Multiple modes of action of myricetin in influenza A virus infection.

Influenza A virus remains a major threat to public health worldwide after its first pandemic. Scientists keep searching novel anti-influenza drugs, of which natural products present to be an important source. Myricetin, a natural flavonol compound, which exists in many edible plants, which has a wide range of biological activities, but its anti-influenza A virus activity is ambiguous. This study aims to evaluate the anti-influenza activity of myricetin and elucidate its underlying mechanism. Our results demonstrated that myricetin could significantly inhibit influenza A virus replication, reduce viral polymerase activity via selective inhibition of viral PB2 subunit, and the production of inflammatory cytokines by inhibiting TLR3 signaling pathway. The binding affinity analysis and the result of molecular docking revealed that myricetin interacted with the PB2 cap-binding pocket of influenza A virus. The above results suggested myricetin could exhibit anti-influenza virus activity with low cytotoxicity as well, and myricetin had low toxicity in BALB/c mice in vivo. Results from this study highlighted myricetin could be considered as a promising anti-influenza virus agent with dual inhibition profile. Furthermore, the compound with similar structure would provide a new option for the development of novel inhibitors against influenza A virus.

Isocorilagin, isolated from Canarium album (Lour.) Raeusch, as a potent neuraminidase inhibitor against influenza A virus.

Canarium album (Lour.) Raeusch (C. album) as a normally medicinal and edible plant has been used widely in Asian countries and is considered a source of phytochemicals that are beneficial to human health. Here, we showed at the first time isocorilagin, a polyphenolic compound isolated from C. album, displayed antiviral activity against diverse strains of influenza A virus (IAV), including A/Puerto Rico/8/34 (H1N1), A/Aichi/2/68 (H3N2) and NA-H274Y (H1N1) with IC50 value of 9.19 ±â€¯1.99, 23.72 ±â€¯2.51 and 4.64 ±â€¯3.01 µM, respectively. Further mechanistic studies revealed that it clearly inhibited neuraminidase activity of IAV and directly influenced the virus release. The molecular docking studies presented isocorilagin could bind to the highly conserved residues in the active sites of NA, implying that isocorilagin may be effective against various influenza strains and not susceptible to produce drug resistance. Taken together, the results strongly suggest that isocorilagin has potential to be an effective, safe and affordable neuraminidase inhibitor against a diverse panel of IAV strains. More importantly, our work expands the biological activities of C. album extracts and provide a new option for the development of anti-influenza drug.

Energy-efficient superparamagnetic Ising machine and its application to traveling salesman problems.

The growth of artificial intelligence leads to a computational burden in solving non-deterministic polynomial-time (NP)-hard problems. The Ising computer, which aims to solve NP-hard problems faces challenges such as high power consumption and limited scalability. Here, we experimentally present an Ising annealing computer based on 80 superparamagnetic tunnel junctions (SMTJs) with all-to-all connections, which solves a 70-city traveling salesman problem (TSP, 4761-node Ising problem). By taking advantage of the intrinsic randomness of SMTJs, implementing global annealing scheme, and using efficient algorithm, our SMTJ-based Ising annealer outperforms other Ising schemes in terms of power consumption and energy efficiency. Additionally, our approach provides a promising way to solve complex problems with limited hardware resources. Moreover, we propose a cross-bar array architecture for scalable integration using conventional magnetic random-access memories. Our results demonstrate that the SMTJ-based Ising computer with high energy efficiency, speed, and scalability is a strong candidate for future unconventional computing schemes.

Development and validation of a diagnostic model for AFP-negative hepatocellular carcinoma.

