extracellular trap axis in neutrophils from COVID-19 patients.

BACKGROUND: Thrombosis and coagulopathy are highly prevalent in critically ill patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. As the primary components of immunothrombosis, neutrophil extracellular traps (NETs) could be induced by complement cascade components and other proinflammatory mediators. We aimed to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19. METHODS: We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase (MPO)-DNA. Besides, the formation of NETs was detected by immunofluorescent staining and the cytotoxicity to vascular endothelial HUVEC cells was evaluated by CCK-8 assay. RESULTS: We found that the plasma levels of complements C3 and MPO-DNA were positively related to coagulation indicator fibrin(-ogen) degradation products (C3: r = 0.300, p = 0.005; MPO-DNA: r = 0.316, p = 0.002) in COVID-19 patients. Besides, C3 was positively related to direct bilirubin (r = 0.303, p = 0.004) and total bilirubin (r = 0.304, p = 0.005), MPO-DNA was positively related to lactate dehydrogenase (r = 0.306, p = 0.003) and creatine kinase (r = 0.308, p = 0.004). By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products. CONCLUSIONS: Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.

Redox mediators as charge agents for changing electrochemical reactions.

Redox mediators (RMs) play pivotal roles in enhancing the performance of electrochemical energy storage and conversion systems. Unlike the widely explored areas of electrode materials, electrolytes, separators, and electrolyte additives, RMs have received little attention. This review provides a comprehensive discussion toward understanding the effects of RMs on electrochemical systems, underlying redox mechanisms, and reaction kinetics both experimentally and theoretically. Our discussion focuses on the roles of RMs in various electrochemical systems such as lithium-ion batteries, Li-O2 batteries, Li-S batteries, decoupling electrolysis, supercapacitors, and microbial fuel cells. Depending on the reaction regions where the RMs become active, we can classify them into bulk, solid-solid interfacial, solid-liquid interfacial, and cell-unit RMs. The prospect of developing RMs with effective charge transfer properties along with minimal side-effects is an exciting research direction. Moreover, the introduction of an efficient RM into an electrochemical system can fundamentally change its chemistry; in particular, the electrode reaction polarization can be considerably decreased. In this context, we discuss the key properties of RMs applied for various purposes, and the main issues are addressed.

Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage.

BACKGROUND: Patients with critical illness due to infection with the 2019 coronavirus disease (COVID-19) show rapid disease progression to acute respiratory failure. The study aimed to screen the most useful predictive factor for critical illness caused by COVID-19. METHODS: The study prospectively involved 61 patients with COVID-19 infection as a derivation cohort, and 54 patients as a validation cohort. The predictive factor for critical illness was selected using LASSO regression analysis. A nomogram based on non-specific laboratory indicators was built to predict the probability of critical illness. RESULTS: The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent risk factor for critical illness in patients with COVID-19 infection. The NLR had an area under receiver operating characteristic of 0.849 (95% confidence interval [CI], 0.707 to 0.991) in the derivation cohort and 0.867 (95% CI 0.747 to 0.944) in the validation cohort, the calibration curves fitted well, and the decision and clinical impact curves showed that the NLR had high standardized net benefit. In addition, the incidence of critical illness was 9.1% (1/11) for patients aged ≥ 50 and having an NLR < 3.13, and 50% (7/14) patients with age ≥ 50 and NLR ≥ 3.13 were predicted to develop critical illness. Based on the risk stratification of NLR according to age, this study has developed a COVID-19 pneumonia management process. CONCLUSIONS: We found that NLR is a predictive factor for early-stage prediction of patients infected with COVID-19 who are likely to develop critical illness. Patients aged ≥ 50 and having an NLR ≥ 3.13 are predicted to develop critical illness, and they should thus have rapid access to an intensive care unit if necessary.