Immunosuppressants exert antiviral effects against influenza A(H1N1)pdm09 virus via inhibition of nucleic acid synthesis, mRNA splicing, and protein stability.

Influenza A virus (IAV) poses a threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even death. Understanding the direct effects of immunosuppressants on IAV infection is critical for optimizing immunosuppression in these patients who are infected or at risk of influenza virus infection. We profiled the effects of 10 immunosuppressants, explored the antiviral mechanisms of immunosuppressants, and demonstrated the combined effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibits viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through a proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibits IAV viral particle production in an additive or synergic manner. Our results suggest that MPA, 6-TG, and filgotinib could be the preferential choices for patients who must take immunosuppressants but are at risk of influenza virus infection.

An Innovative model of magnetically intercalated expanded graphite for calculating radar attenuation performance at 2-18 GHz.

With the emergence of various filtering technologies, the radar jamming efficiency of the technology based on radar cross section is ever lower, therefore cannot meet military requirements. In this context, the jamming technology based on attenuation mechanism has been developed and plays an increasingly important role in disturbing radar detecting. Magnetically expanded graphite (MEG) has excellent attenuation efficiency because it can cause dielectric loss as well as magnetic loss. Moreover, MEG features good impedance matching, which makes more incidence of electromagnetic waves into the material; and its multi-layer structure is conducive for electromagnetic wave reflection and absorption. In this work, the structure model of MEG was established by analyzing the layered structure of expanded graphite (EG) and the dispersion of intercalated magnetic particles. The electromagnetic parameters of thus-modeled MEG were calculated based on the equivalent medium theory; and effects of EG size, magnetic particle type and volume fraction on the attenuation performance were studied by the variational method. It is indicated that MEG with 500-µm diameter has the best attenuation effect and the highest increment of absorption cross section appears at 50% volume fraction of the magnetic particles at 2 GHz. The imaginary part of complex permeability of the magnetic material has the most significant influence on the attenuation effect of MEG. This study provides guidance for the design and application of MEG materials in disturbing radar detecting field.

(±)-Involucrasins A and B, two pairs of flavanone enantiomers from Shuteria involucrata and their inhibitory effects on the proliferation of various cancer cell lines.

(±)-Involucrasins A (1) and B (2), two pairs of flavanone enantiomers were isolated from Shuteria involucrata. Structurally, both 1 and 2 are rare representatives of 5-dehydroxy/5-demethoxy 2',3',4'-trisubstituted flavanones. Their structures were elucidated on the basis of comprehensive spectroscopic data analysis and comparison with the literature data. Involucrasin B (2) exhibited moderate anti-proliferative activity against Caco-2, MCF-7, MDA-MB-468, and HCT116 cell lines with IC50 values ranging from 7.9-22.7 µM. Involucrasin A (1) exhibited weak inhibitory activity against Caco-2 and MCF-7 cell lines with IC50 values of 25.8 and 26.5 µM, respectively.

Codon Usage Bias in Autophagy-Related Gene 13 in Eukaryotes: Uncovering the Genetic Divergence by the Interplay Between Nucleotides and Codon Usages.

Synonymous codon usage bias is a universal characteristic of genomes across various organisms. Autophagy-related gene 13 (atg13) is one essential gene for autophagy initiation, yet the evolutionary trends of the atg13 gene at the usages of nucleotide and synonymous codon remains unexplored. According to phylogenetic analyses for the atg13 gene of 226 eukaryotic organisms at the nucleotide and amino acid levels, it is clear that their nucleotide usages exhibit more genetic information than their amino acid usages. Specifically, the overall nucleotide usage bias quantified by information entropy reflected that the usage biases at the first and second codon positions were stronger than those at the third position of the atg13 genes. Furthermore, the bias level of nucleotide 'G' usage is highest, while that of nucleotide 'C' usage is lowest in the atg13 genes. On top of that, genetic features represented by synonymous codon usage exhibits a species-specific pattern on the evolution of the atg13 genes to some extent. Interestingly, the codon usages of atg13 genes in the ancestor animals (Latimeria chalumnae, Petromyzon marinus, and Rhinatrema bivittatum) are strongly influenced by mutation pressure from nucleotide composition constraint. However, the distributions of nucleotide composition at different codon positions in the atg13 gene display that natural selection still dominates atg13 codon usages during organisms' evolution.

Inhibiting pyrimidine biosynthesis impairs Peste des Petits Ruminants Virus replication through depletion of nucleoside pools and activation of cellular immunity.