PURPOSE: AFP appears to be negative in about 30% of overall hepatocellular carcinoma (HCC). Our study aimed to develop a nomogram model to diagnose AFP-negative HCC (AFPN-HCC). PATIENTS AND METHODS: The training set included 294 AFPN-HCC patients, 159 healthy objects, 63 patients with chronic hepatitis B(CHB), and 64 patients with liver cirrhosis (LC). And the validation set enrolled 137 healthy controls objects, 47 CHB patients and 45 patients with LC. LASSO, univariate, and multivariable logistic regression analysis were performed to construct the model and then transformed into a visualized nomogram. The receiver operating characteristic (ROC) curves, the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were further used for validation. RESULTS: Four variables including age, PIVKA-II, platelet (PLT) counts, and prothrombin time (PT) were selected to establish the nomogram. The area under the curve (AUC) of the ROC to distinguish AFPN-HCC patients was 0.937(95% CI 0.892-0.938) in training set and 0.942(95% CI 0.921-0.963) in validation set. We also found that the model had high diagnostic value for small-size HCC (tumor size < 5 cm) (AUC = 0.886) and HBV surface antigen-positive AFPN-HCC (AUC = 0.883). CONCLUSIONS: Our model was effective for discrimination of AFPN-HCC from patients with benign liver diseases and healthy controls, and might be helpful for the diagnosis for AFPN-HCC.

Nisoldipine Inhibits Influenza A Virus Infection by Interfering with Virus Internalization Process.

Influenza virus infections and the continuing spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are global public health concerns. As there are limited therapeutic options available in clinical practice, the rapid development of safe, effective and globally available antiviral drugs is crucial. Drug repurposing is a therapeutic strategy used in treatments for newly emerging and re-emerging infectious diseases. It has recently been shown that the voltage-dependent Ca2+ channel Cav1.2 is critical for influenza A virus entry, providing a potential target for antiviral strategies. Nisoldipine, a selective Ca2+ channel inhibitor, is commonly used in the treatment of hypertension. Here, we assessed the antiviral potential of nisoldipine against the influenza A virus and explored the mechanism of action of this compound. We found that nisoldipine treatment could potently inhibit infection with multiple influenza A virus strains. Mechanistic studies further revealed that nisoldipine impaired the internalization of the influenza virus into host cells. Overall, our findings demonstrate that nisoldipine exerts antiviral effects against influenza A virus infection and could serve as a lead compound in the design and development of new antivirals.

Trends in the application of deep learning networks in medical image analysis: Evolution between 2012 and 2020.

PURPOSE: To evaluate the general rules and future trajectories of deep learning (DL) networks in medical image analysis through bibliometric and hot spot analysis of original articles published between 2012 and 2020. METHODS: Original articles related to DL and medical imaging were retrieved from the PubMed database. For the analysis, data regarding radiological subspecialties; imaging techniques; DL networks; sample size; study purposes, setting, origins and design; statistical analysis; funding sources; authors; and first authors' affiliation was manually extracted from each article. The Bibliographic Item Co-Occurrence Matrix Builder and VOSviewer were used to identify the research topics of the included articles and illustrate the future trajectories of studies. RESULTS: The study included 2685 original articles. The number of publications on DL and medical imaging has increased substantially since 2017, accounting for 97.2% of all included articles. We evaluated the rules of the application of 47 DL networks to eight radiological tasks on 11 human organ sites. Neuroradiology, thorax, and abdomen were frequent research subjects, while thyroid was under-represented. Segmentation and classification tasks were the primary purposes. U-Net, ResNet, and VGG were the most frequently used Convolutional neural network-derived networks. GAN-derived networks were widely developed and applied in 2020, and transfer learning was highlighted in the COVID-19 studies. Brain, prostate, and diabetic retinopathy-related studies were mature research topics in the field. Breast- and lung-related studies were in a stage of rapid development. CONCLUSIONS: This study evaluates the general rules and future trajectories of DL network application in medical image analyses and provides guidance for future studies.

Antiviral activity and mechanism of ESC-1GN from skin secretion of Hylarana guentheri against influenza A virus.

