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2'-O-methylation (Nm) is a prominent RNA modification well known in noncoding RNAs and more recently also found at many mRNA internal sites. However, their function and base-resolution stoichiometry remain underexplored. Here, we investigate the transcriptome-wide effect of internal site Nm on mRNA stability. Combining nanopore sequencing with our developed machine learning method, NanoNm, we identify thousands of Nm sites on mRNAs with a single-base resolution. We observe a positive effect of FBL-mediated Nm modification on mRNA stability and expression level. Elevated FBL expression in cancer cells is associated with increased expression levels for 2'-O-methylated mRNAs of cancer pathways, implying the role of FBL in post-transcriptional regulation. Lastly, we find that FBL-mediated 2'-O-methylation connects to widespread 3' UTR shortening, a mechanism that globally increases RNA stability. Collectively, we demonstrate that FBL-mediated Nm modifications at mRNA internal sites regulate gene expression by enhancing mRNA stability.
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Regiões 3' não Traduzidas , Estabilidade de RNA , RNA Mensageiro , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Metilação , Processamento Pós-Transcricional do RNA , Sequenciamento por Nanoporos/métodos , Transcriptoma , Regulação Neoplásica da Expressão Gênica , Aprendizado de MáquinaRESUMO
Exitron splicing (EIS) creates a cryptic intron (called an exitron) within a protein-coding exon to increase proteome diversity. EIS is poorly characterized, but emerging evidence suggests a role for EIS in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered that EIS affected 63% of human coding genes and that 95% of those events were tumor specific. Notably, we observed a mutually exclusive pattern between EIS and somatic mutations in their affected genes. Functionally, we discovered that EIS altered known and novel cancer driver genes for causing gain- or loss-of-function, which promotes tumor progression. Importantly, we identified EIS-derived neoepitopes that bind to major histocompatibility complex (MHC) class I or II. Analysis of clinical data from a clear cell renal cell carcinoma cohort revealed an association between EIS-derived neoantigen load and checkpoint inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens.
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Epitopos/genética , Éxons/genética , Perfilação da Expressão Gênica , Íntrons/genética , Neoplasias/genética , Oncogenes , Splicing de RNA/genética , Sequência de Aminoácidos , Linhagem Celular , Estudos de Coortes , Humanos , Mutação/genéticaRESUMO
The gene encoding PTEN is one of the most frequently mutated tumor suppressor-encoding genes in human cancer. While PTEN's function in tumor suppression is well established, its relationship to anti-microbial immunity remains unknown. Here we found a pivotal role for PTEN in the induction of type I interferon, the hallmark of antiviral innate immunity, that was independent of the pathway of the kinases PI(3)K and Akt. PTEN controlled the import of IRF3, a master transcription factor responsible for IFN-ß production, into the nucleus. We further identified a PTEN-controlled negative phosphorylation site at Ser97 of IRF3 and found that release from this negative regulation via the phosphatase activity of PTEN was essential for the activation of IRF3 and its import into the nucleus. Our study identifies crosstalk between PTEN and IRF3 in tumor suppression and innate immunity.
