A small protein encoded by PCBP1-AS1 is identified as a key regulator of influenza virus replication via enhancing autophagy.

Many annotated long noncoding RNAs (lncRNAs) contain small open reading frames (sORFs), some of which have been demonstrated to encode small proteins or micropeptides with fundamental biological importance. However, functions of lncRNAs-encoded small proteins or micropeptides in viral pathogenesis remain largely unexplored. Here, we identified a 110-amino acid small protein as a key regulator of influenza A virus (IAV) replication. This small protein that we call PESP was encoded by the putative lncRNA PCBP1-AS1. It was observed that both PCBP1-AS1 and PESP were significantly upregulated by IAV infection. Furthermore, they were markedly induced by treatment with either type I or type III interferon. Overexpression of either PCBP1-AS1 or PESP alone significantly enhanced IAV replication. In contrast, shRNA-mediated knockdown of PCBP1-AS1 or CRISPR/Cas9-mediated knockout of PESP markedly inhibited the viral production. Moreover, the targeted deletion or mutation of the sORF within the PCBP1-AS1 transcript, which resulted in the disruption of PESP expression, significantly diminished the capacity of PCBP1-AS1 to enhance IAV replication, underscoring the indispensable role of PESP in the facilitation of IAV replication by PCBP1-AS1. Interestingly, overexpression of PESP enhanced the IAV-induced autophagy by increasing the expression of ATG7, an essential autophagy effector enzyme. We also found that the 7-22 amino acids at the N-terminus of PESP were crucial for its functionality in modulating ATG7 expression and action as an enhancer of IAV replication. Additionally, HSP90AA1, a protein identified previously as a facilitator of autophagy, was found to interact with PESP, resulting in the stabilization of PESP and consequently an increase in the production of IAV. These data reveal a critical lncRNA-encoded small protein that is induced and exploited by IAV during its infection, and provide a significant insight into IAV-host interaction network.

ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus.

Autophagy-related protein 7 (ATG7) is an essential autophagy effector enzyme. Although it is well known that autophagy plays crucial roles in the infections with various viruses including influenza A virus (IAV), function and underlying mechanism of ATG7 in infection and pathogenesis of IAV remain poorly understood. Here, in vitro studies showed that ATG7 had profound effects on replication of IAV. Depletion of ATG7 markedly attenuated the replication of IAV, whereas overexpression of ATG7 facilitated the viral replication. ATG7 conditional knockout mice were further employed and exhibited significantly resistant to viral infections, as evidenced by a lower degree of tissue injury, slower body weight loss, and better survival, than the wild type animals challenged with either IAV (RNA virus) or pseudorabies virus (DNA virus). Interestingly, we found that ATG7 promoted the replication of IAV in autophagy-dependent and -independent manners, as inhibition of autophagy failed to completely block the upregulation of IAV replication by ATG7. To determine the autophagy-independent mechanism, transcriptome analysis was utilized and demonstrated that ATG7 restrained the production of interferons (IFNs). Loss of ATG7 obviously enhanced the expression of type I and III IFNs in ATG7-depleted cells and mice, whereas overexpression of ATG7 impaired the interferon response to IAV infection. Consistently, our experiments demonstrated that ATG7 significantly suppressed IRF3 activation during the IAV infection. Furthermore, we identified long noncoding RNA (lncRNA) GAPLINC as a critical regulator involved in the promotion of IAV replication by ATG7. Importantly, both inactivation of IRF3 and inhibition of IFN response caused by ATG7 were mediated through control over GAPLINC expression, suggesting that GAPLINC contributes to the suppression of antiviral immunity by ATG7. Together, these results uncover an autophagy-independent mechanism by which ATG7 suppresses host innate immunity and establish a critical role for ATG7/GAPLINC/IRF3 axis in regulating IAV infection and pathogenesis.

Zonation of bulk and rhizosphere soil bacterial communities and their covariation patterns along the elevation gradient in riparian zones of three Gorges reservoir, China.