Replication of peste des petits ruminants virus (PPRV) strongly depends on the cellular environment and resources of host cells including nucleoside pool. Thus, enzymes involved in nucleoside biosynthesis (such as pyrimidine biosynthesis pathway) are regarded as attractive targets for antiviral drug development. Here, we demonstrate that brequinar (BQR) and leflunomide (LFM) which are two specific inhibitors of DHODH enzyme and 6-azauracil (6-AU) which is an ODase enzyme inhibitor robustly inhibit PPRV replication in HEK293T cell line as well as in peripheral blood mononuclear cells isolated from goat. We further demonstrate that these agents exert anti-PPRV activity via the depletion of purimidine nucleotide. Interestingly, these inhibitors can trigger the transcription of antiviral interferon-stimulated genes (ISGs). However, the induction of ISGs is largely independent of the classical JAK-STAT pathway. Combination of BQR with interferons (IFNs) exerts enhanced ISG induction and anti-PPRV activity. Taken together, this study reveals an unconventional novel mechanism of crosstalk between nucleotide biosynthesis pathways and cellular antiviral immunity in inhibiting PPRV replication. In conclusion, targeting pyrimidine biosynthesis represents a potential strategy for developing antiviral strategies against PPRV.

Effect of mangrove restoration on sediment properties and bacterial community.

Mangrove reconstruction is an efficient approach for mangrove conservation and restoration. The present study aimed to explore the effects of mangrove reconstruction on sediment properties and bacterial community. The results showed that mangrove restoration greatly promoted sediment fertility, whereas the improvements were more obvious induced by Kandelia obovata when compared to Avicennia marina. In all the samples, the dominant top5 bacterial group were Proteobacteria (48.31-54.52%), Planctomycetes (5.98-8.48%), Bacteroidetes (4.49-11.14%) and Acidobacteria (5.69-8.16%). As for the differences among the groups, the relative abundance of Chloroflexi was higher in the sediments of K. obovata, while Bacteroidetes was more abundant in A. marina group. Furthermore, the two bacterial genera (Rhodoplanes and Novosphingobium) were more dominant in the sediments of K. obovata, while the sediments of A. marina contained higher abundance of Vibrio and Marinobacterium. Besides, bacterial community was highly correlated with mangrove species and sediment property and nutrient status. The results of this study would provide a better understanding of the ecological benefits of mangroves and highlighted the information on biogeochemical processes driven by mangrove restoration and microorganisms.

Sweritranslactone D, a hepatoprotective novel secoiridoid dimer with tetracyclic lactone skeleton from heat-transformed swertiamarin.

Swertia mileensis, known as Qing-Ye-Dan (QYD), has been documented in Chinese Pharmacopoeia to cure hepatitis. Interestingly, its announced main active component, swertiamarin, could not be detected in the decoction, which indicated that the efficacy of QYD might be attributed to heat-transformed products of swertiamarin (HTPS). Further investigation on HTPS led to the isolation of sweritranslactone D (1), a novel secoiridoid dimer possessing a tetracyclic lactone skeleton, with better hepatoprotective activity than N-acetyl-L-cysteine in vitro.

The nucleotide usages significantly impact synonymous codon usage in Mycoplasma hyorhinis.

Five annotated genomes of Mycoplasma hyorhinis were analyzed for clarifying evolutionary dynamics driving the overall codon usage pattern. Information entropy used for estimating nucleotide usage pattern at the gene level indicates that multiple evolutionary dynamics participate in forcing nucleotide usage bias at every codon position. Moreover, nucleotide usage bias directly contributes to synonymous codon usage biases with two different extremes. The overrepresented codons tended to have A/T in the third codon position, and the underrepresented codons strongly used G/C in the third position. Furthermore, correspondence analysis and neutrality plot reflect an obvious interplay between mutation pressure and natural selection mediating codon usage in M. hyorhinis genome. Due to significant bias in usages between A/T and G/C at the gene level, different selective forces have been proposed to contribute to codon usage preference in M. hyorhinis genome, including nucleotide composition constraint derived from mutation pressure, translational selection involved in natural selection, and strand-specific mutational bias represented by different nucleotide skew index. The systemic analyses of codon usage for M. hyorhinis can enable us to better understand the mechanisms of evolution in this species.

Prevalence and clinical features of hepatitis E virus infection in pregnant women: A large cohort study in Inner Mongolia, China.

