A splicing silencer in SMN2 intron 6 is critical in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a fatal neuromuscular disease caused by homozygous deletions or mutations of the SMN1 gene. SMN2 is a paralogous gene of SMN1 and a modifying gene of SMA. A better understanding of how SMN2 exon 7 splicing is regulated helps discover new therapeutic targets for SMA therapy. Based on an antisense walk method to map exonic and intronic splicing silencers (ESSs and ISSs) in SMN2 exon 7 and the proximal regions of its flanking introns, we identified one ISS (ISS6-KH) at upstream of the branch point site in intron 6. By using mutagenesis-coupled RT-PCR with SMN1/2 minigenes, immunochromatography, overexpression and siRNA-knockdown, we found this ISS consists of a bipartite hnRNP A1 binding cis-element and a poly-U sequence located between the proximal hnRNP A1 binding site (UAGCUA) and the branch site. Both HuR and hnRNP C1 proteins promote exon 7 skipping through the poly-U stretch. Mutations or deletions of these motifs lead to efficient SMN2 exon 7 inclusion comparable to SMN1 gene. Furthermore, we identified an optimal antisense oligonucleotide that binds the intron six ISS and causes striking exon 7 inclusion in the SMN2 gene in patient fibroblasts and SMA mouse model. Our findings demonstrate that this novel ISS plays an important role in SMN2 exon 7 skipping and highlight a new therapeutic target for SMA therapy.

Systematic characterization of short intronic splicing-regulatory elements in SMN2 pre-mRNA.

Intronic splicing enhancers and silencers (ISEs and ISSs) are two groups of splicing-regulatory elements (SREs) that play critical roles in determining splice-site selection, particularly for alternatively spliced introns or exons. SREs are often short motifs; their mutation or dysregulation of their cognate proteins frequently causes aberrant splicing and results in disease. To date, however, knowledge about SRE sequences and how they regulate splicing remains limited. Here, using an SMN2 minigene, we generated a complete pentamer-sequence library that comprises all possible combinations of 5 nucleotides in intron 7, at a fixed site downstream of the 5' splice site. We systematically analyzed the effects of all 1023 mutant pentamers on exon 7 splicing, in comparison to the wild-type minigene, in HEK293 cells. Our data show that the majority of pentamers significantly affect exon 7 splicing: 584 of them are stimulatory and 230 are inhibitory. To identify actual SREs, we utilized a motif set enrichment analysis (MSEA), from which we identified groups of stimulatory and inhibitory SRE motifs. We experimentally validated several strong SREs in SMN1/2 and other minigene settings. Our results provide a valuable resource for understanding how short RNA sequences regulate splicing. Many novel SREs can be explored further to elucidate their mechanism of action.

Regulation of HeLa cell proliferation and apoptosis by bovine lactoferrin.

Cervical cancer is one of the foremost common cancers in women. Lactoferrin (LF) has many biological functions, such as antitumor. This study aimed to explore the regulatory effect of bovine lactoferrin (bLF) on the proliferation and apoptosis of cervical cancer HeLa cells and to clarify the potential mechanism of action of bLF against HeLa cells. This study used CCK-8, Trypan blue staining, and colony formation assays to verify the effect of bLF on HeLa cell proliferation. Hoechst 33258 fluorescence staining, AO/EB staining, and western blotting were used to determine the effects of bLF on apoptosis and autophagy in HeLa cells. We discovered that bLF significantly reduced the proliferation of HeLa cells in a dose- and time-dependent manner compared to the control group. Furthermore, bLF primarily induced apoptosis in HeLa cells by increasing the expression of the proapoptotic proteins p53, Bax, and Cleaved-caspase-3 and downregulating the expression of the antiapoptotic protein Bcl-2. In addition, the present study also showed that bLF treatment significantly activated autophagy-related proteins LC3B-II and Beclin I and down regulated the autophagosome transporter protein p62, indicating that bLF treatment can induce autophagy in HeLa cells. After pretreatment with the autophagy inhibitor, 3-MA, which markedly found that autophagy inhibition by 3-MA reversed bLF-induced apoptosis, indicating that bLF can induce apoptosis by activating intracellular autophagy in HeLa cells. In the present study, our results support the theory of bLF significantly inhibited the proliferation of Hela cells by promoting apoptosis and reinforcing autophagy. The study will play an important role in therapying cervical cancer.

