Primary and Orthotopic Murine Models of Nasopharyngeal Carcinoma Reveal Molecular Mechanisms Underlying its Malignant Progression.

Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein-Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV- (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC-associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene-edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV-coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV- and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.

A cocktail nanovaccine targeting key entry glycoproteins elicits high neutralizing antibody levels against EBV infection.

Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is closely associated with various malignancies. Considering the complex life cycle of EBV, developing vaccines targeting key entry glycoproteins to elicit robust and durable adaptive immune responses may provide better protection. EBV gHgL-, gB- and gp42-specific antibodies in healthy EBV carriers contributed to sera neutralizing abilities in vitro, indicating that they are potential antigen candidates. To enhance the immunogenicity of these antigens, we formulate three nanovaccines by co-delivering molecular adjuvants (CpG and MPLA) and antigens (gHgL, gB or gp42). These nanovaccines induce robust humoral and cellular responses through efficient activation of dendritic cells and germinal center response. Importantly, these nanovaccines generate high levels of neutralizing antibodies recognizing vulnerable sites of all three antigens. IgGs induced by a cocktail vaccine containing three nanovaccines confer superior protection from lethal EBV challenge in female humanized mice compared to IgG elicited by individual NP-gHgL, NP-gB and NP-gp42. Importantly, serum antibodies elicited by cocktail nanovaccine immunization confer durable protection against EBV-associated lymphoma. Overall, the cocktail nanovaccine shows robust immunogenicity and is a promising candidate for further clinical trials.

A pan-KRAS degrader for the treatment of KRAS-mutant cancers.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

Potent human monoclonal antibodies targeting Epstein-Barr virus gp42 reveal vulnerable sites for virus infection.

Epstein-Barr virus (EBV) is linked to various malignancies and autoimmune diseases, posing a significant global health challenge due to the lack of specific treatments or vaccines. Despite its crucial role in EBV infection in B cells, the mechanisms of the glycoprotein gp42 remain elusive. In this study, we construct an antibody phage library from 100 EBV-positive individuals, leading to the identification of two human monoclonal antibodies, 2B7 and 2C1. These antibodies effectively neutralize EBV infection in vitro and in vivo while preserving gp42's interaction with the human leukocyte antigen class II (HLA-II) receptor. Structural analysis unveils their distinct binding epitopes on gp42, different from the HLA-II binding site. Furthermore, both 2B7 and 2C1 demonstrate potent neutralization of EBV infection in HLA-II-positive epithelial cells, expanding our understanding of gp42's role. Overall, this study introduces two human anti-gp42 antibodies with potential implications for developing EBV vaccines targeting gp42 epitopes, addressing a critical gap in EBV research.

Crucial roles of specialized chitinases in elytral and hindwing cuticles construction in Leptinotarsa decemlineata.

BACKGROUND: The Colorado potato beetle (CPB), Leptinotarsa decemlineata, is a major potato (Solanum tuberosum) pest, infesting over 16 million km2 and causing substantial economic losses. The insect cuticle forms an apical extracellular matrix (ECM) envelope covering exposed organs to direct morphogenesis and confer structural protection. While select chitinase (Cht) genes have proven essential for larval development, their potential activities directing ECM remodeling underlying adult wing maturation remain undefined. RESULTS: We investigated the expression patterns and performed an oral RNA interference (RNAi) screen targeting 19 LdChts in late-instar L. decemlineata larvae. Subsequently, we assessed their effects on adult eclosion and wing characteristics. Knockdown of LdCht5, LdCht7, LdCht10, LdIDGF2, and LdIDGF4, as well as others from Group IV (LdCht15, LdCht12, LdCht17, and LdCht13) and Groups VII-X (LdCht2, LdCht11, LdCht1, and LdCht3), resulting in shrunken, misshapen elytra with reduced areal density, as well as transverse wrinkling and impaired wing-tip folding in hindwings. Scanning electron micrographs revealed eroded elytral ridges alongside thinned, ruptured hindwing veins, indicative of mechanical fragility post-LdCht suppression. Spectroscopic analysis uncovered biomolecular alterations underlying the elytral anomalies, including decreases in peaks representing chitin, proteins, and lipids. This loss of essential ECM components provides evidence for the fragility, wrinkling, and shrinkage observed in the RNAi groups. CONCLUSION: Our findings elucidate the crucial role of chitinases in the turnover of chitinous cuticles on beetle wings, offering insights into RNAi-based control strategies against this invasive pest. © 2024 Society of Chemical Industry.

