Material basis and pharmacodynamic mechanism of YangshenDingzhi granules in the intervention of viral pneumonia:Based on serum pharmacochemistry and network pharmacology

Background:YangshenDingzhi granules(YSDZ)are clinically effective in preventing and treating COVID-19.The present study elucidates the underlying mechanism of YSDZ intervention in viral pneumonia by employing serum pharmacochemistry and network pharmacology.Methods:The chemical constituents of YSDZ in the blood were examined using ultraperformance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry(UPLC-Q-Exactive Orbitrap MS).Potential protein targets were obtained from the SwissTargetPrediction database,and the target genes associated with viral pneumonia were identified using GeneCards,DisGeNET,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection of blood component-related targets and disease-related targets was determined using Venny 2.1.Protein-protein interaction networks were constructed using the STRING database.The Metascape database was employed to perform enrichment analyses of Gene Ontology(GO)functions and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathways for the targets,while the Cytoscape 3.9.1 software was utilized to construct drug-component-disease-target-pathway networks.Further,in vitro and in vivo experiments were performed to establish the therapeutic effectiveness of YSDZ against viral pneumonia.Results:Fifteen compounds and 124 targets linked to viral pneumonia were detected in serum.Among these,MAPK1,MAPK3,AKT1,EGFR,and TNF play significant roles.In vitro tests revealed that the medicated serum suppressed the replication of H1N1,RSV,and SARS-CoV-2 replicon.Further,in vivo testing analysis shows that YSDZ decreases the viral load in the lungs of mice infected with RSV and H1N1.Conclusion:The chemical constituents of YSDZ in the blood may elicit therapeutic effects against viral pneumonia by targeting multiple proteins and pathways.

Variable Physical Constants and Beyond

We previously revealed that the speed of light in vacuum c, the gravitational constant G, the vacuum permittivity ε, and the vacuum permeability μ can be defined by the temperature T (or the expected average frequency f) of cosmic microwave background (CMB) radiation. Given that CMB is continuously cooling, that is, T is continuously decreasing, we proposed that the above “constants” are variable and their values at some space-time with CMB temperature T (cT, GT, εT, and μT) can be described using their values (c0, G0, ε0, and μ0) and the temperature (T0) of CMB at present space-time. Based on the above observation, a number of physical equations related with these constants are re-described in this study, including relativity equation, mass-energy equation, and Maxwell’s equations, etc.

Possible Relations of Cosmic Microwave Background with Gravity and Fine-Structure Constant

Gravity is the only force that cannot be explained by the Standard Model (SM), the current best theory describing all the known fundamental particles and their forces. Here we reveal that gravitational force can be precisely given by mass of objects and microwave background (CMB) radiation. Moreover, using the same strategy we reveal a relation by which CMB can also precisely define fine-structure constant α.

On the Possibility of Variable Speed of Light in Vacuum

We previously revealed a quantitative relation by which the fine-structure constant α can be described by the temperature T of cosmic microwave background (CMB) with several other fundamental constants, including the elementary charge e, the Boltzmann constant k, the Planck constant h, and the light of speed in vacuum c. Given that the value of α is quite conserved but T is variable across CMBs, we propose that c changes with T and can be given by T, the present CMB temperature T0 and the present light speed c0. As T is continuously decreasing, c is thus predicted to decrease at a rate of ~2.15 centimeters/second (cm/s) per year. Moreover, we provide a lot of evidence to support this finding. In conclusion, this study suggests a possibility of variable speed of light in vacuum.

LiOH: A "double-edged" effect toward electrochemical oxidation of Li_(2)O_(2)

The aprotic lithium-oxygen battery(Li-O_(2) battery) has attracted much attraction for the future advanced battery technologies due to its ultra-high theoretical energy density that can well meet the ever-growing energy demand of portable electronic products,electric vehicles(EVs),smart grids,and so on [1-5].In principle.