Encephalomyocarditis Virus Abrogates the Interferon Beta Signaling Pathway via Its Structural Protein VP2.

Type I interferon (IFN)-mediated antiviral responses are critical for modulating host-virus responses, and indeed, viruses have evolved strategies to antagonize this pathway. Encephalomyocarditis virus (EMCV) is an important zoonotic pathogen, which causes myocarditis, encephalitis, neurological disease, reproductive disorders, and diabetes in pigs. This study aims to understand how EMCV interacts with the IFN pathway. EMCV circumvents the type I IFN response by expressing proteins that antagonize cellular innate immunity. Here, we show that EMCV VP2 is a negative regulator of the IFN-ß pathway. This occurs via the degradation of the MDA5-mediated cytoplasmic double-stranded RNA (dsRNA) antiviral sensing RIG-I-like receptor (RLR) pathway. We show that structural protein VP2 of EMCV interacts with MDA5, MAVS, and TBK1 through its C terminus. In addition, we found that EMCV VP2 could significantly degrade RLRs by the proteasomal and lysosomal pathways. For the first time, EMCV VP2 was shown to play an important role in EMCV evasion of the type I IFN signaling pathway. This study expands our understanding that EMCV utilizes its capsid protein VP2 to evade the host antiviral response.IMPORTANCE Encephalomyocarditis virus is an important pathogen that can cause encephalitis, myocarditis, neurological diseases, and reproductive disorders. It also causes huge economic losses for the swine industry worldwide. Innate immunity plays an important role in defending the host from pathogen infection. Understanding pathogen microorganisms evading the host immune system is of great importance. Currently, whether EMCV evades cytosolic RNA sensing and signaling is still poorly understood. In the present study, we found that viral protein VP2 antagonized the RLR signaling pathway by degrading MDA5, MAVS, and TBK1 protein expression to facilitate viral replication in HEK293 cells. The findings in this study identify a new mechanism for EMCV evading the host's innate immune response, which provide new insights into the virus-host interaction and help develop new antiviral approaches against EMCV.

Insights into the functional divergence of the haloacid dehalogenase superfamily from phosphomonoesterase to inorganic pyrophosphatase.

The evolution of enzyme catalytic structures and mechanisms has drawn increasing attention. In this study, we investigate the functional divergence from phosphomonoesterase to inorganic pyrophosphatase in the haloacid dehalogenase (HAD) superfamily. In this study, a series of models was constructed, and calculations were performed by using density functional theory with the B3LYP functional. The calculations suggest that in most HAD members, the active-site structure is unstable due to the binding of the substrate inorganic pyrophosphate (PPi), and reactions involving PPi cannot be catalyzed. In BT2127, which is a unique member of the HAD superfamily, the Mg2+-coordinating residues Asn172 and Glu47 play a role in stabilizing the active-site structure to adapt to the substrate PPi by providing much stronger coordination interactions with the Mg2+ ion. The calculation results suggest that Asn172 and Glu47 are crucial in the evolution of the inorganic pyrophosphatase activity in the HAD superfamily. Our study provides definitive chemical insight into the functional divergence of the HAD superfamily, and helps in understanding the evolution of enzyme catalytic structures and mechanisms.

Caveolin-1 is involved in encephalomyocarditis virus replication in BHK-21 cells.