BACKGROUND AND AIM: Hepatitis E virus (HEV) infection causes severe maternal and fetal outcomes in pregnant women. These patients are exclusively from resource-limited regions with genotype 1 HEV infection, but not from western countries with genotype 3 prevalence. Since the circulating strains in China have evolved from the waterborne genotype 1 to the zoonotic genotype 4 HEV in the past decades, this study aims to evaluate the prevalence and clinical features of HEV infection in a large cohort of pregnant women in Inner Mongolia, China. METHODS: A total of 3278 pregnant women who visited the Inner Mongolia Maternal and Child Care hospital during 2018 were enrolled. Serum samples were examined for anti-HEV IgG and anti-HEV IgM antibodies using ELISA. Demographic information, results of clinical biochemical tests, maternal and neonatal outcomes were collected. RESULTS: Among the recruited 3278 pregnant women, 6.0% were anti-HEV IgG antibody positive, 0.3% were anti-HEV IgM antibody positive and 0.3% were positive for both anti-HEV IgG and anti-HEV IgM antibodies. HEV viral RNA was not detected. Pregnant women with recent/ongoing HEV infection indicated by anti-HEV IgM positivity have slightly higher ALT level, and potential risk of developing hyperlipidemia, preterm delivery and neonatal jaundice. CONCLUSIONS: These findings indicated that HEV infection is associated with a possible increase in adverse maternal, fetal and neonatal outcomes in our cohort. Thus, the burden of HEV infection in pregnant women in China appears distinct from resource-limited regions and western countries. Nevertheless, future studies are required to confirm and extend our findings.

Antiviral responses of ATG13 to the infection of peste des petits ruminants virus through activation of interferon response.

Not only are autophagy-related (ATG) proteins the essential orchestrators of the autophagy machinery, but also they regulate many other cellular pathways. Here, we demonstrated that ATG13 exerted an obviously antiviral activity against the infection of peste des petits ruminants virus (PPRV) in cell culture model. We found that PPRV infection or the treatment with interferon (IFN) against PPRV infection significantly induced ATG13 expression. Mechanistically, ATG13 stimulated interferon expression and the subsequent activation of the JAK-STAT cascade. These activations triggered the transcription of interferon-stimulated genes (ISGs) to exert antiviral activity. Conversely, the loss of ATG13 significantly attenuated the potency of RIG-IN in activating IFN responses. In summary, we have demonstrated that basal ATG13 was involved in host antiviral activities against PPRV infection and the over-expression of ATG13 activated IFN production to inhibit PPRV replication in an unconventional fashion.

Nitrogen dynamics in the mangrove sediments affected by crabs in the intertidal regions.

Crab is an important benthonic animal in mangrove ecosystem, however, the potential function of crabs on nitrogen (N) transformation in mangrove ecosystems is still poorly understood. The present study aimed to explore the potential effect of crab burrows on nitrification/denitrification within the sediments. The results showed that the presence of crab burrows could directly promote soil nitrification, the regions within more crab burrows appeared to possess higher nitrification. Higher AOA and AOB gene copies were also observed in the sediments surrounding crab burrows than those in the sediments without crab burrow. On the contrary, lower nirS copies, a denitrification related gene, were detected in the sediments surrounding crab burrows. In summary, the present study proposed new evidences of nitrification enhancement deriving by crabs, the presence of crabs might be significant in alleviating nitrification inhibition and benefits the growth of mangroves under tidal flooding.

Significance and roles of synonymous codon usage in the evolutionary process of Proteus.

Proteus spp. bacteria frequently serve as opportunistic pathogens that can infect many animals and show positive survival and existence in various natural environments. The evolutionary pattern of Proteus spp. is an unknown topic, which benefits understanding the different evolutionary dynamics for excellent bacterial adaptation to various environments. Here, the eight whole genomes of different Proteus species were analyzed for the interplay between nucleotide usage and synonymous codon usage. Although the orthologous average nucleotide identity and average nucleotide identity display the genetic diversity of these Proteus species at the genome level, the principal component analysis further shows that these species sustain the specific genetic niche at the aspect of synonymous codon usage patterns. Interestingly, although these Proteus species have A/T rich genes with underrepresented G (guanine) or C (cytosine) at the third codon positions and overrepresented A or T at these positions, some synonymous codons with A or T end are obviously suppressed in usage. The overall codon usage pattern reflected by the effective number of codons (ENC) has a significantly positive correlation with GC3 content (GC content at the third codon position), and ENC has a significantly negative correlation with the adaptation index for these species. These results suggest that the mutation pressure caused by nucleotide composition constraint serves as a dominant evolutionary dynamic driving evolutionary trend of Proteus spp., along with other selections related to natural selection, replication and fine-tune translation, and so on. Taken together, the analyses help to understand the evolutionary interplay between nucleotide and codon usage at the gene level of Proteus.