Development of new and effective antiinfluenza drugs is critical for prophylaxis and treatment of influenza A virus (IAV) infection. A wide range of amphibian skin secretions have been identified to show antiviral activity. Our previously reported ESC-1GN, a peptide from the skin secretion of Hylarana guentheri, displayed good antimicrobial and antiinflammatory effects. Here, we found that ESC-1GN possessed significant antiviral effects against IAVs. Moreover, ESC-1GN could inhibit the entry of divergent H5N1 and H1N1 virus strains with the IC50 values from 1.29 to 4.59 µM. Mechanism studies demonstrated that ESC-1GN disrupted membrane fusion activity of IAVs by interaction with HA2 subunit. The results of site-directed mutant assay and molecular docking revealed that E105, N50 and the residues around them on HA2 subunit could form hydrogen bonds with amino acid on ESC-1GN, which were critical for ESC-1GN binding to HA2 and inhibiting the entry of IAVs. Altogether, these not only suggest that ESC-1GN maybe represent a new type of excellent template designing drugs against IAVs, but also it may shed light on the immune mechanism and survival strategy of H.guentheri against viral pathogens.

Methyl brevifolincarboxylate, a novel influenza virus PB2 inhibitor from Canarium Album (Lour.) Raeusch.

Methyl brevifolincarboxylate (MBC) was isolated from ethyl acetate extract of Canarium album (Lour.) Raeusch. The structure was identified, and the effect on influenza A virus infection was evaluated. MBC exhibited inhibitory activity against influenza virus A/Puerto Rico/8/34 (H1N1) and A/Aichi/2/68 (H3N2) with IC50 values of 27.16 ± 1.39 µM and 33.41 ± 2.34 µM. Mechanism studies indicated that MBC inhibited the replication of influenza A virus by targeting PB2 cap-binding domain. Our results demonstrated MBC was a potent PB2 cap-binding inhibitor and represented as a new type of promising lead compound for the development of anti-influenza virus drugs from natural products.

Discovery of dihydropyrrolidones as novel inhibitors against influenza A virus.

More effective prophylactic and therapeutic strategies to combat influenza viruses are urgently required worldwide because the conventional anti-influenza drugs are facing drug resistance. Here, dihydropyrrolidones (DHPs), the products of an efficient multi-components reaction, were found to possess good activities against influenza A virus (IAV). Primary structure-activity relationship indicated that the activities of DHPs were greatly influenced by substituents and four of them had IC50 values lower than 10 µM (DHPs 5-2, 8, 14 and 19: IC50 = 3.11-9.23 µM). The activities against multiple IAV strains and mechanism of DHPs were further investigated by using 5-2 (IC50 = 3.11 µM). It was found that 5-2 possessed antiviral effects against all the investigated subtypes of IAVs with the IC50 values from 3.11 to 7.13 µM. Moreover, 5-2 showed very low cytotoxicity with CC50 > 400 µM. Results of mechanism study indicated that 5-2 could efficiently inhibit replication of IAV, up-regulate the expression of key antiviral cytokines IFN-ß and antiviral protein MxA, and suppress the production of the NDAPH oxidase NOX1 in MDCK cells. These results indicated that 5-2 could be used as a potential inhibitor against wide subtypes of IAVs.

Dihydromyricetin is a new inhibitor of influenza polymerase PB2 subunit and influenza-induced inflammation.

Development of new and effective anti-influenza drugs is critical for the treatment of influenza virus infection. The polymerase basic 2 (PB2) subunit as a core subunit of influenza A virus RNA polymerase complex is considered to be an attractive drug target for anti-influenza drug discovery. Dihydromyricetin, as a natural flavonoid, has a wide range of biological activities, but its anti-influenza A virus activity is ambiguous. Here, we found dihydromyricetin could inhibit the replication of a variety of influenza A virus strains. Mechanism studies demonstrated that dihydromyricetin reduced viral polymerase activity via selective inhibition of viral PB2 subunit, and decreased relative amounts of viral mRNA and genomic RNA during influenza A virus infection. The binding affinity and molecular docking analyses revealed that dihydromyricetin interacted with the PB2 cap-binding pocket, functioned as a cap-binding competitor. Interestingly, dihydromyricetin also reduced cellular immune injury by inhibiting TLR3 signaling pathway. Additionally, combination treatment of dihydromyricetin with zanamivir exerted a synergistic anti-influenza effect. Altogether, our experiments reveal the antiviral and anti-inflammatory activities of dihydromyricetin in vitro against influenza virus infection, which provides a new insight into the development of novel anti-influenza drugs.