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Imunidade Inata/imunologia , Fator Regulador 3 de Interferon/imunologia , Interferon Tipo I/imunologia , PTEN Fosfo-Hidrolase/imunologia , Infecções por Respirovirus/imunologia , Infecções por Rhabdoviridae/imunologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular , Proliferação de Células , Citocinas/imunologia , Células Dendríticas/imunologia , Eletroforese em Gel de Poliacrilamida , Imunofluorescência , Técnicas de Transferência de Genes , Células HEK293 , Humanos , Immunoblotting , Imunoprecipitação , Fator Regulador 3 de Interferon/genética , Fator Regulador 7 de Interferon/genética , Células MCF-7 , Macrófagos/imunologia , Espectrometria de Massas , Camundongos , Microscopia Confocal , Mutagênese Sítio-Dirigida , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vírus Sendai , VesiculovirusRESUMO
The heterogeneity of the tumour immune microenvironment (TIME), organized by various immune and stromal cells, is a major contributing factor of tumour metastasis, relapse and drug resistance1-3, but how different TIME subtypes are connected to the clinical relevance in liver cancer remains unclear. Here we performed single-cell RNA-sequencing (scRNA-seq) analysis of 189 samples collected from 124 patients and 8 mice with liver cancer. With more than 1 million cells analysed, we stratified patients into five TIME subtypes, including immune activation, immune suppression mediated by myeloid or stromal cells, immune exclusion and immune residence phenotypes. Different TIME subtypes were spatially organized and associated with chemokine networks and genomic features. Notably, tumour-associated neutrophil (TAN) populations enriched in the myeloid-cell-enriched subtype were associated with an unfavourable prognosis. Through in vitro induction of TANs and ex vivo analyses of patient TANs, we showed that CCL4+ TANs can recruit macrophages and that PD-L1+ TANs can suppress T cell cytotoxicity. Furthermore, scRNA-seq analysis of mouse neutrophil subsets revealed that they are largely conserved with those of humans. In vivo neutrophil depletion in mouse models attenuated tumour progression, confirming the pro-tumour phenotypes of TANs. With this detailed cellular heterogeneity landscape of liver cancer, our study illustrates diverse TIME subtypes, highlights immunosuppressive functions of TANs and sheds light on potential immunotherapies targeting TANs.
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Neoplasias Hepáticas , Neutrófilos , Microambiente Tumoral , Animais , Humanos , Camundongos , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Recidiva Local de Neoplasia , Neutrófilos/citologia , Neutrófilos/imunologia , Microambiente Tumoral/imunologia , Linfócitos T/imunologia , Macrófagos/imunologia , Prognóstico , Progressão da DoençaRESUMO
Recognition of viral RNA by the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiates innate antiviral immune response. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified ZCCHC3 as a positive regulator of the RLRs including RIG-I and MDA5. ZCCHC3 deficiency markedly inhibited RNA virus-triggered induction of downstream antiviral genes, and ZCCHC3-deficient mice were more susceptible to RNA virus infection. ZCCHC3 was associated with RIG-I and MDA5 and functions in two distinct processes for regulation of RIG-I and MDA5 activities. ZCCHC3 bound to dsRNA and enhanced the binding of RIG-I and MDA5 to dsRNA. ZCCHC3 also recruited the E3 ubiquitin ligase TRIM25 to the RIG-I and MDA5 complexes to facilitate its K63-linked polyubiquitination and activation. Thus, ZCCHC3 is a co-receptor for RIG-I and MDA5, which is critical for RLR-mediated innate immune response to RNA virus.
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Proteína DEAD-box 58/metabolismo , Infecções por Vírus de RNA/imunologia , Vírus de RNA/fisiologia , RNA Viral/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Proteínas de Ligação a DNA/metabolismo , Regulação Viral da Expressão Gênica , Células HEK293 , Humanos , Imunidade Inata , Helicase IFIH1 Induzida por Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , RNA Viral/imunologia , Proteínas de Ligação a RNA/genética , Células THP-1 , Fatores de Transcrição/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.
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Dependovirus , Terapia Genética , Humanos , Terapia Genética/métodos , Dependovirus/genética , Criança , Masculino , Pré-Escolar , Feminino , Adolescente , Lactente , Vetores Genéticos , Resultado do Tratamento , Surdez/genética , Surdez/terapia , Mutação , Proteínas de MembranaRESUMO
RNA expression of a gene is determined by not only transcriptional regulation, but also post-transcriptional regulation of RNA decay. The precise regulation of RNA stability in the cell plays an important role in normal development. Dysregulation of RNA stability can lead to diseases such as cancer. Here we found tumor suppressor RNAs tended to decay fast in normal cell types when compared with other RNAs. Consistent with a negative effect of m6A modification on RNA stability, we observed preferential deposition of m6A on tumor suppressor RNAs. Moreover, abundant m6A and fast decay of tumor suppressor RNAs both tended to be further enhanced in prostate cancer cells relative to normal prostate epithelial cells. Further, knockdown of m6A methyltransferase METTL3 and reader YTHDF2 in prostate cancer cells both posed stronger effect on tumor suppressor RNAs than on other RNAs. These results indicated a strong post transcriptional expression regulatability mediated by abundant m6A modification on tumor suppressor RNAs.