BACKGROUND: Encephalomyocarditis virus, member of Cardiovirus genus within Picornaviridae family, is an important pathogen that infects different domestic and wild animals. However, the molecular mechanism of its entry remains unclear. In this study, we investigated the mechanism of EMCV infectivity in relation to endocytic pathway using BHK-21 cells. METHODS: The function of numerous cellular key factors implicated in the various endocytic mechanisms were systematically explored using chemical inhibitors. Furthermore, RNA interference (RNAi) as well as the overexpression of dominant protein combined to virus infectivity assays, and confocal microscopy was used to examine EMCV infection in details. RESULTS: The results indicated that the EMCV entry into BHK-21 cells depends on caveolin, dynamin, and actin but not clathrin nor macropinocytosis pathways. The effects of overexpression and knockdown of caveolin-1, one components of the caveolae, was examined on EMCV infection. The results showed that EMCV infection was positive correlation with caveolin-1 expression. Confocal microscopy analysis and internalization assay showed that caveolin-1 is required at the early stage of EMCV infection. CONCLUSIONS: Caveolin-1, dynamin, and actin-dependent endocytosis pathways are necessary for EMCV infection in vitro.

Modulation of PDCD1 exon 3 splicing.

The PDCD1 gene encodes PD-1, an important immune checkpoint protein and key immunotherapy target to treat cancer. PDCD1 is alternatively spliced to generate an exon 3-skipped isoform PD-1Δ3 that has been suggested to play an antagonistic role to PD-1, but the mechanism underlying alternative splicing of PDCD1 has never been explored. Here using a minigene system, we analysed the splicing pattern of PDCD1 in multiple cell lines and confirmed exon 3 skipping as the main alternative splicing event. Using deletion analysis of exon 3, we mapped two splicing enhancers in the exon: ESE3a and ESE3b. Using mutagenesis, RNA-affinity chromatography, mass spectrometry as well as depletion and overexpression of MATR3, we defined MATR3 as a splicing activator during PDCD1 exon 3 splicing that operates through binding to ESE3b. MATR3's splicing-stimulatory activity is counteracted by an RNA secondary structure around ESE3b and an RNA helicase DDX5. Furthermore, we identified ASOs that efficiently promotes PDCD1 exon 3 skipping in both minigene and endogenous-gene contexts. Our data support further study of the ASOs as potential drug candidates to treat cancer.

Emitting color tunable carbon dots by adjusting solvent towards light-emitting devices.

Carbon dots (CDs), one of the most significant classes of carbon-based nanophosphors, have attracted extensive attention in recent years. However, few attempts have been reported for realizing CDs with tunable emissions, especially for obtaining the red-light emissions with high photoluminescence quantum yields. Herein, we synthesized CDs with different chromatic blue, green and red emissions by facilely changing the reaction solvent during hydrothermal conditions. The photoluminescence quantum yields of 34%, 19% and 47% for the blue, green and red emissions, respectively, were achieved. Furthermore, the solid-state CD/PVA composite films were constructed through mixing the CDs with PVA polymer, in which the self-quenching of photoluminescence of CDs had been successfully avoided benefiting from the formation of hydrogen bonds between the CDs and PVA molecules. Finally, the warm white light emitting diode (WLED) was fabricated by integrating CD/PVA film on a UV-LED chip. The WLED exhibited the Commission International de l'Eclairage coordinates (CIE) of (0.38, 0.34), correlated color temperature of 3913 K and color rendering index of 91, respectively, which were comparable with the commercial WLEDs.

Transcriptional profiling of host cell responses to encephalomyocarditis virus (EMCV).

BACKGROUD: Encephalomyocarditis virus (EMCV) has been discovered on pig farms worldwide and can cause myocarditis in piglets and reproductive failure in sows. However, little is known about the host transcriptional responses to infection and host-pathogen interactions. METHODS: In this study, transcription profiling was performed by Illumina RNA-Sequencing (RNA-seq) to identify EMCV induced differentially expressed genes in BHK-21 cells at serial time points (12, 24, and 30 h post infection (hpi)), using mock infected cells as control. RESULTS: We identified 237, 241, and 207 differentially expressed genes (DEGs) respectively, majority of which were up-regulated. A large number of DEGs clustered into host defense, cellular signaling and metabolism categories. Moreover, short time series expression analysis revealed that 12 hpi was an important time point for expression change, indicating host virus resistance. CONCLUSIONS: This RNA-seq analysis provides the first data for understanding the network of virus host interactions under EMCV infection in vitro, and for identifying host components which involved in the virus infection course.