Zonation is a typical pattern of soil distribution and species assembly across riparian habitats. Microorganisms are essential members of riparian ecosystems and whether soil microbial communities demonstrate similar zonation patterns and how bulk and rhizosphere soil microorganisms interact along the elevation (submergence stress) gradient remain largely unknown. In this study, bulk and rhizosphere (dominant plant) soil samples were collected and investigated across riparian zones where the submergence stress intensity increased as the elevation decreased. Results showed that the richness of bacterial communities in bulk and rhizosphere soil samples was significantly different and presented a zonation pattern along with the submergence stress gradient. Bulk soil at medium elevation that underwent moderate submergence stress had the most abundant bacterial communities, while the species richness of rhizobacteria at low elevation that experienced serious submergence stress was the highest. Additionally, principal coordinate analysis (PCoA) and significance tests showed that bulk and rhizosphere soil samples were distinguished according to the structure of bacterial communities, and so were bulk or rhizosphere soil samples from different elevations. Redundancy analysis (RDA) and Mantel test suggested that bacterial communities of bulk soil mainly relied on the contents of soil organic matter, total carbon (TC), total nitrogen (TN), sodium (Na), calcium (Ca) and magnesium (Mg). Contrastingly, the contents of Na and Mg were the main factors explaining the variation in rhizobacterial community composition. Correlation and microbial source tracking analyses showed thatthe relationship of bulk and rhizosphere soil bacteria became much stronger, and the rhizosphere soil may get more bacterial communities from bulk soil with the increase in submergence severity. Our results suggest that the abiotic and biotic components of the riparian ecosystem are closely covariant along the submergence stress gradient and imply that the bacterial community may be a key node linking soil physiochemical properties and vegetation communities.

Citric Acid Promotes Immune Function by Modulating the Intestinal Barrier.

Amidst increasing concern about antibiotic resistance resulting from the overuse of antibiotics, there is a growing interest in exploring alternative agents. One such agent is citric acid, an organic compound commonly used for various applications. Our research findings indicate that the inclusion of citric acid can have several beneficial effects on the tight junctions found in the mouse intestine. Firstly, the study suggests that citric acid may contribute to weight gain by stimulating the growth of intestinal epithelial cells (IE-6). Citric acid enhances the small intestinal villus-crypt ratio in mice, thereby promoting intestinal structural morphology. Additionally, citric acid has been found to increase the population of beneficial intestinal microorganisms, including Bifidobacterium and Lactobacillus. It also promotes the expression of important protein genes such as occludin, ZO-1, and claudin-1, which play crucial roles in maintaining the integrity of the tight junction barrier in the intestines. Furthermore, in infected IEC-6 cells with H9N2 avian influenza virus, citric acid augmented the expression of genes closely associated with the influenza virus infection. Moreover, it reduces the inflammatory response caused by the viral infection and thwarted influenza virus replication. These findings suggest that citric acid fortifies the intestinal tight junction barrier, inhibits the replication of influenza viruses targeting the intestinal tract, and boosts intestinal immune function.

Syk Facilitates Influenza A Virus Replication by Restraining Innate Immunity at the Late Stage of Viral Infection.

Spleen tyrosine kinase (Syk) has recently come forth as a critical regulator of innate immune response. Previous studies identify Syk as a key kinase for STAT1 activation at the early stage of influenza A virus (IAV) infection that is involved in initial antiviral immunity. However, the involvement of Syk in host antiviral immunity during the late phase of IAV infection and its effect on pathogenesis of the virus remain unknown. Here, we found through time course studies that Syk restrained antiviral immune response at the late stage of IAV infection, thereby promoting viral replication. Depletion of Syk suppressed IAV replication in vitro, whereas ectopic expression of Syk facilitated viral replication. Moreover, Syk-deficient mice were employed, and we observed that knockout of Syk rendered mice more resistant to IAV infection, as evidenced by a lower degree of lung injury, slower body weight loss, and an increased survival rate of Syk knockout mice challenged with IAV. Furthermore, we revealed that Syk repressed the interferon response at the late stage of viral infection. Loss of Syk potentiated the expression of type I and III interferons in both Syk-depleted cells and mice. Mechanistically, Syk interacted with TBK1 and modulated its phosphorylation status, thereby impeding TBK1 activation and restraining innate immune signaling that governs interferon response. Together, these findings unveil a role of Syk in temporally regulating host antiviral immunity and advance our understanding of complicated mechanisms underlying regulation of innate immunity against viral invasion. IMPORTANCE Innate immunity must be tightly controlled to eliminate invading pathogens while avoiding autoimmune or inflammatory diseases. Syk is essential for STAT1 activation at the early stage of IAV infection, which is critical for initial antiviral responses. Surprisingly, here a time course study showed that Syk suppressed innate immunity during late phases of IAV infection and thereby promoted IAV replication. Syk deficiency enhanced the expression of type I and III interferons, inhibited IAV replication, and rendered mice more resistant to IAV infection. Syk impaired innate immune signaling through impeding TBK1 activation. These data reveal that Syk participates in the initiation of antiviral defense against IAV infection and simultaneously contributes to the restriction of innate immunity at the late stage of viral infection, suggesting that Syk serves a dual function in regulating antiviral responses. This finding provides new insights into complicated mechanisms underlying interaction between virus and host immune system.

