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Tumor progression locus 2 (TPL2) is a serine/threonine kinase that belongs to the mitogen-activated protein 3 kinase (MAP3K) family, and it plays an important role in pathogen infection. The trimer complex of TPL2, p105, and ABIN2 is essential for maintenance of TPL2 steady-state levels and host cell response to pathogens. Foot-and-mouth disease virus (FMDV) is a positive-strand RNA virus of the family Picornaviridae that encodes proteins capable of antagonizing host immune responses to achieve infection. The VP1 protein of FMDV is a multifunctional protein that can bind host cells and induce an immune response as well as cell apoptosis. However, the role and mechanisms of TPL2 in FMDV infection remain unknown. Here, we determined that FMDV infection could inhibit TPL2, p105, and ABIN2 at the transcription and protein levels, while VP1 could only inhibit TPL2, p105 and ABIN2 at protein level. TPL2 inhibited the replication of FMDV in vivo and in vitro, the 268 to 283 amino-acid region in the TPL2 kinase domain was essential for interaction with VP1. Moreover, VP1 promoted K48-linked polyubiquitination of TPL2 and degraded TPL2 by the proteasome pathway. However, VP1-induced degradation of p105 and ABIN2 was independent of proteasome, autophagy, lysosome, and caspase-dependent pathways. Further studies showed that VP1 destroyed the stability of the TPL2-p105-ABIN2 complex. Taken together, these results revealed that VP1 antagonized TPL2-meditated antivirus activity by degrading TPL2 and destroying its complex. These findings may contribute to understand FMDV-host interactions and improve development of a novel vaccine to prevent FMDV infection.Importance Virus-host interactions are critical for virus infection. This study was the first to demonstrate the antiviral effect of host TPL2 during FMDV replication by increasing production of interferons and antiviral cytokines. Both FMDV and VP1 protein can reduce host TPL2, ABIN2 and p105 to destroy TPL2-p105-ABIN2 trimer complex. VP1 interacted with TPL2 and degrade TPL2 via proteasome pathway to repress TPL2-mediated antivirus activity. This study provided new insights into FMDV immune evasion mechanisms, elucidating new informations regarding FMDV counteraction of host antivirus activity.
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An amendment to this paper has been published and can be accessed via the original article.
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Seneca Valley virus (SVV) is a non-encapsulated single-stranded positive-strand RNA virus whose transmission routes have not yet been fully elucidated. Exosomes have been implicated in the intercellular transport of a variety of materials, such as proteins, RNA, and liposomes. However, whether exosomes can mediate SVV intercellular transmission remains unknown. In this study, we extracted exosomes from SVV-infected IBRS-2 cells to investigate intercellular transmission. Our results suggest that the intercellular transmission of SVV is mediated by exosomes. The results of co-localization and RT-qPCR studies showed that exosomes harbor SVV and enable the virus to proliferate in both susceptible and non-susceptible cells. Furthermore, the replication of SVV was inhibited when IBRS-2 cells were treated with interfering RNA Rab27a and exosome inhibitor GW4869. Finally, neutralization experiments were performed to further verify whether the virus was encapsulated by the exosomes that mediated transmission between cells. It was found that exosome-mediated intercellular transmission was not blocked by SVV-specific neutralizing antibodies. This study reveals a new transmission route of SVV and provides clear evidence regarding the pathogenesis of SVV, information which can also be useful for identifying therapeutic interventions.
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Exosomas/virología , Infecciones por Picornaviridae/veterinaria , Picornaviridae/fisiología , Enfermedades de los Porcinos/transmisión , Animales , Infecciones por Picornaviridae/transmisión , Infecciones por Picornaviridae/virología , Sus scrofa , Porcinos , Enfermedades de los Porcinos/virologíaRESUMEN
Orf virus (ORFV) infects sheep and goat tissues, resulting in severe proliferative lesions. To analyze cellular protein expression in ORFV-infected goat skin fibroblast (GSF) cells, we used two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ). The proteomics approach was used along with quantitative reverse transcription polymerase chain reaction (RT-qPCR) to detect differentially expressed proteins in ORFV-infected GSF cells and mock-infected GSF cells. A total of 282 differentially expressed proteins were identified. It was found that 222 host proteins were upregulated and 60 were downregulated following viral infection. We confirmed that these proteins were differentially expressed and found that heat shock 70-kDa protein 1B (HSPA1B) was differentially expressed and localized in the cytoplasm. It was also noted that HSPA1B caused inhibition of viral proliferation, in the middle and late stages of viral infection. The differentially expressed proteins were associated with the biological processes of viral binding, cell structure, signal transduction, cell adhesion, and cell proliferation.