National serosurvey of encephalomyocarditis virus in healthy people and pigs in China.

Encephalomyocarditis virus (EMCV) is a zoonotic pathogen that has a wide spectrum of host range. The virus has been discovered on swine farms worldwide and can cause acute fatal myocarditis in piglets and reproductive disorders in sows. Although EMCV infection has been documented in farmed pigs in China, seroprevalence in humans has not been reported. In this study, we conducted nationwide serological surveys for EMCV in humans and farmed pigs in China in 2013, by the use of a double antigen sandwich ELISA method. A total of 3305 serum samples from healthy people were obtained from seven geographical regions in China, of which 1010 samples (30.56%) were positive for EMCV antibodies. The overall seroprevalence for EMCV in the age groups of 0-20, 21-40, 41-60 and >60 years were 13.5%, 30.25%, 36.83% and 38.71% respectively, showing a tendency of increasing with age (P = 0.000). A total of 3470 serum samples from farmed pigs were collected and tested for antibodies to EMCV. A high seroprevalence of 77% was recorded, and significant regional differences were observed. It was concluded that people and pigs in China were commonly infected by EMCV. In addition, in order to characterize changes of seroprevalence during natural EMCV infection in pigs, 240 serial serum samples were collected from 30 pigs (at 0, 15, 30, 60, 75, 90, 120, and 150 days of age) in a farrow-to-finish farm in China. The data showed that there were two EMCV antibody peaks: the first peak appeared at day 30, followed by a decrease in EMCV antibody titer, and the second occurred after day 75. Thus, the most susceptible period of pigs for EMCV infection was between day 30 and day 75 of age.

Memory-Enabled Quantum-Dot Light-Emitting Diodes.

Quantum-dot light-emitting diodes (QLEDs) with memory capability can provide multifunctional integration properties in on-chip and intelligent electronic applications. Herein, memory properties are achieved by inserting a tungsten oxide (WOx) film between the ZnO electron-transporting layer and cathode. Pentavalent tungsten ions (W5+) in this nonstoichiometric WOx film can be oxidized to W6+ by storing holes, inducing significant electrons in the adjacent ZnO layer. Hole storage in the WOx layer suppresses electron injection into the quantum dot emissive layer, hence reducing electroluminescence intensity on the onset stage of the QLEDs. This operation-history correlation for the electroluminescence intensity means a memory behavior for the QLEDs. Furthermore, the power efficiency of the devices is greatly improved after inserting the WOx layer due to electrical field-dependent self-adaptive electron injection into the quantum dots (QDs). We anticipate this type of QLEDs have potential applications in on-chip integration applications, such as the optical computing field and storage.

High-Performance Tandem Quantum-Dot Light-Emitting Diodes Based on Bulk-Heterojunction-Like Charge-Generation Layers.

In this study, the fundamental but previously overlooked factors of charge generation efficiency and light extraction efficiency (LEE) are explored and collaboratively optimized in tandem quantum-dot light-emitting diodes (QLEDs). By spontaneously forming a microstructured interface, a bulk-heterojunction-like charge-generation layer composed of a poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate)/ZnO bilayer is fabricated and an ideal charge-generation efficiency surpassing 115% is obtained. The coupling strength of the waveguide mode for the top unit and the plasmon polariton loss for the bottom unit are highly suppressed using precise thickness control, which increases the LEE of the tandem devices. The red tandem QLED achieves an exceptionally low turn-on voltage for electroluminescence at 4.0 V and outstanding peak external quantum efficiency of 42.9%. The ultralow turn-on voltage originates from the sequential electroluminescence turn-on of the two emissive units of the tandem QLED. Benefiting from its unique electroluminescent features, an easily fabricated optical-electrical dual anti-counterfeiting display is built by combining a dichromatic tandem QLED with masking technology.

Effect of Graphitization Degree of Mesocarbon Microbeads (MCMBs) on the Microstructure and Properties of MCMB-SiC Composites.