The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection.

The clinical benefits of targeting programmed death-ligand 1 (PD-L1) in various cancers represent a strategy for the treatment of immunosuppressive diseases. Here, it was demonstrated that the expression levels of PD-L1 in cells were greatly upregulated in response to H1N1 influenza A virus (IAV) infection. Overexpression of PD-L1 promoted viral replication and downregulated type-I and type-III interferons and interferon-stimulated genes. Moreover, the association between PD-L1 and Src homology region-2, containing protein tyrosine phosphatase (SHP2), during IAV/H1N1 infection was analyzed by employing the SHP2 inhibitor (SHP099), siSHP2, and pNL-SHP2. The results showed that the expressions of PD-L1 mRNA and protein were decreased under SHP099 or siSHP2 treatment, whereas the cells overexpressing SHP2 exhibited the opposite effects. Additionally, the effects of PD-L1 on the expression of p-ERK and p-SHP2 were investigated in PD-L1-overexpressed cells following WSN or PR8 infection, determining that the PD-L1 overexpression led to the decreased expression of p-SHP2 and p-ERK induced by WSN or PR8 infection. Taken together, these data reveal that PD-L1 could play an important role in immunosuppression during IAV/H1N1 infection; thus, it may serve as a promising therapeutic target for development of novel anti-IAV drugs.

LncRNA LINC02574 Inhibits Influenza A Virus Replication by Positively Regulating the Innate Immune Response.

Studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in regulating virus infection, host immune response, and other biological processes. Although some lncRNAs have been reported to be involved in antiviral immunity, many lncRNAs have unknown functions in interactions between the host and various viruses, especially influenza A virus (IAV). Herein, we demonstrate that the expression of lncRNA LINC02574 can be induced by IAV infection. Treatment with viral genomic RNA, poly (I:C), or interferons (IFNs) significantly stimulated LINC02574 expression, while RIG-I knockdown and IFNAR1 knockout significantly decreased LINC02574 expression after viral infection or IFN treatment. In addition, inhibition of LINC02574 expression in A549 cells enhanced IAV replication, while overexpression of LINC02574 inhibited viral production. Interestingly, knockdown of LINC02574 attenuated the expression of type I and type III IFNs and multiple ISGs, as well as the activation of STAT1 triggered by IAV infection. Moreover, LINC02574 deficiency impaired the expression of RIG-I, TLR3, and MDA5, and decreased the phosphorylation level of IRF3. In conclusion, the RIG-I-dependent interferon signaling pathway can induce LINC02574 expression. Moreover, the data reveal that LINC02574 inhibits IAV replication by positively regulating the innate immune response.

A novel imatinib-upregulated long noncoding RNA plays a critical role in inhibition of tumor growth induced by Abl oncogenes.

