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Angiogenesis-Targeted 68Ga-DOTA-RGD2 PET/CT Photo: a prospective Theranostic Application in the Case of Chondrosarcoma.
The eradication rate was 92.0% [95% confidence interval (CI) 84.0-98.0%) in intention-to-treat (ITT) analysis and 91.8% (95% CI 83.7-98.0%) in per protocol (PP) analysis. Side effects (mainly dizziness, dry mouth, and skin rash) occurred in 10 patients, all of which resolved after cessation of antibiotics. Conclusions Patients who failed multiple attempts at H. pylori eradication may benefit from a treatment with probiotics followed by a tetracycline- and furazolidone-containing quadruple regimen.The polyadenosine (poly(A)) tail, which is found on the 3' end of almost all eukaryotic messenger RNAs (mRNAs), plays an important role in the posttranscriptional regulation of gene expression. Shortening of the poly(A) tail, a process known as deadenylation, is thought to be the first and rate-limiting step of mRNA turnover. Deadenylation is performed by the Pan2-Pan3 and Ccr4-Not complexes that contain highly conserved exonuclease enzymes Pan2, and Ccr4 and Caf1, respectively. These complexes have been extensively studied, but the mechanisms of how the deadenylase enzymes recognize the poly(A) tail were poorly understood until recently. Here, we summarize recent work from our laboratory demonstrating that the highly conserved Pan2 exonuclease recognizes the poly(A) tail, not through adenine-specific functional groups, but through the conformation of poly(A) RNA. Our biochemical, biophysical, and structural investigations suggest that poly(A) forms an intrinsic base-stacked, single-stranded helical conformation that is recognized by Pan2, and that disruption of this structure inhibits both Pan2 and Caf1. This intrinsic structure has been shown to be important in poly(A) recognition in other biological processes, further underlining the importance of the unique conformation of poly(A). check details © 2019 Tang and Passmore; Published by Cold Spring Harbor Laboratory Press.Mammalian cells have many quality-control mechanisms that regulate protein-coding gene expression to ensure proper transcript synthesis, processing, and translation. Should a step in transcript metabolism fail to fulfill requisite spatial, temporal, or structural criteria, including the proper acquisition of RNA-binding proteins, then that step will halt, fail to proceed to the next step, and ultimately result in transcript degradation. Quality-control mechanisms constitute a continuum of processes that initiate in the nucleus and extend to the cytoplasm. Here, we present published and unpublished data for protein-coding genes whose expression is activated by the transcriptional coactivator PGC-1α. We show that PGC-1α movement from chromatin, to which it is recruited by DNA-binding proteins, to CBP80 at the 5' cap of nascent transcripts begins a series of co- and posttranscriptional quality- and quantity-control steps that, in total, ensure proper gene expression. © 2019 Rambout et al.; Published by Cold Spring Harbor Laboratory Press.Herpes simplex virus (HSV) is among the most prevalent viral infections worldwide and remains incurable. While nucleoside analogs are used to relieve symptoms of infection, they suffer serious adverse effects and are unable to abolish the virus from the host. Here, we demonstrate a unique antiviral effect of prodigiosin (PG), a natural secondary metabolite produced by Serratia marcescens, on HSV infection. We show that PG naturally exerts antiviral activity against HSV-1 and HSV-2 infections.PG treatment resulted in robust inhibition of viral replication in-vitro and ex-vivo in cultured porcine corneas. Additionally, PG protected against HSV-1 infection and disease progression in a murine model of ocular infection. In our quest to determine the molecular mechanisms of its antiviral activity, we show that PG specifically inhibits NFκB and Akt signaling pathways and promotes accelerated cell death in HSV infected cells. Our findings reveal novel antiviral properties of PG, suggesting its high potential as an alith commensal bacteria may inhibit HSV infection, underscoring the importance of studying these microbial metabolites and their implications for viral pathogenesis and treatment. Copyright © 2020 American Society for Microbiology.Fusion with, and subsequent entry into, the host cell is one of the critical steps in the life cycle of enveloped viruses. For Middle East respiratory syndrome coronavirus (MERS-CoV), the spike protein (S) is the main determinant of viral entry. Proteolytic cleavage of S exposes its fusion peptide (FP), which initiates the process of membrane fusion. Previous studies on the related severe acute respiratory syndrome coronavirus (SARS-CoV) FP have shown that calcium ions (Ca2+) play an important role for fusogenic activity via a Ca2+ binding pocket with conserved glutamic acid (E) and aspartic acid (D) residues. SARS-CoV and MERS-CoV FP share a high sequence homology and here, we investigated whether Ca2+ is required for MERS-CoV fusion by screening a mutant array in which E and D residues in the MERS-CoV FP were substituted with neutrally charged alanines (A). Upon verifying mutant cell surface expression and proteolytic cleavage, we tested their ability to mediate infection of pseudo-particles (PPs) on host cth emergency. In order to develop novel drugs and vaccines, it is important to understand the molecular mechanisms that enable the virus to infect host cells. Our data has found that calcium is an important regulator of viral fusion by interacting with negatively charged residues in the MERS-CoV FP region. This can guide therapeutic solutions to either block this calcium interaction and also repurpose already approved drugs for this use for a fast response to MERS-CoV outbreaks. Copyright © 2020 American Society for Microbiology.hnRNPA2B1, an abundant cellular protein has been reported to recruit RNAs bearing a specific sequence (EXO motif) into exosomes. We characterized an exosome population averaging 100+/- 50 nm in diameter and containing a defined set of constitutive