Mesocarbon microbead-silicon carbide (MCMB-SiC) composites were prepared by hot-press sintering (2100 °C/40 MPa/1 h) with two different graphitized MCMBs as the second phase, which exhibited good self-lubricating properties. The effects of the graphitization degree of the MCMBs on the microstructure and properties of the composites were investigated contrastively. The results showed that the composites that added raw MCMBs with a low degree of graphitization had excellent self-sintering properties, higher densities, and better mechanical properties; by comparison, the composites that added mature MCMBs with a high degree of graphitization, which has regular and orderly lamellar structures, not only had good mechanical properties but also exhibited a lower and more stable dry friction coefficient (0.35), despite the higher wear rate (2.66 × 10-6 mm3·N-1·m-1). Large amounts of mature MCMBs were peeled off during the friction process to form a uniform and flat graphite lubricating film, which was the main reason for reducing the dry friction coefficient of the self-lubricating composites and making the friction coefficient more stable.

The chloroplast genome sequence and phylogenetic analysis of Apocynum venetum L.

Apocynum venetum L. (Apocynaceae) is valuable for its medicinal compounds and fiber content. Native A. venetum populations are threatened and require protection. Wild A. venetum resources are limited relative to market demand and a poor understanding of the composition of A. venetum at the molecular level. The chloroplast genome contains genetic markers for phylogenetic analysis, genetic diversity evaluation, and molecular identification. In this study, the entire genome of the A. venetum chloroplast was sequenced and analyzed. The A. venetum cp genome is 150,878 bp, with a pair of inverted repeat regions (IRA and IRB). Each inverted repeat region is 25,810 bp, which consist of large (LSC, 81,951 bp) and small (SSC, 17,307 bp) single copy areas. The genome-wide GC content was 38.35%, LSC made up 36.49%, SSC made up 32.41%, and IR made up 43.3%. The A. venetum chloroplast genome encodes 131 genes, including 86 protein-coding genes, eight ribosomal RNA genes, and 37 transfer RNA genes. This study identified the unique characteristics of the A. venetum chloroplast genome, which will help formulate effective conservation and management strategies as well as molecular identification approaches for this important medicinal plant.

Calibrating the Hole Mobility Measurements Implemented by Transient Electroluminescence Technology.

To date, measuring the carrier mobility in semiconductor films, especially for the amorphous organic small-molecule films, is still a big challenge. Here, we demonstrate that transient electroluminescence (TrEL) spectroscopy with quantum-dot light-emitting diodes as the platform is a feasible and reliable method to evaluate the carrier mobility of such amorphous films. The position of the exciton formation zone is precisely determined and controlled by employing a quantum dot monolayer as the emissive layer. The electrical field intensity across the organic layer is evaluated through the charge density at the electrode calculated by the transient current. Then, the charge carrier mobility is obtained by combining the electroluminescence (EL) delay time and the thickness of the organic layer. Additionally, we demonstrate that the large roughness of the organic layer leads to serious charge accumulation and, hence, a high localized electrical field, which provides preferred charge injection paths, reducing the EL delay time and underestimating the EL delay time. Therefore, a thick organic film is the prerequisite for a reliable measurement of charge carrier mobility, which can circumvent the negative effect of film roughness.

Surface Engineering of Carbon-Supported Platinum as a Route to Electrocatalysts with Superior Durability and Activity for PEMFC Cathodes.

Hydrogen fuel cells are regarded as a promising new carbon mitigation strategy to realize carbon neutrality. The exploitation of robust and efficient cathode catalysts is thus vital to the commercialization of proton exchange membrane fuel cells (PEMFCs). Herein, we demonstrate a facile and scalable surface engineering route to achieve superior durability and high activity of a Pt-based material as a PEMFC cathode catalyst through a controllable liquid-phase reduction approach. The proposed surface engineering strategy by modifying Pt/C reduces the oxygen content on the carbon support and also decreases the surface defects on Pt nanoparticles (NPs), which effectively alleviate the corrosion of carbon and inhibit the detachment, agglomeration, and growth of Pt NPs. The resulting catalyst exhibits superior durability after a 10,000 potential cycling test in an acid electrolyte─outperforming commercial Pt/C. Moreover, the catalyst also demonstrates an improved oxygen reduction reaction (ORR) activity in comparison to commercial Pt/C by virtue of the high content of metallic Pt and the weakened Pt-OH bonding that releases more Pt active sites for ORR catalysis. Most importantly, the developed catalyst shows outstanding PEMFC performance and excellent long-term durability over 50 h of a constant-current test and 100 h of a load-cycling operation. This effective route provides a new avenue for exploiting robust Pt-based catalysts with superior activity in practical applications of PEMFCs.

