Long non-coding RNAs (lncRNAs) are important regulators of diverse biological processes. Here we report on functional identification and characterization of a novel long intergenic non-coding RNA with MyoD-regulated and skeletal muscle-restricted expression that promotes the activation of the myogenic program, and is therefore termed Linc-RAM (Linc-RNA Activator of Myogenesis). Linc-RAM is transcribed from an intergenic region of myogenic cells and its expression is upregulated during myogenesis. Notably, in vivo functional studies show that Linc-RAM knockout mice display impaired muscle regeneration due to the differentiation defect of satellite cells. Mechanistically, Linc-RAM regulates expression of myogenic genes by directly binding MyoD, which in turn promotes the assembly of the MyoD–Baf60c–Brg1 complex on the regulatory elements of target genes. Collectively, our findings reveal the functional role and molecular mechanism of a lineage-specific Linc-RAM as a regulatory lncRNA required for tissues-specific chromatin remodelling and gene expression.

African swine fever virus (ASFV) is a devastating infectious disease in pigs, severely threatening the global pig industry. To efficiently infect animals, ASFV must evade or inhibit fundamental elements of the innate immune system, namely the type I IFN response. In this study, we identified that ASFV MGF-505-7R protein exerts a negative regulatory effect on STING-dependent antiviral responses. MGF-505-7R interacted with STING and inhibited the cGAS–STING signaling pathway at STING level. MGF-505-7R overexpression either degraded STING or STING expression was reduced in ASFV-infected cells via autophagy, whereas STING expression was elevated in MGF-505-7R–deficient ASFV-infected cells. We further found that MGF-505-7R promoted the expression of the autophagy-related protein ULK1 to degrade STING, whereas ULK1 was elevated in MGF-505-7R–deficient ASFV-infected cells. Moreover, MGF-505-7R–deficient ASFV induced more IFN-β production than wild-type ASFV and was attenuated in replication compared with wild-type ASFV. The replicative ability of MGF-505-7R–deficient ASFV was also attenuated compared with wild-type. Importantly, MGF-505-7R–deficient ASFV was fully attenuated in pigs. Our results showed for the first time, to our knowledge, a relationship involving the cGAS–STING pathway and ASFV MGF-505-7R, contributing to uncover the molecular mechanisms of ASFV virulence and to the rational development of ASFV vaccines.

Growing evidence indicates that systemic inflammation response and malnutrition status are correlated with survival in certain types of solid tumors. The aim of this study is to evaluate the association between the systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) and overall survival (OS) in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. A consecutive series of 655 patients with resected ESCC who underwent esophagectomy were enrolled in the retrospective study. The preoperative SII was defined as platelet × neutrophil/lymphocyte counts. The PNI was calculated as albumin concentration (g/L) + 5 × total lymphocyte count (10 /L). The optimal cut-off values of SII, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and PNI were determined by receiver operating characteristic analysis. Survival analysis was performed using the Kaplan-Meier method with a log-rank test, followed by a multivariate Cox proportional hazards model. A high SII was significantly related to tumor size, histological type, invasion depth, and TNM stage (p < 0.05). A low PNI was significantly associated with age, tumor size, invasion depth, lymph node metastasis, and TNM stage (p < 0.05). Univariate analysis revealed that age, smoking history, tumor size, invasion depth, lymph node metastasis, SII, NLR, PLR, and PNI were predictors of OS (p < 0.05). Multivariate analysis identified age (p = 0.041), tumor size (p = 0.016), invasion depth (p < 0.001), lymph node metastasis (p < 0.001), SII (p = 0.033), and PNI (p = 0.022) as independent prognostic factors correlated with OS. There was a significant inverse relationship between the SII and PNI (r = 0.309; p < 0.001). The predictive value increased when the SII and PNI were considered in combination. Our results demonstrate that the preoperative high SII and low PNI are powerful indicators of aggressive biology and poor prognosis for patients with ESCC. The combination of SII and PNI can enhance the accuracy of prognosis.