Revisiting influenza A virus life cycle from a perspective of genome balance

Influenza A virus(IAV)genome comprises eight negative-sense RNA segments,of which the replication is well orchestrated and the delicate balance of multiple segments are dynamically regulated throughout IAV life cycle.However,previous studies seldom discuss these balances except for functional hemagglutinin-neuraminidase balance that is pivotal for both virus entry and release.Therefore,we attempt to revisit IAV life cycle by highlighting the critical role of“genome balance”.Moreover,we raise a“balance regression”model of IAV evolution that the virus evolves to rebalance its genome after reassortment or interspecies transmission,and direct a“balance compensation”strategy to rectify the“genome imbalance”as a result of artificial modifications during creation of recombinant IAVs.This review not only improves our understanding of IAV life cycle,but also facilitates both basic and applied research of IAV in future.

Optimization and applications of an in vivo bioluminescence imaging model of influenza A virus infections

Dear Editor,In vivo bioluminescence imaging(BLI)models of virus infection possess unique advantages over conventional assays.For instance,the BLI model enables rapid and real-time detection of viral load and dissemination in the same animal over time(Mehle,2015;Wen et al.,2022).

MicroRNA–disease Network Analysis Repurposes Methotrexate for the Treatment of Abdominal Aortic Aneurysm in Mice

Abdominal aortic aneurysm(AAA)is a permanent dilatation of the abdominal aorta and is highly lethal.The main purpose of the current study is to search for noninvasive medical therapies for AAA,for which there is currently no effective drug therapy.Network medicine represents a cuttingedge technology,as analysis and modeling of disease networks can provide critical clues regarding the etiology of specific diseases and therapeutics that may be effective.Here,we proposed a novel algorithm to quantify disease relations based on a large accumulated microRNA–disease association dataset and then built a disease network covering 15 disease classes and 304 diseases.Analysis revealed some patterns for these diseases.For instance,diseases tended to be clustered and coherent in the network.Surprisingly,we found that AAA showed the strongest similarity with rheumatoid arthritis and systemic lupus erythematosus,both of which are autoimmune diseases,suggesting that AAA could be one type of autoimmune diseases in etiology.Based on this observation,we further hypothesized that drugs for autoimmune diseases could be repurposed for the prevention and therapy of AAA.Finally,animal experiments confirmed that methotrexate,a drug for autoimmune diseases,was able to alleviate the formation and development of AAA.

Allopregnanolone targets nucleoprotein as a novel influenza virus inhibitor

Influenza A virus(IAV)poses a global public health concern and remains an imminent threat to human health.Emerging antiviral resistance to the currently approved influenza drugs emphasizes the urgent need for new therapeutic entities against IAV.Allopregnanolone(ALLO)is a natural product that has been approved as an antidepressant drug.In the present study,we repurposed ALLO as a novel inhibitor against IAVs.Mechanistic studies demonstrated that ALLO inhibited virus replication by interfering with the nucleus translocation of viral nucleoprotein(NP).In addition,ALLO showed significant synergistic activity with compound 16,a hemagglutinin inhibitor of IAVs.In summary,we have identified ALLO as a novel influenza virus inhibitor targeting NP,providing a promising candidate that deserves further investigation as a useful anti-influenza strategy in the future.

SARS-CoV-2 cell entry and targeted antiviral development

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative agent of the pandemic coronavirus disease 2019(COVID-19),which threatens human health and public safety.In the urgent campaign to develop anti-S ARS-CoV-2 therapies,the initial entry step is one of the most appealing targets.In this review,we summarize the current understanding of SARS-CoV-2 cell entry,and the development of targeted antiviral strategies.Moreover,we speculate upon future directions toward nextgeneration of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.