Evaluation of serum Epstein-Barr virus envelope glycoproteins antibodies and their association with systemic autoimmune diseases.

Systemic autoimmune diseases (SADs) are a growing spectrum of autoimmune disorders that commonly affect multiple organs. The role of Epstein-Barr virus (EBV) infection or reactivation as a trigger for the initiation and progression of SADs has been established, while the relationship between EBV envelope glycoproteins and SADs remains unclear. Here, we assessed the levels of IgG, IgA, and IgM against EBV glycoproteins (including gp350, gp42, gHgL, and gB) in serum samples obtained from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and found that RA and SLE patients exhibited a statistically significant increase in the levels of 8 and 11 glycoprotein antibodies, respectively, compared to healthy controls (p < 0.05). The LASSO model identified four factors as significant diagnostic markers for RA: gp350 IgG, gp350 IgA, gHgL IgM, and gp42 IgA; whereas for SLE it included gp350 IgG, gp350 IgA, gHgL IgA, and gp42 IgM. Combining these selected biomarkers yielded an area under the curve (AUC) of 0.749 for RA and 0.843 for SLE. We subsequently quantified the levels of autoantibodies associated with SADs in mouse sera following immunization with gp350. Remarkably, none of the tested autoantibody levels exhibited statistically significant alterations. Elevation of glycoprotein antibody concentration suggests that Epstein-Barr virus reactivation and replication occurred in SADs patients, potentially serving as a promising biomarker for diagnosing SADs. Moreover, the absence of cross-reactivity between gp350 antibodies and SADs-associated autoantigens indicates the safety profile of a vaccine based on gp350 antigen.

Coronary Microvascular Dysfunction and Diffuse Myocardial Fibrosis in Patients With Type 2 Diabetes Using Quantitative Perfusion MRI.

BACKGROUND: Imaging techniques that quantitatively and automatically measure changes in the myocardial microcirculation in patients with diabetes are lacking. PURPOSE: To detect diabetic myocardial microvascular complications using a novel automatic quantitative perfusion MRI technique, and to explore the relationship between myocardial microcirculation dysfunction and fibrosis. STUDY TYPE: Prospective. SUBJECTS: 101 patients with type 2 diabetes mellitus (T2DM) (53 without and 48 with complications), 20 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3.0T; modified Look-Locker inversion-recovery sequence; saturation recovery sequence and dual-bolus technique; segmented fast low-angle shot sequence. ASSESSMENT: All participants underwent MRI to determine the rest myocardial blood flow (MBF), stress MBF, myocardial perfusion reserve (MPR), and extracellular volume (ECV), which represents the extent of myocardial fibrosis. STATISTICAL TESTS: Kolmogorov-Smirnov test, Shapiro-Wilk test, Kruskal-Wallis H test, Mann-Whitney U test, chi-square test, Spearman correlation coefficient, multivariable linear regression analysis. P < 0.05 was considered statistically significant. RESULTS: The rest MBF was not significantly different between the T2DM without complications group (1.1, IQR: 0.9-1.3) and the control group (1.1, 1.0-1.3) (P = 1.000), but it was significantly lower in the T2DM with complications group (0.8, 0.6-1.0) than in both other groups. The stress MBF and MPR were significantly lower in the T2DM without complications group (1.9, 1.5-2.3, and 1.7, 1.4-2.1, respectively) than in the control group (3.0, 2.6-3.5, and 2.7, 2.4-3.1, respectively), and were also significantly lower in the T2DM with complications group (1.1, 0.9-1.4, and 1.4, 1.2-1.8, respectively) than in the T2DM without complications group. A decrease in MBF and MPR were significantly associated with an increase in the ECV. DATA CONCLUSION: Quantitative perfusion MRI can evaluate myocardial microcirculation dysfunction. In T2DM, there was a significant decrease in both MBF and MPR compared to healthy controls, with the decrease being significantly different between T2DM with and without complications groups. The decrease of MBF was significantly associated with the development of myocardial fibrosis, as determined by ECV. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

EBV abortive lytic cycle promotes nasopharyngeal carcinoma progression through recruiting monocytes and regulating their directed differentiation.