Nanotheranostics with integrated diagnostic and therapeutic functions show exciting potentials towards precision nanomedicine. However, targeted delivery of nanotheranostics is hindered by several biological barriers. Here, we report the development of a dual size/charge- transformable, Trojan-Horse nanoparticle (pPhD NP) for delivery of ultra-small, full active pharmaceutical ingredients (API) nanotheranostics with integrated dual-modal imaging and trimodal therapeutic functions. pPhD NPs exhibit ideal size and charge for drug transportation. In tumour microenvironment, pPhD NPs responsively transform to full API nanotheranostics with ultra-small size and higher surface charge, which dramatically facilitate the tumour penetration and cell internalisation. pPhD NPs enable visualisation of biodistribution by near-infrared fluorescence imaging, tumour accumulation and therapeutic effect by magnetic resonance imaging. Moreover, the synergistic photothermal-, photodynamic- and chemo-therapies achieve a 100% complete cure rate on both subcutaneous and orthotopic oral cancer models. This nanoplatform with powerful delivery efficiency and versatile theranostic functions shows enormous potentials to improve cancer treatment.

Molecular Beacons (MBs) composed of 2'-O-methyl RNA (2Me) and phosphorothioate (PS) linkages throughout the backbone (2Me/PSFULL MBs) have enabled long-term imaging of RNA in living cells, but excess PS modification can induce nonspecific binding, causing false-positive signals. In this study, we evaluate the intracellular stability of MBs composed of 2Me with various PS modifications, and found that false-positive signals could be reduced to marginal levels when the MBs possess a fully PS-modified loop domain and a phosphodiester stem (2Me/PSLOOP MB). Additionally, 2Me/PSLOOP MBs exhibited uncompromised hybridization kinetics, prolonged functionality and >88% detection accuracy for single RNA transcripts, and could do so without interfering with gene expression or cell growth. Finally, 2Me/PSLOOP MBs could image the dynamics of single mRNA transcripts in the nucleus and the cytoplasm simultaneously, regardless of whether the MBs targeted the 5'- or the 3'-UTR. Together, these findings demonstrate the effectiveness of loop-domain PS modification in reducing nonspecific signals and the potential for sensitive and accurate imaging of individual RNAs at the single-molecule level. With the growing interest in the role of RNA localization and dynamics in health and disease, 2Me/PSLOOP MBs could enable new discoveries in RNA research.

N6‐methyladenosine (m6A) RNA methylation, one of the common RNA modifications, has been determined to execute crucial functions in tumorigenesis and cancer development. The m6A “writers” including methyltransferase like 3 (METTL3), METTL14, and Wilms tumor 1‐associated protein (WTAP) contribute to the m6A modification process initiation. However, the coordination of m6A methyltransferase complex is not fully understood in endometrioid epithelial ovarian cancer (EEOC). In this study, mRNA and protein levels of METTL3, METTL14, and WTAP were detected in 33 EEOC cases using quantitative polymerase chain reaction (qPCR), immunohistochemistry, and western blot analysis. The overall m6A methylation was detected by dot plot. The METTL3 expression and overall m6A level were elevated in EEOC tissues, while the expressions of METTL14 and WTAP have no significant difference in EEOC compared to the adjacent tissues. The expression of METTL3 was an independent factor that correlated with poor malignancy and survival of EEOC patients. Moreover, METTL3 knockdown in TOV‐112D and CRL‐11731D cells weakened the capability of cell proliferation and migration, and promoted cell apoptosis compared to negative control and cells with WTAP or METTL14 knockdown using CCK‐8 assay, transwell assay, wound healing assay, and TUNEL assay. Furthermore, METTL3 knockdown also reduced m6A enrichment of the genes associated with ovarian cancer including EIF3C, AXL, CSF‐1, FZD10 in TOV‐112D, and CRL‐11731D cells by RIP‐qPCR assay. Taken together, the high expressed METTL3 indicated poor malignancy and survival of EEOC via modulating the aberrant m6A RNA methylation. METTL3‐mediated m6A modification, independent of WTAP and METTL14, was considered as a novel mechanism underlying m6A modulation and a potential therapeutic target of EEOC.

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Reactive oxygen species (ROS) often have significant roles in mediating redox modifications and other essential physiological processes, such as biological process regulation and signal transduction. Considering that H2O2 is a substantial member of ROS, detection and quantitation of H2O2 undertakes important but urgent responsibility. In this report, a bioluminescent probe for detecting H2O2 was well designed, synthesized, and evaluated. This probe was designed into three parts: a H2O2-sensitive aryl boronic acid, a bioluminescent aminoluciferin moiety, and a self-immolative linker. After extensive evaluation, this probe can selectively and sensitively react with H2O2 to release aminoluciferin. It should be pointed out that this probe is a potential bioluminescent sensor for H2O2 since it can provide a promising toolkit for real-time detection of the H2O2 level in vitro, in cellulo, and in vivo.