Basal interferon signaling and therapeutic use of interferons in controlling peste des petits ruminants virus infection.

Peste des petits ruminants virus (PPRV) is a morbillivirus which causes severe disease in ruminants. Since interferons (IFNs) serve as the important defense line against viral infection, we have investigated the roles of types I and III IFNs in PPRV infection in vitro. Upon PPRV infection, IFN-λ3 was strongly induced, while IFN-ß and IFN-λ2 were moderately induced at transcriptional level in human embryonic kidney 293 T (HEK293T) cells. Although the transcription of type I and III IFNs were triggered, the production of functional IFN products was not detected. Importantly, the replication of PPRV was strongly inhibited in HEK293T cells treated by the exogenous IFNs (IFN-α-2b, IFN-ß and IFN-λ3). Consistently, these IFNs significantly activate a panel of IFN-stimulated genes (ISGs). The inhibition of JAK-STAT pathway by JAK I inhibitor can abrogate the anti-PPRV activity of IFNs. Thus, our study shall contribute to better understanding of the complex PPRV-host interactions and provide rationale for therapeutic development of IFN-based treatment against PPRV infection.

Outcome of a screening program for the prevention of neonatal early-onset group B Streptococcus infection: a population-based cohort study in Inner Mongolia, China.

PURPOSE: Invasive early-onset group B Streptococcus infection (EOGBS) is an important cause of severe neonatal complications but study on comprehensive GBS screening is lacking in China. This study aims to investigate the outcome of a regional anterpartum screening program for EOGBS prevention and to estimate the pros and cons of a new GBS screening strategy employed. METHODS: We performed an optimized hospital strategy for GBS screening, which targeted expectant mothers (including those with preterm births) from January 2016 to December 2016 in a population-based cohort. Three common screening strategies were simulated to estimate the availability of the hospital strategy used in this study. RESULTS: Altogether, 9770 eligible women were tested and the rate of GBS carriage was 2.7  % (266/9770). In total, 198 of the 266 maternal GBS carriers accepted intrapartum antibiotic prophylaxis (IAP) treatment. Among the 9860 neonates of 9770 mothers, four cases of EOGBS infection were identified and one case was missed (EOGBS incidence with screening and IAP: 0.5/1000). Risk factors for maternal GBS colonization included preterm birth (between 35 and 37 weeks) [odds ratio (OR)=1.7 (95  % confidence interval: 1.22-2.33)], region of origin, resident areas, maternal age (older than 34 years) [OR=1.5 (1.06-2.09)], prelabour rupture of membranes [OR=1.8 (1.34-2.35)], gestational diabetes mellitus [OR=1.6 (1.14-2.28)] and maternal mild anemia (Hb: 90-110 g dl-1) [OR=1.5 (1.16-2.06)]. This new screening strategy resulted in less antibiotic exposure and least number of cases missed. CONCLUSIONS: Our findings illustrate that this perinatal screening (including preterm births) for prevention of EOGBS infection can be implemented in the Inner Mongolian area.

The complete chloroplast genome sequence of Aconitum austroyunnanense W. T. Wang (Ranunculaceae): a medicinal plant endemic to China.

The complete chloroplast (cp) genome of Aconitum austroyunnanense W. T. Wang, a rare and endangered medicinal plant endemic to southwestern China, was sequenced to be 155,818 bp in length, including two inverted repeat (IR, 26,128 bp) regions, one large single-copy region (LSC) and one small single-copy region (SSC) of 86,555 bp and 17,007 bp, respectively. The cp genome has 131 annotated genes, including 85 protein-coding genes, 37 tRNA genes, 8 rRNA genes, and a pseudogene (ycf1). The overall GC content of it is 38.1%. Phylogenetic analysis revealed that the cp genome of A. austroyunnanense is closely related to that of Aconitum hemsleyanum.

The Burden of Human Papillomavirus and Chlamydia trachomatis Coinfection in Women: A Large Cohort Study in Inner Mongolia, China.