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Genes Supressores de Tumor , Neoplasias da Próstata , Estabilidade de RNA , RNA Mensageiro , Humanos , Masculino , Metiltransferases/genética , Neoplasias da Próstata/química , Neoplasias da Próstata/genética , RNA/genética , RNA Mensageiro/químicaRESUMO
Cell identity genes are distinct from other genes with respect to the epigenetic mechanisms to activate their transcription, e.g. by super-enhancers and broad H3K4me3 domains. However, it remains unclear whether their post-transcriptional regulation is also unique. We performed a systematic analysis of transcriptome-wide RNA stability in nine cell types and found that unstable transcripts were enriched in cell identity-related pathways while stable transcripts were enriched in housekeeping pathways. Joint analyses of RNA stability and chromatin state revealed significant enrichment of super-enhancers and broad H3K4me3 domains at the gene loci of unstable transcripts. Intriguingly, the RNA m6A methyltransferase, METTL3, preferentially binds to chromatin at super-enhancers, broad H3K4me3 domains and their associated genes. METTL3 binding intensity is positively correlated with RNA m6A methylation and negatively correlated with RNA stability of cell identity genes, probably due to co-transcriptional m6A modifications promoting RNA decay. Nanopore direct RNA-sequencing showed that METTL3 knockdown has a stronger effect on RNA m6A and mRNA stability for cell identity genes. Our data suggest a run-and-brake model, where cell identity genes undergo both frequent transcription and fast RNA decay to achieve precise regulation of RNA expression.
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Cromatina , Regulação da Expressão Gênica , Estabilidade de RNA , Cromatina/genética , Epigênese Genética , Metiltransferases/metabolismo , RNA/químicaRESUMO
During viral infection, sensing of viral RNA by retinoic acid-inducible gene-I-like receptors (RLRs) initiates an antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA (virus-induced signal adaptor; also known as mitochondrial antiviral signaling protein [MAVS]). VISA is regulated by various posttranslational modifications (PTMs), such as polyubiquitination, phosphorylation, O-linked ß-d-N-acetylglucosaminylation (O-GlcNAcylation), and monomethylation. However, whether other forms of PTMs regulate VISA-mediated innate immune signaling remains elusive. Here, we report that Poly(ADP-ribosyl)ation (PARylation) is a PTM of VISA, which attenuates innate immune response to RNA viruses. Using a biochemical purification approach, we identified tankyrase 1 (TNKS1) as a VISA-associated protein. Viral infection led to the induction of TNKS1 and its homolog TNKS2, which translocated from cytosol to mitochondria and interacted with VISA. TNKS1 and TNKS2 catalyze the PARylation of VISA at Glu137 residue, thereby priming it for K48-linked polyubiquitination by the E3 ligase Ring figure protein 146 (RNF146) and subsequent degradation. Consistently, TNKS1, TNKS2, or RNF146 deficiency increased the RNA virus-triggered induction of downstream effector genes and impaired the replication of the virus. Moreover, TNKS1- or TNKS2-deficient mice produced higher levels of type I interferons (IFNs) and proinflammatory cytokines after virus infection and markedly reduced virus loads in the brains and lungs. Together, our findings uncover an essential role of PARylation of VISA in virus-triggered innate immune signaling, which represents a mechanism to avoid excessive harmful immune response.
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Proteínas Adaptadoras de Transdução de Sinal , Imunidade Inata , Infecções por Vírus de RNA , Vírus de RNA , Tanquirases , Ubiquitina-Proteína Ligases , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células HEK293 , Humanos , Imunidade Inata/genética , Camundongos , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Tanquirases/genética , Tanquirases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
The cyclic GMP-AMP synthase and stimulator of interferon (IFN) genes (cGAS-STING) pathway serves as a crucial component of innate immune defense and exerts immense antiviral activity by inducing the expression of type I IFNs. Currently, STING-activated production of type I IFNs has been thought to be mediated only by TANK-binding kinase 1 (TBK1). Here, we identified that porcine IKKε (pIKKε) is also directly involved in STING-induced type I IFN expression and antiviral response by using IKKε-/- porcine macrophages. Similar to pTBK1, pIKKε interacts directly with pSTING on the C-terminal tail. Furthermore, the TBK1-binding motif of pSTING C-terminal tail is essential for its interaction with pIKKε, and within the TBK1-binding motif, the leucine (L) 373 is also critical for the interaction. On the other hand, both kinase domain and scaffold dimerization domain of pIKKε participate in the interactions with pSTING. Consistently, the reconstitution of pIKKε and its mutants in IKKε-/- porcine macrophages corroborated that IKKε and its kinase domain and scaffold dimerization domain are all involved in the STING signaling and antiviral function. Thus, our findings deepen the understanding of porcine cGAS-STING pathway, which lays a foundation for effective antiviral therapeutics against porcine viral diseases.