History of development of the life-saving drug "Nusinersen" in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with an incidence of 1/6,000-1/10,000 and is the leading fatal disease among infants. Previously, there was no effective treatment for SMA. The first effective drug, nusinersen, was approved by the US FDA in December 2016, providing hope to SMA patients worldwide. The drug was introduced in the European Union in 2017 and China in 2019 and has so far saved the lives of several patients in most parts of the world. Nusinersen are fixed sequence antisense oligonucleotides with special chemical modifications. The development of nusinersen progressed through major scientific discoveries in medicine, genetics, biology, and other disciplines, wherein several scientists have made substantial contributions. In this article, we will briefly describe the pathogenesis and therapeutic strategies of SMA, summarize the timeline of important scientific findings during the development of nusinersen in a detailed, scientific, and objective manner, and finally discuss the implications of the development of nusinersen for SMA research.

Yak Gut Microbiota: A Systematic Review and Meta-Analysis.

The yak (Bos grunniens) is closely related to common cows (Bos taurus), but is clearly a distinct species. Yaks are of substantial importance to food and leather production in certain high-altitude regions of Asia. The animal is increasing elsewhere as well, mainly because of the perceived health benefits of its milk. Like all ruminants, the animal harbors a complex community of microbial cells in its gut, crucial for its physiology. Despite yaks being important domestic animals, the composition of its gut microbiota and how the composition is guided by its specific high-altitude environment remains largely uncategorized. Hence, online databases (Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar) were searched for articles on yak intestinal microbiota. The pooled taxonomic abundance was compared between regions, sexes, different age groups, and feeding patterns. The gut microbiota distribution across different yak intestinal segments was established through pooled average taxonomic abundance. A total of 34 studies met the inclusion criteria and yielded information on 982 unique yak gut microbiota samples. An analysis of overall pooled microbiota revealed a segmented microbial community composition of the yak gut. Yak rumen microbiota was significantly influenced by difference in region, sex, and feeding patterns, the latter factor being dominant in this respect. Yak microbiome is shaped by the feeding strategy and provides an obvious avenue for improving health and productivity of the animal. More generally, the current segmental description of physiological gut microbiome provides insight into how the microbiology of this animal has adapted itself to help comping yaks with its high-altitude habitat.

Genetic diversity and positive selection analysis of classical swine fever virus isolates in south China.

Classical swine fever virus (CSFV) causes a highly contagious disease that leads to significant economic losses in the pig industry worldwide. However, there is a paucity of knowledge on the accurate genotyping of CSFV isolates in south China. This study genotyped the E2 gene of 14 CSFV strains isolated during 2008-2010 from domestic pigs in different districts of south China. Phylogenetic analyses revealed that all of the 14 CSFV isolates were clustered into genetic subgroup 1.1. This contrasts with most parts of China, where group 2 isolates are predominant. Furthermore, the positive selection pressures acting on the E(rns) and E2 envelope protein genes of CSFV were assessed and a site-by-site analysis of the dN/dS ratio was performed to identify specific codons that undergo diversification under positive selection. While no significant evidence for positive selection was observed in E(rns), two positively selected sites at amino acid residues 49 and 72 in the E2 encoding region were identified. Our results revealed that a predominance of subgroup 1.1 CSFV isolates is currently circulating in some districts of south China, which appear to be unrelated to the Chinese C-strain vaccine. Moreover, the envelope protein gene, E2, has undergone positive selection in 14 CSFV strains and two positively selected sites have been identified in this study. Understanding the molecular epidemiology and functional importance of these positively selected amino acid positions could help to predict possible changes in virulence, the development of vaccines and disease control.

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.