Background: Chlamydia trachomatis may coinfect with human papillomavirus (HPV) and complicate the cervical pathogenesis. This study aimed to evaluate the prevalence, risk factors, and clinical outcomes of HPV/C. trachomatis coinfection in women from Inner Mongolia, China. Methods: We performed a polymerase chain reaction (PCR)-based HPV/C. trachomatis screening and cervical samples were analyzed by thinprep cytologic test. Statistical analysis was used to assess the association between demographic factors and coinfection. Results: Among the 2345 women recruited, the prevalences of HPV, C. trachomatis, and HPV/C. trachomatis coinfection were 36.0%, 14.3%, and 4.8%, respectively. The rate of multiple HPV genotypes was higher in coinfected women. HPV66 was the most frequently identified genotype in coinfected participants. The HPV DNA load was significantly higher in HPV monoinfected cases. In contrast, the DNA load of C. trachomatis was significantly higher in the coinfection group. Risk factors, including single women (odds ratio [OR] = 6.0, 95% confidence interval [CI], 4.044-8.782) and women with multiple sex partners (OR = 1.9, 95% CI, 1.324-2.824), were associated with coinfection. Importantly, coinfection was associated with increased risk for high-grade squamous intraepithelial lesions. Conclusions: HPV and C. trachomatis coinfection is an important risk factor for the progression of cervical lesions.

The IMPDH inhibitors, ribavirin and mycophenolic acid, inhibit peste des petits ruminants virus infection.

Peste des petits ruminants virus (PPRV) causes highly contagious diseases in domestic and particular wild small ruminants, leading to substantial economic loss. The development of effective and cheap antiviral medications shall help to circumvent this emerging burden. In this study, we found that ribavirin, a competitive inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor, significantly inhibits the replication of PPRV. As IMPDH is a key enzyme in purine nucleotide synthesis, supplementation of exogenous guanosine attenuate the anti-PPRV effect of ribavirin. Interestingly, an uncompetitive IMPDH inhibitor, mycophenolic acid (MPA), exerted more potent antiviral effect again PPRV. Similarly, this effect was largely restored upon supplementation of guanosine. Thus, we have demonstrated that the IMPDH inhibitors ribavirin and MPA combat PPRV infection through purine nucleotide depletion. Because both regimens have been widely used in the clinic for treating viral infection or organ rejection in transplantation patients for decades, respectively, repurposing these existing safe and cheap medications may provide a new avenue for combating PPRV infection.

The effects of codon usage on the formation of secondary structures of nucleocapsid protein of peste des petits ruminants virus.

The nucleocapsid (N) protein of peste des petits ruminants virus (PPRV) with a conserved amino acid usage pattern plays an important role in viral replication. The primary objective of this study was to estimate roles of synonymous codon usages of PPRV N gene and tRNA abundances of host in the formation of secondary structure of N protein. The potential effects of synonymous codon usages of N gene and tRNA abundances of host on shaping different folding units (α-helix, ß-strand and the coil) in N protein were estimated, based on the information about the modeling secondary structure of PPRV N protein. The synonymous codon usage bias was found in different folding units in PPRV N protein. To better understand the role of translation speed caused by variant tRNA abundances in shaping the specific folding unit in N protein, we modeled the changing trends of tRNA abundance at the transition boundaries from one folding unit to another folding unit (ß-strand â†’ coil, coil â†’ ß-strand, α-helix â†’ coil, coil â†’ α-helix). The obvious fluctuations of tRNA abundance were identified at the two transition boundaries (ß-strand â†’ coil and coil â†’ ß-strand) in PPRV N protein. Our findings suggested that viral synonymous codon usage bias and cellular tRNA abundance variation might have potential effects on the formation of secondary structure of PPRV N protein.

Type I Interferon Induced and Antagonized by Foot-and-Mouth Disease Virus.

Viral infections trigger the innate immune system, serving as the first line of defense, and are characterized by the production of type I interferon (IFN). Type I IFN is expressed in a broad spectrum of cells and tissues in the host and includes various subtypes (IFN-α, IFN-ß, IFN-δ, IFN-ε, IFN-κ, IFN-τ, IFN-ω, IFN-ν, and IFN-ζ). Since the discovery of type I IFN, our knowledge of the biology of type I IFN has accumulated immensely, and we now have a substantial amount of information on the molecular mechanisms of the response and induction of type I IFN, as well as the strategies utilized by viruses to evade the type I IFN response. Foot-and-mouth disease virus (FMDV) can selectively alter cellular pathways to promote viral replication and evade antiviral immune activation of type I IFN. RNA molecules generated by FMDV are sensed by the cellular receptor for pathogen-associated molecular patterns (PAMPs). FMDV preferentially activates different sensor molecules and various signal transduction pathways. Based on knowledge of the virus or RNA pathogen specificity as well as the function-structure relationship of RNA sensing, it is necessary to summarize numerous signaling adaptors that are reported to participate in the regulation of IFN gene activation.