PTMD: A Database of Human Disease-associated Post-translational Modifications

Various posttranslational modifications （PTMs） participate in nearly all aspects of biological processes by regulating protein functions, and aberrant states of PTMs are frequently implicated in human diseases. Therefore, an integral resource of PTM–disease associations （PDAs）would be a great help for both academic research and clinical use. In this work, we reported PTMD,a well-curated database containing PTMs that are associated with human diseases. We manually collected 1950 known PDAs in 749 proteins for 23 types of PTMs and 275 types of diseases from the literature. Database analyses show that phosphorylation has the largest number of disease associations, whereas neurologic diseases have the largest number of PTM associations. We classified all known PDAs into six classes according to the PTM status in diseases and demonstrated that the upregulation and presence of PTM events account for a predominant proportion of diseaseassociated PTM events. By reconstructing a disease–gene network, we observed that breast cancers have the largest number of associated PTMs and AKT1 has the largest number of PTMs connected to diseases. Finally, the PTMD database was developed with detailed annotations and can be a useful resource for further analyzing the relations between PTMs and human diseases. PTMD is freely accessible at http：//ptmd.biocuckoo.org.

Li_2O_2 oxidation: the charging reaction in the aprotic Li-O_2 batteries

Aprotic Li-O2 battery has attracted a great deal of interest because of its high theoretical energy density that is far beyond what the best Li-ion technologies can achieve.However, the present Li-O2 batteries suffer from the low energy efficiency that is limited mainly by the high overpotentials required to re-oxidize Li2O2, the discharge product. Over the past few years, considerable research efforts have been devoted to the understanding of the Li2O2 oxidation reactions. Here, we summarize the results obtained from the fundamental study of the Li2O2 oxidation, including its morphology, reaction route, kinetics, the initial location upon oxidation and the charge transport within Li2O2. A better mechanistic understanding of the Li2O2 oxidation reaction will provide a solid foundation for the realization of practical Li-O2 cells with a higher energy efficiency.

Commutative regulation between endothelial NO synthase and insulin receptor substrate 2 by microRNAs

Endothelial NO synthase (eNOS) expression is regulated by a number of transcriptional and post-transcriptional mechanisms, but the effects of competing endogenous RNAs (ceRNAs) on eNOS mRNA and the underlying mechanisms are still unknown. Our bioinformatic analysis revealed three highly expressed eNOS-targeting miRNAs (miR-15b, miR-16, and miR-30b) in human endothelial cells (ECs). Among the 1103 mRNA targets of these three miRNAs, 15 mRNAs share a common disease association with eNOS. Gene expression and correlation analysis in patients with cardiovascular diseases identified insulin receptor substrate 2 (IRS2) as the most correlated eNOS-ceRNA. The expression levels of eNOS and IRS2 were coincidentally increased by application of laminar shear but reduced with eNOS or IRS2 siRNA transfection in human ECs, which was impeded by Dicer siRNA treatment. Moreover, luciferase reporter assay showed that these three miRNAs directly target the 3′UTR of eNOS and IRS2. Overexpression of these three miRNAs decreased, whereas inhibition of them increased, both mRNA and protein levels of eNOS and IRS2. Functionally, silencing eNOS suppressed the Akt signal pathway, while IRS2 knockdown reduced NO production in ECs. Thus, we identified eNOS and IRS2 as ceRNAs and revealed a novel mechanism explaining the coincidence of metabolic and cardiovascular diseases.

Comparative Analysis of Human Genes Frequently and Occasionally Regulated by m^6A Modification

The m^6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only some genes are repeatedly modified across various conditions and the principle of m^6A regulation remains elusive. In this study, we performed a systems-level analysis of human genes frequently regulated by m^6A modification （m^6Afreq genes） and those occasionally regulated by m^6A modification （m^6Aocca genes）. Compared to the m^6Aocca genes, the m^6Afreq genes exhibit gene importance-related features, such as lower dN/dS ratio, higher protein-protein interaction network degree, and reduced tissue expression specificity. Signaling network analysis indicates that the m^6Afreq genes are associated with downstream components of signaling cascades, high-linked signaling adaptors, and specific network motifs like incoherent feed forward loops. Moreover, functional enrichment analysis indicates significant overlaps between the m^6Afreq genes and genes involved in various layers of gene expression, such as being the microRNA targets and the regulators of RNA processing. Therefore, our findings suggest the potential interplay between m^6A epitranscriptomic regulation and other gene expression regulatory machineries.

