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Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here, we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, whereas ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways. The latter pathway involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a, or p21, indicating that PHF20 is required for reprogramming. Our findings demonstrate, to the best of our knowledge, a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process.
Assuntos
Reprogramação Celular , Proteínas de Homeodomínio/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas de Ligação a DNA , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Cinética , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Fatores de Transcrição , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Regulação para CimaRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1004524.].
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Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-ß (IFN-α/ß) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/ß production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/ß-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection.
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Imunidade Adaptativa/imunologia , Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Malária/imunologia , Transdução de Sinais/imunologia , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Técnicas de Silenciamento de Genes , Camundongos , Camundongos Knockout , Plasmodium yoelii , Reação em Cadeia da PolimeraseRESUMO
Microbial products, such as lipopolysaccharide (LPS), can elicit efficient innate immune responses against invading pathogens. However, priming with LPS can induce a form of innate immune memory, termed innate immune "tolerance", which blunts subsequent NF-κB signaling. Although epigenetic and transcriptional reprogramming has been shown to play a role in innate immune memory, the involvement of post-translational regulation remains unclear. Here, we report that ubiquitin-specific protease 3 (USP3) participates in establishing "tolerance" innate immune memory through non-transcriptional feedback. Upon NF-κB signaling activation, USP3 is stabilized and exits the nucleus. The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1ß-induced inflammatory signaling activation. Importantly, cytoplasmic translocation is a prerequisite step for USP3 to deubiquitinate MyD88. Additionally, LPS priming could induce cytoplasmic retention and faster and stronger cytoplasmic translocation of USP3, enabling it to quickly shut down NF-κB signaling upon the second LPS challenge. This work identifies a previously unrecognized post-translational feedback loop in the MyD88-USP3 axis, which is critical for inducing normal "tolerance" innate immune memory.
Assuntos
Fator 88 de Diferenciação Mieloide , NF-kappa B , NF-kappa B/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Imunidade Inata , Tolerância ImunológicaRESUMO
Stringent control of the NF-kappaB and type I interferon signaling pathways is critical to effective host immune responses, yet the molecular mechanisms that negatively regulate these pathways are poorly understood. Here, we show that NLRC5, a member of the highly conserved NOD-like protein family, can inhibit the IKK complex and RIG-I/MDA5 function. NLRC5 inhibited NF-kappaB-dependent responses by interacting with IKKalpha and IKKbeta and blocking their phosphorylation. It also interacted with RIG-I and MDA5, but not with MAVS, to inhibit RLR-mediated type I interferon responses. Consistent with these observations, NLRC5-specific siRNA knockdown not only enhanced the activation of NF-kappaB and its responsive genes, TNF-alpha and IL-6, but also promoted type I interferon signaling and antiviral immunity. Our findings identify NLRC5 as a negative regulator that blocks two central components of the NF-kappaB and type I interferon signaling pathways and suggest an important role for NLRC5 in homeostatic control of innate immunity.
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Imunidade Inata , Interferon Tipo I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Clonagem Molecular , RNA Helicases DEAD-box/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Inflamação , Peptídeos e Proteínas de Sinalização Intracelular/química , Ligantes , Camundongos , Fosforilação , Receptores Toll-Like/metabolismoRESUMO
Mitochondrial antiviral signaling platform protein (MAVS) acts as a central hub for RIG-I receptor proximal signal propagation. However, key components in the assembly of the MAVS mitochondrial platform that promote RIG-I mitochondrial localization and optimal activation are still largely undefined. Employing pooled RNAi and yeast two-hybrid screenings, we report that the mitochondrial adaptor protein tripartite motif (TRIM)14 provides a docking platform for the assembly of the mitochondrial signaling complex required for maximal activation of RIG-I-mediated signaling, consisting of WHIP and protein phosphatase PPP6C. Following viral infection, the ubiquitin-binding domain in WHIP bridges RIG-I with MAVS by binding to polyUb chains of RIG-I at lysine 164. The ATPase domain in WHIP contributes to stabilization of the RIG-I-dsRNA interaction. Moreover, phosphatase PPP6C is responsible for RIG-I dephosphorylation. Together, our findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated innate antiviral immunity.