Epstein-Barr virus (EBV) is associated with several types of human cancer including nasopharyngeal carcinoma (NPC). The activation of EBV to the lytic cycle has been observed in advanced NPC and is believed to contribute to late-stage NPC development. However, how EBV lytic cycle promotes NPC progression remains elusive. Analysis of clinical NPC samples indicated that EBV reactivation and immunosuppression were found in advanced NPC samples, as well as abnormal angiogenesis and invasiveness. To investigate the role of the EBV lytic cycle in tumor development, we established a system that consists of two NPC cell lines, respectively, in EBV abortive lytic cycle and latency. In a comparative analysis using this system, we found that the NPC cell line in EBV abortive lytic cycle exhibited the superior chemotactic capacity to recruit monocytes and polarized their differentiation toward tumor-associated macrophage (TAM)-like phenotype and away from DCs, compared to EBV-negative or EBV-latency NPC cells. EBV-encoded transcription activator ZTA is responsible for regulating monocyte chemotaxis and TAM phenotype by up-regulating the expression of GM-CSF, IL-8, and GRO-α. As a result, TAM induced by EBV abortive lytic cycle promotes NPC angiogenesis, invasion, and migration. Overall, this study elucidated the role of the EBV lytic life cycle in the late development of NPC and revealed a mechanism underlying the ZTA-mediated establishment of the tumor microenvironment (TME) that promotes NPC late-stage progression.

Assessment of Myocardial Viability and Risk Stratification in Coronary Chronic Total Occlusion: A Qualitative and Quantitative Stress Cardiac MRI Study.

BACKGROUND: Indicators for assessing myocardial viability and risk stratification in patients with coronary chronic total occlusion (CTO) are still in the research stage. PURPOSE: To use stress-MRI to assess myocardial function, blood perfusion, and viability and to explore their relationship with collateral circulation. STUDY TYPE: Prospective. SUBJECTS: Fifty-one patients with CTO in at least one major artery confirmed by X-ray coronary angiography (male: 46; age 55.2 ± 10.8 years). FIELD STRENGTH/SEQUENCE: 3.0T; TurboFlash, balanced steady-state free precession cine, and phase-sensitive inversion recovery sequences. ASSESSMENT: Stress-MRI was used to obtain qualitative and quantitative parameters of segmental myocardium. Myocardial segments supplied by CTO target vessels were grouped according to the degree of collateral circulation assessed by radiographic coronary angiography (no/mild, moderate, or good). Depending on qualitative stress perfusion assessment and late gadolinium enhancement (LGE) extent, segments were also categorized as negative, viable, or trans-infarcted. STATISTICAL TESTS: Independent sample Student's t-test, one-way analysis of variance (ANOVA) test, Mann-Whitney U test, Kruskal-Wallis test, Spearman correlation coefficient (r). P < 0.05 was considered statistically significant. RESULTS: A total of 334 segments were supplied by CTO target vessels. The radial strain (RS), circumferential strain (CS), longitudinal strain (LS) of the negative, viable, and trans-infarcted regions showed a significant and stepwise impairment. Myocardial blood flow at rest was positively correlated with RS, CS, and LS (r = 0.42, 0.43, 0.38, respectively). Among the different collateral circulation, there were no significant differences in RS, CS, LS, and LGE volume (P = 0.788, 0.562, 0.122, 0.170, respectively), and there were also no statistically significant differences in the proportions of negative, viable, and trans-infarcted regions (P = 0.372). DATA CONCLUSION: Myocardial perfusion obtained by stress-MRI combined with strain and LGE may comprehensively evaluate myocardial function and viability, and has potential to facilitate risk stratification of CTO. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Feature-Tracking-Derived Strain Analysis for Identification of Subendocardium-Involved Late Gadolinium Enhancement in Load-Induced Left Ventricular Hypertrophy: A Multicenter Study of Cardiac Magnetic Resonance Data.