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BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.
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BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is known for abnormal lipid metabolism and widespread activation of HIF-2α. Recently, the importance of autophagy in ccRCC has been focused, and it has potential connections with HIF-2α and lipid metabolism. However, the specific regulatory mechanism between HIF-2α, autophagy, and lipid metabolism in ccRCC is still unclear. METHODS: In this study, Bioinformatics Analysis and Sequencing of the whole transcriptome were used to screen our target. The expression of TBC1D5 in renal clear cell carcinoma was confirmed by database analysis, immunohistochemistry, PCR and Western blot. The effects of TBC1D5 on tumor cell growth, migration, invasion and lipid metabolism were examined by CCK8, Transwell and oil red staining, and the mechanism of TBC1D5 on autophagy was investigated by Western blot, fluorescence microscopy and electron microscopy. Chloroquine and rapamycin were used to verified the key role of autophagy in effects of TBC1D5 on tumor cell. The regulatory mechanism of TBC1D5 in renal clear cell carcinoma (RCC) was investigated by shhif-2α, shTBC1D5, mimic, inhibitor, ChIP and Luciferase experiments. The animal model of ccRCC was used to evaluate the biological function of TBC1D5 in vivo. RESULTS: In this study, TBC1D5 was found to be an important bridge between autophagy and HIF-2α. Specifically, TBC1D5 is significantly underexpressed in ccRCC, serving as a tumor suppressor which inhibits tumor progression and lipid accumulation, and is negatively regulated by HIF-2α. Further research has found that TBC1D5 regulates the autophagy pathway to reverse the biological function of HIF-2α in ccRCC. Mechanism studies have shown that HIF-2α regulates TBC1D5 through hsa-miR-7-5p in ccRCC, thereby affecting tumor progression and lipid metabolism through autophagy. CONCLUSIONS: Our research reveals a completely new pathway, HIF-2α/hsa-miR-7-5p/TBC1D5 pathway affects ccRCC progression and lipid metabolism by regulating autophagy.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Metabolismo dos Lipídeos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão GênicaRESUMO
Poorly differentiated (PD) chordoma, a rare, aggressive tumor originating from notochordal tissue, shows loss of SMARCB1 expression, a core component of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes. To determine the impact of SMARCB1 re-expression on cell growth and gene expression, two SMARCB1-negative PD chordoma cell lines with an inducible SMARCB1 expression system were generated. After 72 hours of induction of SMARCB1, both SMARCB1-negative PD chordoma cell lines continued to proliferate. This result contrasted with those observed with SMARCB1-negative rhabdoid cell lines in which SMARCB1 re-expression caused the rapid inhibition of growth. We found that the lack of growth inhibition may arise from the loss of CDKN2A (p16INK4A) expression in PD chordoma cell lines. RNA-sequencing of cell lines after SMARCB1 re-expression showed a down-regulation for rRNA and RNA processing as well as metabolic processing and increased expression of genes involved in cell adhesion, cell migration, and development. Taken together, these data establish that SMARCB1 re-expression in PD chordomas alters the repertoire of SWI/SNF complexes, perhaps restoring those associated with cellular differentiation. These novel findings support a model in which SMARCB1 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones, and they implicate SMARCB1 loss as a late event in tumorigenic progression. Importantly, the absence of growth inhibition after SMARCB1 restoration creates a unique opportunity to identify therapeutic vulnerabilities.