BACKGROUND: Dysregulation of long noncoding RNAs (lncRNAs) has been linked to various human cancers. Bcr-Abl oncogene that results from a reciprocal translocation between human chromosome 9 and 22, is associated with several hematological malignancies. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. METHODS: LncRNA cDNA microarray was employed to identify key lncRNAs involved in Bcr-Abl-mediated cellular transformation. Abl-transformed cell survival and xenografted tumor growth in mice were evaluated to dissect the role of imatinib-upregulated lncRNA 1 (IUR1) in Abl-induced tumorigenesis. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR1 knockout (KO) mice were further conducted to address the functional relevance of lncRNA-IUR1 in Abl-mediated leukemia. Transcriptome RNA-seq and Western blotting were performed to determine the mechanisms by which lncRNA-IUR1 regulates Bcr-Abl-induced tumorigenesis. RESULTS: We identified lncRNA-IUR1 as a critical negative regulator of Bcr-Abl-induced tumorigenesis. LncRNA-IUR1 expressed in a very low level in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, it was significantly induced in Abl-positive leukemic cells treated by imatinib. Depletion of lncRNA-IUR1 promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of lncRNA-IUR1 sensitized the cells to apoptosis and suppressed tumor growth. In concert, silencing murine lncRNA-IUR1 in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, lncRNA-IUR1 deficient mice were generated, and we observed that knockout of murine lncRNA-IUR1 facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA-IUR1 deficiency promoted Abl-transformed cell survival and development of leukemia in mice. Mechanistically, we demonstrated that lncRNA-IUR1 suppressed Bcr-Abl-induced tumorigenesis through negatively regulating STAT5-mediated GATA3 expression. CONCLUSIONS: These findings unveil an inhibitory role of lncRNA-IUR1 in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis.

Long Noncoding RNA IFITM4P Regulates Host Antiviral Responses by Acting as a Competing Endogenous RNA.

Long noncoding RNAs (lncRNAs) are involved in numerous cellular processes. Increasing evidence suggests that some lncRNAs function in immunity through various complex mechanisms. However, implication of a large fraction of lncRNAs in antiviral innate immunity remains uncharacterized. Here, we identified an lncRNA called lncRNA IFITM4P that was transcribed from interferon-induced transmembrane protein 4 pseudogene (IFITM4P), a pseudogene belonging to the interferon-induced transmembrane protein (IFITM) family. We found that expression of lncRNA IFITM4P was significantly induced by infection with several viruses, including influenza A virus (IAV). Importantly, lncRNA IFITM4P acted as a positive regulator of innate antiviral immunity. Ectopic expression of lncRNA IFITM4P significantly suppressed IAV replication in vitro, whereas IFITM4P deficiency promoted viral production. We further observed that expression of lncRNA IFITM4P was upregulated by interferon (IFN) signaling during viral infection, and altering the expression of this lncRNA had significant effects on the mRNA levels of several IFITM family members, including IFITM1, IFITM2, and IFITM3. Moreover, lncRNA IFITM4P was identified as a target of the microRNA miR-24-3p, which represses mRNA of IFITM1, IFITM2, and IFITM3. The experiments demonstrated that lncRNA IFITM4P was able to cross-regulate the expression of IFITM family members as a competing endogenous RNA (ceRNA), leading to increased stability of these IFITM mRNAs. Together, our results reveal that lncRNA IFITM4P, as a ceRNA, is involved in innate immunity against viral infection through the lncRNA IFITM4P-miR-24-3p-IFITM1/2/3 regulatory network. IMPORTANCE lncRNAs play important roles in various biological processes, but their involvement in host antiviral responses remains largely unknown. In this study, we revealed that the pseudogene IFITM4P belonging to the IFITM family can transcribe a functional long noncoding RNA termed lncRNA IFITM4P. Importantly, results showed that lncRNA IFITM4P was involved in innate antiviral immunity, which resembles some interferon-stimulated genes (ISGs). Furthermore, lncRNA IFITM4P was identified as a target of miR-24-3p and acts as a ceRNA to inhibit the replication of IAV through regulating the mRNA levels of IFITM1, IFITM2, and IFITM3. These data provide new insight into the role of a previously uncharacterized lncRNA encoded by a pseudogene in the host antiviral response and a better understanding of the IFITM antiviral network.

Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling.

Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, including epidermal growth factor receptor (EGFR) activation. However, how EGFR mediates the suppression of antiviral systems remains unclear. Here, we examined host innate immune responses and their relevant signaling to EGFR upon IAV infection. IAV was found to induce the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) at an early stage of infection. Inhibition of EGFR or ERK suppressed the viral replication but increased the expression of type I and type III interferons (IFNs) and interferon-stimulated genes (ISGs), supporting the idea that IAV escapes from antiviral innate immunity by activating EGFR/ERK signaling. Meanwhile, IAV infection also induced the activation of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Pharmacological inhibition or small interfering RNA (siRNA)-based silencing of SHP2 enhanced the IFN-dependent antiviral activity and reduced virion production. Furthermore, knockdown of SHP2 attenuated the EGFR-mediated ERK phosphorylation triggered by viral infection or EGF stimulation. Conversely, ectopic expression of constitutively active SHP2 noticeably promoted ERK activation and viral replication, concomitant with diminished immune function. Altogether, the results indicate that SHP2 is crucial for IAV-induced activation of the EGFR/ERK pathway to suppress host antiviral responses.IMPORTANCE Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both in vitro and in vivo The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection.

Reciprocal SH2-SH3 Domain Contacts between ITK Molecules Limit T Cell Receptor Signaling in Th2-type CD4+ T Cells.

The nonreceptor tyrosine kinase ITK is a key component of the T cell receptor (TCR) signaling pathway and is required for cytokine production by CD4+ T cells that have differentiated into Th2 cells. Structural and biochemical studies suggest that contacts between the SH2 and SH3 domains of ITK mediate intermolecular self-association, forming a structure that restrains ITK activity by interfering with interactions between ITK and other components of the TCR signaling pathway. Wild-type (WT) ITK and a panel of ITK mutants containing amino acid substitutions in the SH2 and SH3 domains were tested for self-association and for binding to the adaptor protein SLP76, a key ligand for the ITK SH2 domain. WT and ITK mutants were also expressed in Itk-deficient CD4+ T cells via retroviral-mediated gene delivery to analyze their ability to support TCR signaling and cytokine production by Th2 cells. Specific amino acid substitutions in the ITK SH2 or SH3 domains impaired self-association, with the greatest effects being seen when both intermolecular SH2-SH3 domain contacts were disrupted. Two of the SH2 domain substitutions tested reduced ITK self-association but had no effect on binding to SLP-76. When their function was analyzed in Th2 cells, ITK proteins with diminished self-association activity supported greater IL-4 production and calcium flux in response to TCR stimulation compared to WT ITK. Our findings indicate that intermolecular contacts between ITK molecules can restrain the amplitude of TCR signaling, suggesting ITK is a limiting factor for responses by CD4+ T cells.

The impact of COVID-19 on commodity options market: Evidence from China.

Considering the severe economic impact of COVID-19, this study examines COVID-19's influence on the Chinese commodity market. The literature shows that COVID-19's influence in China during its abatement period has not been well investigated. We address this issue by the intraday analysis of the volatility from 16 commodity options contracts in the Chinese commodity options market over the period 2019-2021. We demonstrate that while the pandemic eased in China after its initial outbreak, it still significantly affected the volatility of Chinese agricultural commodities options. In contrast, its impacts on the volatility of options for petrochemicals, ores, and metals are negligible. This pattern reflects the role of pandemic-led supply disruptions affecting agricultural commodity prices as necessities, contributing to higher price volatility relative to non-agricultural commodities, which are less volatile.

Genome-wide analysis of the synonymous codon usage pattern of Streptococcus suis.

Streptococcus suis (S. suis) is a gram-positive coccus that causes disease in humans and animals. The codon usage pattern of bacteria reveals a range of evolutionary changes that assist them to enhance tolerance to environments. To better understand the genetic features during the evolution of S. suis, we performed codon usage analysis. Nine pathogenic strains of different serotypes and different geographical distribution were analyzed to better understand the differences in their evolutionary process. Nucleotide compositions and relative synonymous codon usage (RSCU) analysis revealed that A/T-ending codons are dominant in S. suis. Neutrality analysis, correspondence analysis and ENC-plot results revealed that natural selection is the predominant element prompting codon usage. Cluster analysis based on RSCU was roughly consistent with the dendrogram rooted genomic BLAST analysis. Comparison of synonymous codon usage pattern between S. suis and susceptible hosts (H. sapiens and S. scrofa) revealed that the codon usage of S. suis is separated from the synonymous codon usage of susceptible hosts. The CAI values implied that S. suis includes a series of predicted highly expressed coding sequences contained in metabolism and transcriptional regulation, revealing the necessity of this pathogen to deal with various environmental conditions. The study of codon usage in S. suis may provide evidence involving the molecular evolution of bacteria and a better understanding of evolutionary relationships between S. suis and its corresponding hosts.