Investigational antiviral therapies for the treatment of influenza.

INTRODUCTION: Influenza viral ribonucleoprotein complexes (vRNPs) play a key role in viral transcription and replication; hence, the recent development of novel anti-influenza drugs targeting vRNPs has garnered widespread interest. AREAS COVERED: We discuss the function of the constituents of vRNPs and summarize those vRNPs-targeted synthetic drugs that are in preclinical and early clinical development. EXPERT OPINION: vRNPs contain high-value drug targets; such targets include the subunits PA, PB1, PB2, and NP. Developing a new generation of antiviral therapies with strategies that utilize existing drugs, natural compounds originated from new resources and novel drug combinations may open up new therapeutic approaches to influenza.

Key amino acid residues of neuraminidase involved in influenza A virus entry.

Generally, influenza virus neuraminidase (NA) plays a critical role in the release stage of influenza virus. Recently, it has been found that NA may promote influenza virus to access the target cells. However, the mechanism remain unclear. Here, we reported that peramivir indeed possessed anti-influenza A virus (IAV) activity in the stage of viral entry. Importantly, we verified the critical residues of influenza NA involved in the viral entry. As a result, peramivir as an efficient NA inhibitor could suppress the initiation of IAV infection. Furthermore, mutational analysis showed NA might be associated with viral entry via amino acids residues R118, E119, D151, R152, W178, I222, E227, E276, R292 and R371. Our results demonstrated NA must contain the key amino acid residues can involve in IAV entry.

Modeling and simulation of point-non-point source effluent trading in Taihu Lake area: perspective of non-point sources control in China.

The past decades have witnessed some efforts in point source water pollution controls in China. However, adequate abatement efforts have not been implemented on non-point source control, and non-point source contributions remain and have increased as a share of surface water degradation. It has been noted that conventional command-and-control regulations are ineffective for agricultural non-point source pollution, and watershed abatement trading between point and non-point sources may serve as a cost-effective way to deal with it. In this paper, the feasibility of point-non-point sources effluent trading in China and cost-effectiveness of the trading system on water pollution control are evaluated using a stochastic programming model and a combined probabilistic watershed simulation of a representative agricultural watershed in the Taihu Lake area. The method and model can be used to assess economic and environmental opportunities of trading in similar watersheds in China. The use of explicit emission target and reliability decision rules in the chance-constrained programming model is a practical simplification to convert a stochastic program into a solvable deterministic problem. Based on the simulation, suggestions on development and implementation of point-non-point sources abatement trading scheme in China were discussed.

PCR-DGGE analysis of the microbial communities in three different Chinese "Baiyunbian" liquor fermentation starters.

A systematic investigation was performed on the bacterial, Bacillus, fungal, and yeast communities of the three types of Daqu (mechanically prepared, manually prepared, and mixed prepared) used in Baiyunbian Company by reconditioning PCR-denaturing gradient gel electrophoresis (PCR-DGGE). The DGGE results showed that the microbes in the three types of Daqu were mainly thermotolerant and thermophilic microbes, and the most dominant bacterial species were Bacillus and Virgibacillus, followed by Lactobacillus and Trichococcus. Furthermore, the dominant fungi were found to be molds, such as Rasamsonia, Penicillium, Aspergillus, and Monascus, and the dominant yeasts were Saccharomyces cerevisiae, Saccharomycopsis fibuligera, Pichia anomala, and Debaryomyces hansenii. In general, the three types of Daqu showed slight differences in microbial communities, and the Shannon indexes (H') of the manually prepared and mechanically prepared Daqu were similar. The results suggest that mechanically prepared Daqu can replace manually prepared Daqu in liquor production, and this research provides useful information for liquor production and process improvement.