exosome markers. This population packages miRNAs and can be directed to block targeted gene expression in a dose dependent fashion. The objectives of these studies were to characterize its role in the recruitment of miRNA. We report 4 key findings (i) hnRNPA2B1 is not a component of exosomes produced in HEp-2 or in HEK293T cells. Hence hnRNPA2B1 carries its cargo at most to the site of exosome assembly but it is not itself incorporated into exosomes. (ii) The accumulation of exosomes produced by cells in which the gene encoding hnRNPA2B1 has been knocked out (ΔhnRNPA2B1) was reduced 3 fold. (iii) In uninfected HEp-2 cells hnRNPA2B1 is localized in the nucleus. In cells infected with herpes simplex virus 1 (HSV-1) hnRNPA2B1 was quantitatively exported to the cytoplasf exosomes and of HSV-1 from infected cells. Copyright © 2020 American Society for Microbiology.The anaphase promoting complex or cyclosome (APC/C) is a large E3 ubiquitin ligase, composed of 14 subunits. The activity of APC/C oscillates during the cell cycle to ensure a timely transition through each phase by promoting the degradation of important cell cycle regulators. Of the human herpesviruses, cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) both impair the activity of APC/C during their lytic replication through virus-encoded protein kinases. Here, we addressed if the oncogenic Kaposi sarcoma herpesvirus (KSHV) deregulates the activity of APC/C during the lytic replication cycle. To this end, we have used the well-characterized iSLK.219 cell model of KSHV-infection and established a new infection model of primary lymphatic endothelial cells (LEC) infected with a lytically replicating KSHV BAC16 mutant. In contrast to EBV and HCMV, KSHV lytic cycle occurs while the APC/C is active. Moreover, interfering with the APC/C activity did not lead to major changes in the production of infectious virus. ormal cell cycle progression, did not affect the virus replication. This suggests that KSHV has evolved to replicate independently of the APC/C activity and in various cell cycle conditions. Copyright © 2020 Elbasani et al.Type I and type III interferons (IFNs) are the frontlines of antiviral defense mechanism that trigger hundreds of downstream antiviral genes. In this study, we observed that MERS-CoV nucleocapsid (N) protein suppresses type I and III IFN gene expression. The N protein suppresses Sendai virus-induced IFN-β and IFN-λ1 by reducing their promoter activity and mRNA levels as well as downstream IFN stimulated genes (ISGs). Retinoic acid-inducible gene-I (RIG-I) is known to recognize viral RNA and induce IFN expression through tripartite motif-containing protein 25 (TRIM25)-mediated ubiquitination of RIG-I caspase activation and recruitment domains (CARDs). We discovered that MERS-CoV N protein suppresses RIG-I-CARD-, but not MDA5-CARD-induced IFN-β and IFN-λ1 promoter activity. By interacting with TRIM25, N protein impedes RIG-I ubiquitination and activation and inhibits the phosphorylation of transcription factors IFN-regulatory factor 3 (IRF3) and NF-κB that are known to be important for IFN gene activation. By e C-terminal domain of the viral N protein plays a pivotal role in the suppression of IFN-β promoter activity. Our findings reveal how MERS-CoV evades innate immunity and provide insights into the interplay between host immune response and viral pathogenicity. Copyright © 2020 American Society for Microbiology.Foot-and-mouth disease virus (FMDV) leader proteinase (Lpro) affects several pathways of the host innate immune response. Previous studies in bovine cells have demonstrated that deletion (LLV, leaderless) or point mutations in Lpro results in increased expression of interferon (IFN) and IFN-stimulated genes (ISG) including among others, the ubiquitin-like protein modifier ISG15 and the ubiquitin specific peptidase USP18. In addition to its conventional papain-like protease activity, Lpro acts as a deUbiquitinase (DUB) and deISGylase. In this study, we identified a conserved residue in Lpro that is involved in its interaction with ISG15. Mutation W105A rendered bacterial-expressed Lpro unable to cleave the synthetic substrate pro-ISG15, while preserving cellular eIF4G cleavage. Interestingly, mutant FMDV W105A was viable. Overexpression of ISG15 and the ISGylation machinery in porcine cells resulted in moderate inhibition of FMDV replication along with a decrease of the overall state of ISGylation in WT infect and did not affect Lpro ability to block expression of type I IFN and other IFN-stimulated genes. Moreover, overexpression of ISG15 resulted in reduction of FMDV viral titers. Thus, our study highlights the potential of Lpro mutants with modified deISGylase activity for the development of live attenuated vaccine candidates and novel biotherapeutics against FMD. Copyright © 2020 Medina et al.The transmission bottleneck is defined as the number of viral particles that transmit from one host to establish an infection in another. Genome sequence data has been used to evaluate the size of the transmission bottleneck between humans infected with the influenza virus, however, the methods used to make these estimates have some limitations. Specifically, viral allele frequencies, which form the basis of many calculations, may not fully capture a process which involves the transmission of entire viral genomes. Here we set out a novel approach for inferring viral transmission bottlenecks; our method combines an algorithm for haplotype reconstruction with maximum likelihood methods for bottleneck inference. This approach allows for rapid calculation, and performs well when applied to data from simulated transmission events; errors in the haplotype reconstruction step did not adversely affect inferences of the population bottleneck. Applied to data from a previous household transmission study of influenza A infection we confirm the result that the majority of transmission events involve a small number of viruses, albeit with slightly looser bottlenecks being inferred, with between 1 and 13 particles transmitted in the majority of cases.
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