BACKGROUND: Subendocardium-involved late gadolinium enhancement (SILGE) is a significant predictor of poor prognosis in patients with load-induced left ventricular hypertrophy (LVH). OBJECTIVES: This multicenter study aimed to investigate whether the diagnostic performance of cardiac magnetic resonance feature-tracking (CMR-FT)-derived strain analysis for detecting subtle subendocardial injury would be influenced by its load dependence in patients with load-induced LVH. METHODS: A total of 149 patients with load-induced LVH were recruited from three centers and underwent enhanced CMR imaging. The patients were divided into two groups based on the presence or absence of SILGE on CMR (SILGE+ group: n = 56; SILGE- group: n = 93). Clinical and CMR parameters were evaluated in both groups. RESULTS: The LV systolic pressure (LVSP) and LV end-diastolic pressure (LVEDP) in the SILGE+ group were higher than those in the SILGE- group (each with p < 0.05), and LVSP and LVEDP were correlated with the LV global longitudinal strain (GLS) (each with p < 0.05) in research center 1. The LV strain parameters were significantly lower in the SILGE+ group than those in the SILGE- group (each with p < 0.05). Logistic regression analysis identified GLS (OR 1.325; 95% CI 1.180 to 1.487, p < 0.001) as a predictive factor of SILGE in the patients with load-induced LVH. The receiver operating characteristic (ROC) curve analysis results indicated that the areas under the curve (AUC) of global radial strain (GRS), global circumferential strain (GCS), and GLS were 0.68, 0.69, and 0.76, respectively. De Long's test results implied that GLS had the best diagnostic performance for SILGE (p = 0.04). CONCLUSION: Despite the load dependency of CMR-FT-derived strain analysis, the GLS exhibits reasonable accuracy in the identification of SILGE and can potentially serve as a feasible alternative for detecting subendocardial involvement in patients with load-induced LVH who are contraindicated for LGE.

Non-overlapping epitopes on the gHgL-gp42 complex for the rational design of a triple-antibody cocktail against EBV infection.

Epstein-Barr virus (EBV) is closely associated with cancer, multiple sclerosis, and post-acute coronavirus disease 2019 (COVID-19) sequelae. There are currently no approved therapeutics or vaccines against EBV. It is noteworthy that combining multiple EBV glycoproteins can elicit potent neutralizing antibodies (nAbs) against viral infection, suggesting possible synergistic effects. Here, we characterize three nAbs (anti-gp42 5E3, anti-gHgL 6H2, and anti-gHgL 10E4) targeting different glycoproteins of the gHgL-gp42 complex. Two antibody cocktails synergistically neutralize infection in B cells (5E3+6H2+10E4) and epithelial cells (6H2+10E4) in vitro. Moreover, 5E3 alone and the 5E3+6H2+10E4 cocktail confer potent in vivo protection against lethal EBV challenge in humanized mice. The cryo-EM structure of a heptatomic gHgL-gp42 immune complex reveals non-overlapping epitopes of 5E3, 6H2, and 10E4 on the gHgL-gp42 complex. Structural and functional analyses highlight different neutralization mechanisms for each of the three nAbs. In summary, our results provide insight for the rational design of therapeutics or vaccines against EBV infection.