Assuntos
Proteínas de Transporte/imunologia , Proteína DEAD-box 58/imunologia , Proteínas de Ligação a DNA/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Proteínas Mitocondriais/imunologia , Complexos Multiproteicos/imunologia , Fosfoproteínas Fosfatases/imunologia , Transdução de Sinais/imunologia , ATPases Associadas a Diversas Atividades Celulares , Animais , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Chlorocebus aethiops , Proteína DEAD-box 58/genética , Proteínas de Ligação a DNA/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Complexos Multiproteicos/genética , Fosfoproteínas Fosfatases/genética , Receptores Imunológicos , Transdução de Sinais/genética , Proteínas com Motivo Tripartido , Células Vero , Viroses/genética , Viroses/imunologia , Vírus/genética , Vírus/imunologiaRESUMO
Community-acquired pneumonia (CAP) is a significant global health concern, responsible for high mortality and morbidity. Recent research has revealed a potential link between disordered microbiome and metabolism in pneumonia, although the precise relationship between these factors and severe CAP remains unclear. To address this knowledge gap, we conducted a comprehensive analysis utilizing 16S sequencing and LC-MS/MS metabolomics data to characterize the microbial profile in sputum and metabolic profile in serum in patients with severe community-acquired pneumonia (sCAP). Our analysis identified 13 genera through LEfSe analysis and 15 metabolites meeting specific criteria (P < 0.05, VIP ≥ 2, and |Log2(FC)| ≥ 2). The findings of this study demonstrate the presence of altered coordination between the microbiome of the lower respiratory tract and host metabolism in patients with sCAP. The observed concentration trends of specific metabolites across different disease stages further support the potential involvement of the serum metabolism in the development of sCAP. These correlations between the airway microbiome and host metabolism in sCAP patients have important implications for optimizing early diagnosis and developing individualized therapeutic strategies.
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Stringent control of the type I interferon signaling pathway is important for maintaining host immune responses and homeostasis, yet the molecular mechanisms responsible for its tight regulation are still poorly understood. Here we report that the pattern-recognition receptor NLRP4 regulated the activation of type I interferon mediated by double-stranded RNA or DNA by targeting the kinase TBK1 for degradation. NLRP4 recruited the E3 ubiquitin ligase DTX4 to TBK1 for Lys48 (K48)-linked polyubiquitination at Lys670, which led to degradation of TBK1. Knockdown of either DTX4 or NLRP4 abrogated K48-linked ubiquitination and degradation of TBK1 and enhanced the phosphorylation of TBK1 and the transcription factor IRF3. Our results identify a previously unrecognized role for NLRP4 in the regulation of type I interferon signaling and provide molecular insight into the mechanisms by which NLRP4-DTX4 targets TBK1 for degradation.
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Interferon Tipo I/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Linhagem Celular , Imunofluorescência , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata/imunologia , Immunoblotting , Imunoprecipitação , Interferon Tipo I/imunologia , Fosforilação , Proteínas Serina-Treonina Quinases/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/imunologia , Transfecção , Ubiquitina-Proteína Ligases/imunologia , UbiquitinaçãoRESUMO
BACKGROUND: Adipose-derived stem cells (ASCs) are recognized for their potential immunomodulatory properties. In the immune system, tolerogenic dendritic cells (DCs), characterized by an immature phenotype, play a crucial role in inducing regulatory T cells (Tregs) and promoting immune tolerance. Notch1 signaling has been identified as a key regulator in the development and function of DCs. However, the precise involvement of Notch1 pathway in ASC-mediated modulation of tolerogenic DCs and its impact on immune modulation remain to be fully elucidated. This study aims to investigate the interplay between ASCs and DCs, focusing the role of Notch1 signaling and downstream pathways in ASC-modulated tolerogenic DCs. METHODS: Rat bone marrow-derived myeloid DCs were directly co-cultured with ASCs to generate ASC-treated DCs (ASC-DCs). Notch signaling was inhibited using DAPT, while NFκB pathways were inhibited by NEMO binding domain peptide and si-NIK. Flow cytometry assessed DC phenotypes. Real-time quantitative PCR, Western blotting and immunofluorescence determined the expression of Notch1, Jagged1 and the p52/RelB complex in ASC- DCs. RESULTS: Notch1 and Jagged1 were highly expressed on both DCs and ASCs. ASC-DCs displayed significantly reduced levels of CD80, CD86 and MHC II compared to mature DCs. Inhibiting the Notch pathway with DAPT reversed the dedifferentiation effects. The percentage of induced CD25+/FOXP3+/CD4+ Tregs decreased when ASC-DCs were treated with DAPT (inhibition of the Notch pathway) and si-NIK (inhibition of the non-canonical NFκB pathway). CONCLUSIONS: ASCs induce DC tolerogenicity by inhibiting maturation and promoting downstream Treg generation, involving the Notch and NFκB pathways. ASC-induced tolerogenic DCs can be a potential immunomodulatory tool for clinical application.