Identification and Analysis of Human Sex-biased MicroRNAs

Sex differences are widely observed under various circumstances ranging from physiolog- ical processes to therapeutic responses, and a myriad of sex-biased genes have been identified. In recent years, transcriptomic datasets of microRNAs （miRNAs）, an important class of non-coding RNAs, become increasingly accessible. However, comprehensive analysis of sex difference in miRNA expression has not been performed. Here, we identified the differentially-expressed miR- NAs between males and females by examining the transcriptomic datasets available in public data- bases and conducted a systemic analysis of their biological characteristics. Consequently, we identified 73 female-biased miRNAs （FmiRs） and 163 male-biased miRNAs （MmiRs） across four tissues including brain, colorectal mucosa, peripheral blood, and cord blood. Our results suggest that compared to FmiRs, MmiRs tend to be clustered in the human genome and exhibit higher evolutionary rate, higher expression tissue specificity, and lower disease spectrum width. In addition.functional enrichment analysis of miRNAs show that FmiR genes are significantly associated with metabolism process and cell cycle process, whereas MmiR genes tend to be enriched for functions like histone modification and circadian rhythm. In all, the identification and analysis of sex-biased miRNAs together could provide new insights into the biological differences between females and males and facilitate the exploration of sex-biased disease susceptibility and therapy.

Flu Universal Vaccines: New Tricks on an Old Virus

Conventional influenza vaccines are based on predicting the circulating viruses year by year,conferring limited effectiveness since the antigenicity of vaccine strains does not always match the circulating viruses.This necessitates development of universal influenza vaccines that provide broader and lasting protection against pan-influenza viruses.The discovery of the highly conserved immunogens(epitopes)of influenza viruses provides attractive targets for universal vaccine design.Here we review the current understanding with broadly protective immunogens(epitopes)and discuss several important considerations to achieve the goal of universal influenza vaccines.

The DrugPattern tool for drug set enrichment analysis and its prediction for beneficial effects of oxLDL on type 2 diabetes

Enrichment analysis methods, e.g., gene set enrichment analysis, represent one class of important bio- informatical resources for mining patterns in biomedical datasets. However, tools for inferring patterns and rules of a list of drugs are limited. In this study, we developed a web-based tool, DrugPattern, for drug set enrichment analysis. We first collected and curated 7019 drug sets, including indications, adverse reactions, targets, pathways, etc. from public databases. For a list of interested drugs, DrugPat- tern then evaluates the significance of the enrichment of these drugs in each of the 7019 drug sets. To validate DrugPattern, we employed it for the prediction of the effects of oxidized low-density lipoprotein （oxLDL）, a factor expected to be deleterious. We predicted that oxLDL has beneficial effects on some diseases, most of which were supported by evidence in the literature. Because DrugPattern predicted the potential beneficial effects of oxLDL in type 2 diabetes （T2D）, animal experiments were then performed to further verify this prediction. As a result, the experimental evidences validated the DrugPattern prediction that oxLDL indeed has beneficial effects on T2D in the case of energy restriction. These data confirmed the prediction accuracy of our approach and revealed unexpected protective roles for oxLDL in various diseases. This study provides a tool to infer patterns and rules in biomedical datasets based on drug set enrichment analysis.

Single-cell RNA sequencing-based immunological feature analysis of a COVID-19 patient with recurrent positive SARS-CoV-2 RNA

To the Editor:Since the outbreak in December 2019,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has infected>2.4 billion people worldwide,resulting in>4.9 million deaths.To understand the pathogenesis of SARS-CoV-2 infection,single-cell RNA-sequencing(scRNA-seq)profiles of peripheral blood mononuclear cells(PBMCs)have been constructed in coronavirus disease-2019(COVID-19)patients at different disease stages.