Super-enhancer driven SOX2 promotes tumor formation by chromatin re-organization in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with a high incidence in Southern China and Southeast Asia. Patients with remote metastasis and recurrent NPC have poor prognosis. Thus, a better understanding of NPC pathogenesis may identify novel therapies to address the unmet clinical needs. METHODS: H3K27ac ChIP-seq and HiChIP was applied to understand the enhancer landscapes and the chromosome interactions. Whole genome sequencing was conducted to analyze the relationship between genomic variations and epigenetic dysregulation. CRISPRi and JQ1 treatment were used to evaluate the transcriptional regulation of SOX2 SEs. Colony formation assay, survival analysis and in vivo subcutaneous patient-derived xenograft assays were applied to explore the function and clinical relevance of SOX2 in NPC. FINDINGS: We globally mapped the enhancer landscapes and generated NPC enhancer connectomes, linking NPC specific enhancers and SEs. We found five overlapped genes, including SOX2, among super-enhancer regulated genes, survival related genes and NPC essential genes. The mRNA expression of SOX2 was repressed when applying CRISPRi targeting different SOX2 SEs or JQ1 treatment. Next, we identified a genetic variation (Chr3:181422197, G > A) in SOX2 SE which is correlated with higher expression of SOX2 and poor survival. In addition, SOX2 was highly expressed in NPC and is correlated with short survival in patients with NPC. Knock-down of SOX2 suppressed tumor growth in vitro and in vivo. INTERPRETATION: Our study demonstrated the super-enhancer landscape with chromosome interactions and identified super-enhancer driven SOX2 promotes tumorigenesis, suggesting that SOX2 is a potential therapeutic target for patients with NPC. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

mRNA-based Vaccines Targeting the T-cell Epitope-rich Domain of Epstein Barr Virus Latent Proteins Elicit Robust Anti-Tumor Immunity in Mice.

Epstein-Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV-associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA-based therapeutic vaccines that express the T-cell-epitope-rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc-LMP2A), truncated EBV nuclear antigen 1 (Trunc-EBNA1), and Trunc-EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor-bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc-LMP2A, Trunc-EBNA1, and Trunc-EBNA3A, are more effective than full-length antigens in activating antigen-specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA-based therapeutic vaccines targeting the T-cell-epitope-rich domain of EBV latent proteins and providing new treatment options for EBV-associated cancers.

A gB nanoparticle vaccine elicits a protective neutralizing antibody response against EBV.

Epstein-Barr virus (EBV) is a global public health concern, as it is known to cause multiple diseases while also being etiologically associated with a wide range of epithelial and lymphoid malignancies. Currently, there is no available prophylactic vaccine against EBV. gB is the EBV fusion protein that mediates viral membrane fusion and participates in host recognition, making it critical for EBV infection in both B cells and epithelial cells. Here, we present a gB nanoparticle, gB-I53-50 NP, that displays multiple copies of gB. Compared with the gB trimer, gB-I53-50 NP shows improved structural integrity and stability, as well as enhanced immunogenicity in mice and non-human primate (NHP) preclinical models. Immunization and passive transfer demonstrate a robust and durable protective antibody response that protects humanized mice against lethal EBV challenge. This vaccine candidate demonstrates significant potential in preventing EBV infection, providing a possible platform for developing prophylactic vaccines for EBV.

Clinical manifestations and computed tomography angiography features of anomalous left coronary artery from the pulmonary artery syndrome. / å·¦å† çŠ¶åŠ¨è„‰å¼‚å¸¸èµ·æºäºŽè‚ºåŠ¨è„‰ç»¼åˆå¾ï¼šä¸´åºŠè¡¨çŽ°åŠCTA影像学特征.