Assuntos
Células Dendríticas , Tolerância Imunológica , NF-kappa B , Transdução de Sinais , Linfócitos T Reguladores , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , NF-kappa B/metabolismo , Ratos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Receptor Notch1/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Proteína Jagged-1/metabolismo , Técnicas de Cocultura , Células-Tronco/metabolismo , Células-Tronco/citologia , Diferenciação CelularRESUMO
Designing nonprecious metal anode catalysts for photoassisted direct methanol fuel cells (PDMFCs) remains a challenge. As a semiconductor catalyst with a spinel structure, NiCo2O4 has good methanol catalytic oxidation activity and photocatalytic activity, making it a highly promising anode non-noble metal catalyst for PDMFCs. However, compared with the noble metal catalyst, the photoelectrocatalytic activity remained to be improved. In this report, an anion regulation strategy was adopted to improve the photoassisted methanol electrocatalytic activity. Using a CoNi-Aspartic (CoNi-Asp) nanorod as the precursor, the anion-regulated NiCo2X4 (X = O, S, Se, Te) was prepared by oxidation, sulfuration, selenization, and telluridation reactions. The regulation of anions and their effects on the electronic structure, intermediate product, and photoelectric catalytic performance of NiCo2X4 (X= O, S, Se, Te) was systematically discussed. Photoelectrochemical characterization and adsorption energy of â¢OH revealing the volcano-like correlation between the anion in NiCo2X4 (X = O, S, Se, Te) and their photoelectrocatalytic performance. The narrowest band gap (2.239 eV), the highest â¢OH adsorption energy (-3.32 eV), and the highest ratio of Co3+/Co2+ (2.19) ensure the best photoelectric catalytic performance of NiCo2S4, under the visible light irradiation, the photoresponse current density was 1.9 A g-1, the current density at 0.6 V was up to 21.9 A g-1. After 9 h of stability testing, the current retention rate was 80%. This report sheds an idea for the rational design of non-noble anode catalysts for PDMFCs.
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Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14-/- mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.
Assuntos
Herpes Simples/genética , Imunidade Inata , Nucleotidiltransferases/genética , Processamento de Proteína Pós-Traducional , Proteína Sequestossoma-1/genética , Transativadores/genética , Ubiquitina Tiolesterase/genética , Animais , Autofagia/efeitos dos fármacos , Retroalimentação Fisiológica , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/mortalidade , Herpes Simples/virologia , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/imunologia , Interações Hospedeiro-Patógeno , Humanos , Interferon Tipo I/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/virologia , Camundongos , Camundongos Knockout , Nucleotidiltransferases/imunologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteína Sequestossoma-1/imunologia , Transdução de Sinais , Análise de Sobrevida , Transativadores/imunologia , Proteínas com Motivo Tripartido , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/deficiênciaRESUMO
TBK1 is a component of the type I interferon (IFN) signaling pathway, yet the mechanisms controlling its activity and degradation remain poorly understood. Here we report that USP38 negatively regulates type I IFN signaling by targeting the active form of TBK1 for degradation in vitro and in vivo. USP38 specifically cleaves K33-linked poly-ubiquitin chains from TBK1 at Lys670, and it allows for subsequent K48-linked ubiquitination at the same position mediated by DTX4 and TRIP. Knockdown or knockout of USP38 increases K33-linked ubiquitination, but it abrogates K48-linked ubiquitination and degradation of TBK1, thus enhancing type I IFN signaling. Our findings identify an essential role for USP38 in negatively regulating type I IFN signaling, and they provide insights into the mechanisms by which USP38 regulates TBK1 ubiquitination through the NLRP4 signalosome.