Assuntos
Cordoma , Humanos , Cordoma/genética , Cordoma/patologia , Fatores de Transcrição/metabolismo , Diferenciação Celular/genética , Carcinogênese , Proteína SMARCB1/genéticaRESUMO
Hybrid microresonators have served an intriguing platform for fundamental research and applied photonics. Here, we study the plasmonics-engineered coupling between degenerate optical whispering gallery modes, which can be tuned in a complex space featuring the dissipative strong, dispersive strong, and weak coupling regimes. Experimentally, the engineering of a single plasmonic resonance to a cavity mode family is examined in a waveguide-integrated high-Q microdisk, from which the complex coupling coefficients are extracted and agree well with theoretical predictions. The coupling strength over 10 GHz is achieved for both dissipative and dispersive interactions, showing a remarkable enhancement compared to that induced by a dielectric scatterer. Furthermore, the far fields of hybridized cavity modes are measured, revealing the coherent interference between the radiative channels. Our results shed light on the engineering of whispering gallery modes through plasmonic resonances, and provide fundamental guidance to practical microcavity devices.
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Agricultural solid waste has become one of the raw materials for hydrothermal carbon production, promoting resource utilization. This study synthesized two types of ball-milling carbons (Fe-MHBC vs MHBC) with and without FeCl3 modification using wheat straw hydrochars. Cr(VI) adsorption on these two types of ball-milling carbons was investigated. According to Langmuir's maximum adsorption capacity analysis, Fe-MHBC had a capacity of 116.29 mg g-1. The thermodynamic analysis based on isothermal adsorption reveals the spontaneous process of the reaction between the two materials. The adsorption of Cr(VI) on Fe-MHBC exhibited excellent agreement with the pseudo-second-order kinetics model. Furthermore, X-ray photoelectron spectroscopy analysis showed that Fe(II) in the material reduced Cr(VI) when it participated in the reaction. The acidic conditions facilitate the elimination of Cr(VI). The Fe-MHBC has a higher zeta potential, which enhances the electrostatic attraction of Cr(VI) particles. Even with a starting pH of 10, the removal rate can be consistently maintained at over 64%. The adsorption of Cr(VI) was inhibited by various anions and higher ion concentrations. Density functional theory demonstrates that the presence of Fe enhances the adsorption capacity and electron transfer flux of Cr(VI). Fe-MHBC effectively eliminates Cr(VI) by the process of electrostatic adsorption, redox, and complexation reactions. This study demonstrated that hydrochar materials modified by FeCl3 through a ball-milling process show considerable potential as effective adsorbents in the treatment of Cr(VI) pollution, offering a viable and environmentally friendly solution for mitigating this prevalent environmental issue.
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The innate immune DNA sensing cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) signaling pathway plays a key role in host antiviral function. Although the cGAS-STING pathway has been extensively studied, the cGAS-STING signaling in livestock and poultry is not well understood, and whether the species specificity exists is still unknown. In this study, we found that porcine and chicken STING, but not cGAS, exhibit species differences in regulation of IFN; that is, porcine (p)STING mediates good induction of IFN in mammalian cells and low IFN induction in chicken DF-1 cells; on the contrary, chicken (ch)STING mediates IFN induction only in chicken cells but not in mammalian cells. Furthermore, it was found that the motifs pLxIS of pSTING and pLxVS of chSTING are responsible for the species disparity, with the IFN activity of pSTING and chSTING exchanged by swapping the two pLxI/VS motifs. The pLxI/VS motifs mediated the interactions of various STING with downstream IFN regulatory factors (IRFs), reflecting the species-specific pIRF3 and chIRF7. Next, the STING, IRFs, and STING-IRFs were reconstituted in porcine and chicken macrophages that were genetically knocked out for STING and/or IRFs by the CRISPR-Cas9 approach. The results showed that pSTING plus pIRF3 or chIRF7 are able to induce IFN; however, chSTING plus chIRF7 but not pIRF3 are able to induce IFN, suggesting that pIRF3 is specific and stringent, which underlies the inability of chSTING to induce IFN in mammalian cells. In summary, our findings reveal the differential species specificity in the cGAS-STING pathway and the underlying mechanisms, thus providing valuable insights on the cGAS-STING-IRF signaling axis for comparative immunology.