OBJECTIVES: Anomalous left coronary artery from the pulmonary artery (ALCAPA) syndrome is a rare congenital coronary artery malformation with a high rate of clinical missed diagnosis and misdiagnosis. At present, there is a lack of reports on the clinical manifestations of ALCAPA and the imaging features of coronary computed tomography angiography (CTA). This study aims to summarize the clinical characteristics and coronary CTA imaging features of ALCAPA to improve the clinical diagnosis and treatment. METHODS: The clinical data of 24 ALCAPA syndrome patients were retrospectively collected, analyzed and summarized from January 1, 2013 to February 1, 2023 in the Second Xiangya Hospital of Central South University. According to the left and right coronary collateral circulation, the patients were classified into infantile type (7 cases) and adult type (17 cases). The differences of clinical manifestations and CTA imaging features were compared between the 2 types of patients. RESULTS: Of the 24 patients, a male-to-female ratio was at 1꞉5, and the median age of onset was 3.22 months for the infant type and 22.0 years for the adult type. The infantile type showed symptoms of left heart insufficiency at an early stage, while the adult type had a variety of clinical manifestations in 7 patients being asymptomatic and presented with a cardiac murmur on physical examination, 6 with symptoms of chronic myocardial ischemia, and 2 with malignant arrhythmias. CTA showed that 11 patients' the left coronary artery originated from the left posterior sinus of the pulmonary artery. All 7 infantile type patients had an enlarged left heart, left ventricular hypertrophy, reduced left heart function, lack of collateral circulation between the left and right coronary arteries, and normal coronary artery diameter. All 17 adult type patients showed dilated and tortuous coronary arteries with rich collateral circulation, and 7 adult type patients had preserved left heart function. CONCLUSIONS: The clinical manifestations and CTA imaging features of patients with the 2 types of ALCAPA are different, while CTA performance is characteristic and can be used as a means of definitive diagnosis, staging, surgical evaluation, and postoperative follow-up of ALCAPA syndrome.

PRRSV alters m6A methylation and alternative splicing to regulate immune, extracellular matrix-associated function.

The alternative splicing and N6-methyladenosine (m6A) modifications occurring during porcine reproductive and respiratory syndrome virus (PRRSV) infections remain poorly understood. Transcriptome and MeRIP-seq analyses were performed to identify the gene expression changes, splicing and m6A modifications in the lungs of PRRSV-infected pigs. In total, 1624 differentially expressed genes (DEGs) were observed between PRRSV-infected and uninfected pigs. We observed significant alterations in alternative splicing (54,367 events) and m6A modifications (2265 DASEs) in numerous genes, including LMO7, SLC25A27, ZNF185, and ECM1, during PRRSV infection. LMO7 and ZNF185 exhibited alternative splicing variants and reduced mRNA expression levels following PRRSV infection. Notably, LMO7 inhibited c-JUN, SMAD3, and FAK expression, whereas ZNF185 affected the expression of FAK, CDH1, and GSK3ß downstream. Additionally, ECM1 influenced FAK expression by targeting ITGB3 and AKT2, suggesting its involvement in extracellular matrix accumulation through the ITGB3-AKT2/FAK pathway. These changes may facilitate viral invasion and replication by modulating the expression of genes and proteins participating in crucial cellular processes associated with immunity and the extracellular matrix. We highlight the importance of these genes and their associated pathways in PRRSV infections and suggest that targeting these may be a promising therapeutic approach for treating viral infections.

Circular RNA transcriptome across multiple tissues reveal skeletal muscle-specific circPSME4 regulating myogenesis.

There are significant differences in meat production, growth rate and other traits between Western commercial pigs and Chinese local pigs. Comparative transcriptome approaches have identified many coding and non-coding candidate genes associated various traits. However, the expression and function of circular RNAs (circRNAs) in different pig tissues are largely unknown. In this study, we conducted a comprehensive analysis of the genome-wide circRNA expression profile across ten tissues in Luchuan (a Chinese local breed) and Duroc (a Western commercial breed) pigs. We identified a total of 56,254 circRNAs, of which 42.9 % were not previously annotated. We found that 33.7 % of these circRNAs were differentially expressed. Enrichment analysis revealed that differentially expressed circRNAs might contribute to the phenotypic differentiation between Luchuan and Duroc pigs. We identified 538 tissue-specific circRNAs, most of which were specifically expressed in the brain and skeletal muscle. Competitive endogenous RNA network analysis suggested that skeletal muscle-specific circPSME4 was co-expressed with MYOD1 and targeted by ssc-miR-181d-3p. Functional analysis revealed that circPSME4 knockdown could promote the proliferation and differentiation of myoblasts. Together, our findings provide valuable resources of circRNAs for animal breeding and biomedical research. We demonstrated that circPSME4 is a novel regulator of skeletal muscle development.