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Imunidade Inata , Interferon Tipo I/metabolismo , Macrófagos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Transdução de Sinais/imunologia , Proteases Específicas de Ubiquitina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/virologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Fatores de Iniciação em Eucariotos/genética , Fatores de Iniciação em Eucariotos/imunologia , Fatores de Iniciação em Eucariotos/metabolismo , Regulação da Expressão Gênica , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/imunologia , Interações Hospedeiro-Patógeno , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/imunologia , Macrófagos/virologia , Camundongos , Camundongos Knockout , Fosforilação , Poliubiquitina/genética , Poliubiquitina/imunologia , Poliubiquitina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas/genética , Proteínas/imunologia , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/imunologia , Ubiquitinação , Vesiculovirus/crescimento & desenvolvimento , Vesiculovirus/imunologiaRESUMO
C-type lectins play a crucial role as pathogen-recognition receptors for the dengue virus, which is responsible for causing both dengue fever (DF) and dengue hemorrhagic fever (DHF). DHF is a serious illness caused by the dengue virus, which exists in four different serotypes: DEN-1, DEN-2, DEN-3, and DEN-4. We conducted a genetic association study, during a significant DEN-2 outbreak in southern Taiwan, to explore how variations in the neck-region length of L-SIGN (also known as CD209L, CD299, or CLEC4M) impact the severity of dengue infection. PCR genotyping was utilized to identify polymorphisms in variable-number tandem repeats. We constructed L-SIGN variants containing either 7- or 9-tandem repeats and transfected these constructs into K562 and U937 cells, and cytokine and chemokine levels were evaluated using enzyme-linked immunosorbent assays (ELISAs) following DEN-2 virus infection. The L-SIGN allele 9 was observed to correlate with a heightened risk of developing DHF. Subsequent results revealed that the 9-tandem repeat was linked to elevated viral load alongside predominant T-helper 2 (Th2) cell responses (IL-4 and IL-10) in K562 and U937 cells. Transfecting K562 cells in vitro with L-SIGN variants containing 7- and 9-tandem repeats confirmed that the 9-tandem repeat transfectants facilitated a higher dengue viral load accompanied by increased cytokine production (MCP-1, IL-6, and IL-8). Considering the higher prevalence of DHF and an increased frequency of the L-SIGN neck's 9-tandem repeat in the Taiwanese population, individuals with the 9-tandem repeat may necessitate more stringent protection against mosquito bites during dengue outbreaks in Taiwan.
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Vírus da Dengue , Lectinas Tipo C , Receptores de Superfície Celular , Dengue Grave , Replicação Viral , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Citocinas/metabolismo , Citocinas/genética , Vírus da Dengue/genética , Vírus da Dengue/imunologia , Células K562 , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Repetições Minissatélites/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Dengue Grave/imunologia , Dengue Grave/virologia , Dengue Grave/genética , Taiwan , Células U937 , Carga Viral , Replicação Viral/genéticaRESUMO
Flavonoids play an important role in forming wine grapes and wine quality characteristics. The flavonoids of three winter red wine grapes, Yeniang No. 2 (YN2), Marselan (Mar), and Guipu No. 6 (GP6), were analyzed by ultra-high-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-QQQ-MS). Furthermore, the flavonoids in GP6 grapevines using two types of training systems, namely, trellis (T) and espaliers (E), were also compared in this study. Overall, 196 flavonoid metabolites, including 96 flavones, 38 flavonols, 19 flavanones, 18 polyphenols, 15 anthocyanins, 7 isoflavones, and 3 proanthocyanidins, were identified. The flavonoid profiles were remarkably different among these three grape varieties, while they did not change much in the GP6 managed on trellis and espaliers. Grape varieties with different genetic backgrounds have their own unique flavonoid profiles. Compared with Mar-T, isoflavones and flavonols presented higher contents in GP6-T and YN2-T, which mainly contain glycitein, genistin, calycosin, kaempferide, isotrifoliin, and ayanin. The anthocyanin content was significantly higher in YN2-T than in the other two varieties. YN2 and GP6-T present a more stable color, with significantly more acetylated diglucosides and methylated anthocyanins in YN2-T and GP6-T than in Mar-T. Notably, GP6 had more varied flavonoids and the better characteristics to its flavonoid profile out of these three varieties, due to it containing a higher number of anthocyanins, flavone, and flavonols and the greatest number of different flavonoid metabolites (DFMs), with higher contents than YN2 and Mar. Compared with the trellis training system, the espaliers training system increased the content of flavonoids detected in GP6 grape berries; however, the composition of flavonoids strictly depends on the grape variety.