Robust expression of p27Kip1 induced by viral infection is critical for antiviral innate immunity.

Influenza A virus (IAV) infection regulates the expression of numerous host genes. However, the precise mechanism underlying implication of these genes in IAV pathogenesis remains largely unknown. Here, we employed isobaric tags for relative and absolute quantification (iTRAQ) to identify host proteins regulated by IAV infection. iTRAQ analysis of mouse lungs infected or uninfected with IAV showed a total of 167 differentially upregulated proteins in response to the viral infection. Interestingly, we observed that p27Kip1, a potent cyclin-dependent kinase inhibitor, was markedly induced by IAV both at mRNA and protein levels through in vitro and in vivo studies. Furthermore, it was shown that innate immune signalling positively regulated p27Kip1 expression in response to IAV infection. Ectopic expression of p27Kip1 in A549 cells dramatically inhibited IAV replication, whereas, p27Kip1 knockdown significantly enhanced the virus replication. in vivo experiments demonstrated that p27Kip1 knockout (KO) mice were more susceptible to IAV than wild-type (WT) mice: exhibiting higher viral load in lung tissue, faster body-weight loss, reduced survival rate and more severe organ damage. Moreover, we found that p27Kip1 overexpression facilitated the degradation of viral NS1 protein, caused a dramatic STAT1 activation and promoted the expression of IFN-ß and several critical antiviral interferon-stimulated genes (ISGs). Increased p27Kip1 expression also restricted infections of several other viruses. Conversely, IAV-infected p27Kip1 KO mice exhibited a sharp increase in NS1 protein accumulation, reduced level of STAT1 activation and decreased expression of IFN-ß and the ISGs in the lung compared to WT animals. These findings reveal a key role of p27Kip1 in enhancing antiviral innate immunity.

GADD34-mediated dephosphorylation of eIF2α facilitates pseudorabies virus replication by maintaining de novo protein synthesis.

Viruses have evolved multiple strategies to manipulate their host's translational machinery for the synthesis of viral proteins. A common viral target is the alpha subunit of eukaryotic initiation factor 2 (eIF2α). In this study, we show that global protein synthesis was increased but the eIF2α phosphorylation level was markedly decreased in porcine kidney 15 (PK15) cells infected with pseudorabies virus (PRV), a swine herpesvirus. An increase in the eIF2α phosphorylation level by salubrinal treatment or transfection of constructs expressing wild-type eIF2α or an eIF2α phosphomimetic [eIF2α(S51D)] attenuated global protein synthesis and suppressed PRV replication. To explore the mechanism involved in the inhibition of eIF2α phosphorylation during PRV infection, we examined the phosphorylation status of protein kinase R-like endoplasmic reticulum kinase (PERK) and double-stranded RNA-dependent protein kinase R (PKR), two kinases that regulate eIF2α phosphorylation during infection with numerous viruses. We found that the level of neither phosphorylated (p)-PERK nor p-PKR was altered in PRV-infected cells or the lungs of infected mice. However, the expression of growth arrest and DNA damage-inducible protein 34 (GADD34), which promotes eIF2α dephosphorylation by recruiting protein phosphatase 1 (PP1), was significantly induced both in vivo and in vitro. Knockdown of GADD34 and inhibition of PP1 activity by okadaic acid treatment led to increased eIF2α phosphorylation but significantly suppressed global protein synthesis and inhibited PRV replication. Collectively, these results demonstrated that PRV induces GADD34 expression to promote eIF2α dephosphorylation, thereby maintaining de novo protein synthesis and facilitating viral replication.

Plant Morphological, Physiological and Anatomical Adaption to Flooding Stress and the Underlying Molecular Mechanisms.