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Galinhas , Interferon beta , Animais , Galinhas/genética , DNA , Imunidade Inata/genética , Mamíferos/genética , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Especificidade da Espécie , SuínosRESUMO
Alveolar bone injury under diabetic conditions can severely impede many oral disease treatments. Rebuilding diabetic alveolar bone in clinics is currently challenging due to persistent infection and inflammatory response. Here, an antibacterial DNA-based hydrogel named Agantigel is developed by integrating silver nanoclusters (AgNCs) and tumor necrosis factor-alpha (TNF-α) antibody into DNA hydrogel to promote diabetic alveolar bone regeneration. Agantigel can effectively inhibit bacterial growth through AgNCs while exhibiting negligible cytotoxicity in vitro. The sustained release of TNF-α antibody from Agantigel effectively blocks TNF-α and promotes M2 polarization of macrophages, ultimately accelerating diabetic alveolar bone regeneration in vivo. After 21 days of treatment, Agantigel significantly accelerates the defect healing rate of diabetic alveolar bone up to 82.58 ± 8.58% and improves trabecular architectures compared to free TNF-α (42.52 ± 15.85%). The results imply that DNA hydrogels are potential bio-scaffolds helping the sustained release of multidrug for treating DABI or other oral diseases.
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Diabetes Mellitus , Hidrogéis , Humanos , Hidrogéis/farmacologia , Fator de Necrose Tumoral alfa , Preparações de Ação Retardada , Antibacterianos/farmacologia , DNARESUMO
BACKGROUND AND AIM: The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS: Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS: For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.
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Carcinoma Hepatocelular , Antígenos do Núcleo do Vírus da Hepatite B , Hepatite B Crônica , Neoplasias Hepáticas , Recidiva Local de Neoplasia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Humanos , Hepatite B Crônica/complicações , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Fatores de Risco , Valor Preditivo dos Testes , Antígenos E da Hepatite B/sangue , Masculino , Feminino , Biomarcadores Tumorais/sangueRESUMO
We investigate the reaction pathways of nine important CO2-related reactions using the revDSD-PBEP86-D3(BJ)/jun-cc-pV(T+d)Z level and simultaneously employ an accurate composite method (jun-Cheap) based on coupled-cluster (CC) theory. Subsequently, the Rice-Ramsperger-Kassel-Marcus/master equation (RRKM/ME) is solved to calculate the temperature- and pressure-dependent rate constants. This work investigates reactions involving transition states that have been overlooked in previous literature, including the dissociation of singlet-state C3O2, the triple channel formation of C2O + CO to form C3O2, and the formation of O3 + CO. The results show that CO3 is highly prone to dissociation at high temperatures. Finally, the kinetic data show that over a wide temperature range, our calculations are consistent with previous experimental measurements. The majority of the reaction rate constants studied exhibit significant pressure dependence, while the O3 + CO reaction is pressure-independent at low temperatures. These results are instrumental in the development of detailed kinetic models for the CO2 radiolysis reaction network.
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BACKGROUND: Inflammatory bowel disease (IBD) is a progressive and debilitating inflammatory disease of the gastrointestinal tract (GIT). Despite recent advances, precise treatment and noninvasive monitoring remain challenging. METHODS: Herein, we developed orally-administered, colitis-targeting and hyaluronic acid (HA)-modified, core-shell curcumin (Cur)- and cerium oxide (CeO2)-loaded nanoprobes (Cur@PC-HA/CeO2 NPs) for computed tomography (CT) imaging-guided treatment and monitoring of IBD in living mice. RESULTS: Following oral administration, high-molecular-weight HA maintains integrity with little absorption in the upper GIT, and then actively accumulates at local colitis sites owing to its colitis-targeting ability, leading to specific CT enhancement lasting for 24 h. The retained NPs are further degraded by hyaluronidase in the colon to release Cur and CeO2, thereby exerting anti-inflammatory and antioxidant effects. Combined with the ability of NPs to regulate intestinal flora, the oral NPs result in substantial relief in symptoms. Following multiple treatments, the gradually decreasing range of the colon with high CT attenuation correlates with the change in the clinical biomarkers, indicating the feasibility of treatment response and remission. CONCLUSION: This study provides a proof-of-concept for the design of a novel theranostic integration strategy for concomitant IBD treatment and the real-time monitoring of treatment responses.