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Flavonoides , Metabolômica , Vitis , Vinho , Vitis/química , Vitis/metabolismo , Flavonoides/análise , Flavonoides/metabolismo , Vinho/análise , Metabolômica/métodos , China , Cromatografia Líquida de Alta Pressão , Antocianinas/análise , Antocianinas/metabolismo , MetabolomaRESUMO
BACKGROUND: The morbidity and mortality of community-acquired pneumonia (CAP) remain high among infectious diseases. It was reported that angiopoietin-like 4 (ANGPTL4) could be a diagnostic biomarker and a therapeutic target for pneumonia. This study aimed to develop a more objective, specific, accurate, and individualized scoring system to predict the severity of CAP. METHODS: Totally, 31 non-severe community-acquired pneumonia (nsCAP) patients and 14 severe community-acquired pneumonia (sCAP) patients were enrolled in this study. The CURB-65 and pneumonia severity index (PSI) scores were calculated from the clinical data. Serum ANGPTL4 level was measured by enzyme-linked immunosorbent assay (ELISA). After screening factors by univariate analysis and receiver operating characteristic (ROC) curve analysis, multivariate logistic regression analysis of ANGPTL4 expression level and other risk factors was performed, and a nomogram was developed to predict the severity of CAP. This nomogram was further internally validated by bootstrap resampling with 1000 replications through the area under the ROC curve (AUC), the calibration curve, and the decision curve analysis (DCA). Finally, the prediction performance of the new nomogram model, CURB-65 score, and PSI score was compared by AUC, net reclassification index (NRI), and integrated discrimination improvement (IDI). RESULTS: A nomogram for predicting the severity of CAP was developed using three factors (C-reactive protein (CRP), procalcitonin (PCT), and ANGPTL4). According to the internal validation, the nomogram showed a great discrimination capability with an AUC of 0.910. The Hosmer-Lemeshow test and the approximately fitting calibration curve suggested a satisfactory accuracy of prediction. The results of DCA exhibited a great net benefit. The AUC values of CURB-65 score, PSI score, and the new prediction model were 0.857, 0.912, and 0.940, respectively. NRI comparing the new model with CURB-65 score was found to be statistically significant (NRI = 0.834, P < 0.05). CONCLUSION: A robust model for predicting the severity of CAP was developed based on the serum ANGPTL4 level. This may provide new insights into accurate assessment of the severity of CAP and its targeted therapy, particularly in the early-stage of the disease.
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Infecções Comunitárias Adquiridas , Pneumonia , Humanos , Nomogramas , Prognóstico , Proteína C-Reativa/análise , Curva ROC , Angiopoietinas , Índice de Gravidade de Doença , Estudos RetrospectivosRESUMO
Malaria infection induces complex and diverse immune responses. To elucidate the mechanisms underlying host-parasite interaction, we performed a genetic screen during early (24 h) Plasmodium yoelii infection in mice and identified a large number of interacting host and parasite genes/loci after transspecies expression quantitative trait locus (Ts-eQTL) analysis. We next investigated a host E3 ubiquitin ligase gene (March1) that was clustered with interferon (IFN)-stimulated genes (ISGs) based on the similarity of the genome-wide pattern of logarithm of the odds (LOD) scores (GPLS). March1 inhibits MAVS/STING/TRIF-induced type I IFN (IFN-I) signaling in vitro and in vivo. However, in malaria-infected hosts, deficiency of March1 reduces IFN-I production by activating inhibitors such as SOCS1, USP18, and TRIM24 and by altering immune cell populations. March1 deficiency increases CD86+DC (dendritic cell) populations and levels of IFN-γ and interleukin 10 (IL-10) at day 4 post infection, leading to improved host survival. T cell depletion reduces IFN-γ level and reverse the protective effects of March1 deficiency, which can also be achieved by antibody neutralization of IFN-γ. This study reveals functions of MARCH1 (membrane-associated ring-CH-type finger 1) in innate immune responses and provides potential avenues for activating antimalaria immunity and enhancing vaccine efficacy.