Globally, flooding is a major threat causing substantial yield decline of cereal crops, and is expected to be even more serious in many parts of the world due to climatic anomaly in the future. Understanding the mechanisms of plants coping with unanticipated flooding will be crucial for developing new flooding-tolerance crop varieties. Here we describe survival strategies of plants adaptation to flooding stress at the morphological, physiological and anatomical scale systemically, such as the formation of adventitious roots (ARs), aerenchyma and radial O2 loss (ROL) barriers. Then molecular mechanisms underlying the adaptive strategies are summarized, and more than thirty identified functional genes or proteins associated with flooding-tolerance are searched out and expounded. Moreover, we elaborated the regulatory roles of phytohormones in plant against flooding stress, especially ethylene and its relevant transcription factors from the group VII Ethylene Response Factor (ERF-VII) family. ERF-VIIs of main crops and several reported ERF-VIIs involving plant tolerance to flooding stress were collected and analyzed according to sequence similarity, which can provide references for screening flooding-tolerant genes more precisely. Finally, the potential research directions in the future were summarized and discussed. Through this review, we aim to provide references for the studies of plant acclimation to flooding stress and breeding new flooding-resistant crops in the future.

Development and Effects of Influenza Antiviral Drugs.

Influenza virus is a highly contagious zoonotic respiratory disease that causes seasonal outbreaks each year and unpredictable pandemics occasionally with high morbidity and mortality rates, posing a great threat to public health worldwide. Besides the limited effect of vaccines, the problem is exacerbated by the lack of drugs with strong antiviral activity against all flu strains. Currently, there are two classes of antiviral drugs available that are chemosynthetic and approved against influenza A virus for prophylactic and therapeutic treatment, but the appearance of drug-resistant virus strains is a serious issue that strikes at the core of influenza control. There is therefore an urgent need to develop new antiviral drugs. Many reports have shown that the development of novel bioactive plant extracts and microbial extracts has significant advantages in influenza treatment. This paper comprehensively reviews the development and effects of chemosynthetic drugs, plant extracts, and microbial extracts with influenza antiviral activity, hoping to provide some references for novel antiviral drug design and promising alternative candidates for further anti-influenza drug development.

The emergence of a novel recombinant porcine reproductive and respiratory syndrome virus with an amino acid insertion in GP5 protein.

As an economic devastating virus, porcine reproductive and respiratory syndrome virus (PRRSV) has spread globally, and seriously hinders the healthy development of the swine industry worldwide. In recent years, however, recombinant PRRSV strains are continuously emerging, resulting in the death of a large number of pigs in China. In this study, we reported a NADC30-like PRRSV strain GD1909, a recombinant virus, which may originate from NADC30-like and HUN4-like strains. The GP5 protein of GD1909 strain has an asparagine insertion at position 60 and has more complex glycosylation pattern. This should be helpful for a better understanding of PRRSV molecular epidemiology and the prevention of PRRSV infection in the future.

Identification of lncRNA-155 encoded by MIR155HG as a novel regulator of innate immunity against influenza A virus infection.

Long noncoding RNAs (lncRNAs) are single-stranded RNA molecules longer than 200 nt that regulate many cellular processes. MicroRNA 155 host gene (MIR155HG) encodes the microRNA (miR)-155 that regulates various signalling pathways of innate and adaptive immune responses against viral infections. MIR155HG also encodes a lncRNA that we call lncRNA-155. Here, we observed that expression of lncRNA-155 was markedly upregulated during influenza A virus (IAV) infection both in vitro (several cell lines) and in vivo (mouse model). Interestingly, robust expression of lncRNA-155 was also induced by infections with several other viruses. Disruption of lncRNA-155 expression in A549 cells diminished the antiviral innate immunity against IAV. Furthermore, knockout of lncRNA-155 in mice significantly increased IAV replication and virulence in the animals. In contrast, overexpression of lncRNA-155 in human cells suppressed IAV replication, suggesting that lncRNA-155 is involved in host antiviral innate immunity induced by IAV infection. Moreover, we found that lncRNA-155 had a profound effect on expression of protein tyrosine phosphatase 1B (PTP1B) during the infection with IAV. Inhibition of PTP1B by lncRNA-155 resulted in higher production of interferon-beta (IFN-ß) and several critical interferon-stimulated genes (ISGs). Together, these observations reveal that MIR155HG derived lncRNA-155 can be induced by IAV, which modulates host innate immunity during the virus infection via regulation of PTP1B-mediated interferon response.

Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway.

BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure. METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis. RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71. CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.