Assuntos
Malária/imunologia , Plasmodium yoelii/fisiologia , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Parasita , Humanos , Imunidade Inata , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Malária/enzimologia , Malária/genética , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium yoelii/imunologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
With the higher requirements of various tactical and technical indicators of the weapon systems, the current research on the ignition and combustion characteristics of different types of solid propellants is not comprehensive. In more complex and harsh environmental conditions, the pressure affects the ignition and combustion characteristics. Therefore, the paper studies the ignition and combustion characteristics of the modified double-base propellants (MDB propellants) and fuel-rich propellants (FR propellants) under low-pressure environment. Combining experiment and theory, the ignition delay time and burning rate of two kinds of solid propellants are compared and analyzed at low pressure by the laser ignition experimental device. The results displayed that the burning flames of the FR and MDB propellant presented evident V-shape and cylindrical, respectively. The flame brightness decreased with the decrease in pressure. With the increase of pressure and heat flux, the ignition delay time of the MDB propellant and the FR propellant decreased. By comparison, Model 2 of the ignition delay time was more effective for the estimation of the ignition delay time of the FR propellant. The experimental results are compared with the three burning rate models, which are the Vielle formula (Model 1), Summerfield formula (Model 2), and B-number burning rate formula (Model 3). The results showed the burning rate was more in accord with Model 3.
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The delayed healing of chronic wounds, such as diabetic foot ulcers (DFUs), is a clinical problem. Few dressings can promote wound healing by satisfying the demands of chronic wound exudate management and tissue granulation. Therefore, the aim of this study was to prepare a high-absorption polyurethane (PU) foam dressing modified by polyethylene glycol (PEG) and triethoxysilane (APTES) to promote wound healing. PEG-modified (PUE) and PEG/APTES-modified (PUESi) dressings were prepared by self-foaming reactions. Gauze and PolyMem were used as controls. Next, Fourier transform-infrared spectroscopy, thermomechanical analyses, scanning electron microscopy and tensile strength, water absorption, anti-protein absorption, surface dryness and biocompatibility tests were performed for in vitro characterization. Wound healing effects were further investigated in nondiabetic (non-DM) and diabetes mellitus (DM) rat models. The PUE and PUESi groups exhibited better physicochemical properties than the gauze and PolyMem groups. Moreover, PUESi dressing showed better anti-adhesion properties and absorption capacity with deformation. Furthermore, the PUESi dressing shortened the inflammatory phase and enhanced collagen deposition in both the non-DM and DM animal models. To conclude, the PUESi dressing not only was fabricated with a simple and effective strategy but also enhanced wound healing via micronegative-pressure generation by its high absorption compacity with deformation.
Assuntos
Diabetes Mellitus , Pé Diabético , Ratos , Animais , Poliuretanos/química , Cicatrização , Bandagens , PolietilenoglicóisRESUMO
The RIG-I-like receptors (RLRs) are critical for protection against RNA virus infection, and their activities must be stringently controlled to maintain immune homeostasis. Here, we report that leucine-rich repeat containing protein 25 (LRRC25) is a key negative regulator of RLR-mediated type I interferon (IFN) signaling. Upon RNA virus infection, LRRC25 specifically binds to ISG15-associated RIG-I to promote interaction between RIG-I and the autophagic cargo receptor p62 and to mediate RIG-I degradation via selective autophagy. Depletion of either LRRC25 or ISG15 abrogates RIG-I-p62 interaction as well as the autophagic degradation of RIG-I. Collectively, our findings identify a previously unrecognized role of LRRC25 in type I IFN signaling activation by which LRRC25 acts as a secondary receptor to assist RIG-I delivery to autophagosomes for degradation in a p62-dependent manner.
Assuntos
Autofagia/imunologia , Proteína DEAD-box 58/metabolismo , Interferon Tipo I/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Citocinas/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/genética , Ligação Proteica/imunologia , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores Imunológicos , Transdução de Sinais/imunologia , Ubiquitinas/metabolismo , Vírus da Estomatite Vesicular Indiana/imunologiaRESUMO
Stringent control of NF-κB and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-ß activated kinase-1 (TAK1) is essential for NF-κB activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7(ΔM/ΔM)) led to development of splenomegaly and lymphomegaly associated with neutrophilia. Compared with wild-type cells, TAK1-deficient neutrophils enhanced the phosphorylation of the kinases IKK, p38, and JNK and the production of interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7(ΔM/ΔM) mice were significantly more susceptible to LPS-induced septic shock and produced higher amounts of IL-1ß, IL-6, and TNF-α in plasma than do wild-type mice. Specific ablation of p38 rescued the phenotype and functional properties of Map3k7(ΔM/ΔM) mice. Our findings identify a previously unrecognized role of TAK1 as a negative regulator of p38 and IKK activation in a cell type-specific manner.