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Fibroblastos/metabolismo , Proteínas HSP70 de Choque Térmico/fisiología , Virus del Orf/fisiología , Proteoma/genética , Replicación Viral , Animales , Células Cultivadas , Cromatografía Liquida , Fibroblastos/virología , Cabras , Interacciones Huésped-Patógeno , Virus del Orf/genética , Proteómica , Espectrometría de Masas en TándemRESUMEN
Comprehensively clarifying China's carbon emission factors and formulating effective strategies are essential and significant for achieving the "30-60" dual carbon target. This manuscript proposed a novel hierarchical framework of multi-factor decomposition, comprehensive evaluation, prediction, and decoupling analysis of the carbon emission. The multi-factor decomposition model from the perspectives of energy, economy, and society based on the expanding the Kaya Identity and LMDI decomposition method can provide the quantification results. On this basis, this manuscript applies the entropy weight method to construct the evaluation system and generate the index from the environment, energy, and economy dimensions for China's six power generation modes. Furthermore, the carbon emission dynamics model is built based on the carbon emission data in the past 40 years and used to predict China's carbon emission in the next 40 years under multi scenarios combined with Tapio's decoupling theory. The results show that income per capita and thermal power generation result in carbon emission, while energy price and intensity are decreasing. Moreover, reducing energy consumption and increasing the proportion of renewable energy are effective ways to make China's carbon emission peak in 2030, with a peak value of 12.276 billion tons. Eventually, with policies implemented, carbon emission, economic growth, and social development are predicted to reach a strong decoupling state, indicating long-lasting negative correlations. In summary, this study will provide a comprehensive analytical solution for factor decomposition, integrated assessment, and predictive decoupling of carbon emission from a national level, aiming to provide scientifically reasonable suggestions for policies and regulations for the "dual carbon" goal.
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Carbono , Objetivos , Carbono/análisis , Dióxido de Carbono/análisis , China , Desarrollo EconómicoRESUMEN
This contribution firstly proposed the concept of annual average power generation hours and analyzed per capita energy consumption, carbon emission, and the human development index from a macro perspective. On this basis, we compared the average household electrical energy consumption of urban and rural residents based on the data from CGSS-2015 from a micro perspective. The results show the positive correlation between carbon emissions per capita and the human development index and China's regional imbalance characteristics between household electricity consumption and renewable energy distribution. Therefore, the distributed energy supply system is proposed as an effective complement to centralized power generation systems and is the key to synergizing human development and carbon emissions in China. Moreover, we analyzed the characteristics of distributed energy supply systems in the context of existing energy supply systems, pointing out the need to fully use solar energy and natural gas. Finally, two types of typical distributed energy supply systems are proposed for satisfying the household energy requirements in remote or rural areas of western and the eastern or coastal areas of China, respectively. Two typical distributed energy systems integrate high-efficiency energy conversion, storage, and transfer devices such as electric heat pumps, photovoltaic thermal, heat and electricity storage, and fuel cells.
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Carbono , Energía Renovable , Carbono/análisis , Dióxido de Carbono/análisis , China , Electricidad , HumanosRESUMEN
The blood-clotting performance and characteristics of hemostatic materials are critical for their development and actual application. Based on the theory of porous media and characteristics of a non-Newtonian fluid, this study proposed an adsorption factor to characterize the porosity generation and blood coagulation process of hemostatic materials. On this basis, we constructed a physical model of blood coagulation in a porous medium integrated with the power-law fluid model to study the proposed poly(vinyl alcohol)-chitosan (PVA-CS) composite hemostatic material. Moreover, we simulated the dynamic blood flow process and blood coagulation process in the PVA-CS hemostatic material by introducing the physical model. The simulation results show that the blood begins to coagulate, which affects the porosity and permeability of the blood-containing area, resulting in changing the porosity after blood flowed into the hemostatic material. The porosity, permeability, and blood flow rate will approach zero until the generated blood coagulation entirely blocked the porous medium. Besides, simulation can provide the pressure and velocity distribution varying in the coagulation process of hemostatic materials. The temperature will also influence the hemostatic performance of the PVA-CS material. In all, the proposed simulation method enabled the coagulation mechanism of PVA-CS to be revealed from the perspective of blood flow in porous media combined with the adsorption factor.
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Materiales Biocompatibles/farmacología , Coagulación Sanguínea/efectos de los fármacos , Quitosano/farmacología , Hemostáticos/farmacología , Alcohol Polivinílico/farmacología , Materiales Biocompatibles/química , Quitosano/química , Hemostáticos/química , Humanos , Tamaño de la Partícula , Alcohol Polivinílico/química , Porosidad , Propiedades de Superficie , TemperaturaRESUMEN
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As a zoonotic disease, ovine contagious pustular dermatitis (Orf) is a serious threat to sheep as well as humans. Orf virus (ORFV) interferon resistance protein (VIR) is the principal virulence protein that encodes a dsRNA-binding protein to inhibit host antiviral response. p53 is one of the key proteins of the host antiviral innate immunity. It not only enhances type I interferon secretion but also induces apoptosis in infected cells, and plays a crucial role in the immune response against various viral infections. However, it remains to be elucidated what role p53 plays in ORFV replication and whether ORFV's own protein VIR regulates p53 expression to promote self-replication. In this study, we showed that p53 has an antiviral effect on ORFV and can inhibit ORFV replication. In addition, ORFV nonstructural protein VIR interacts with p53 and degrades p53, which inhibits p53-mediated positive regulation of downstream antiviral genes. This study provides new insight into the immune evasion mediated by ORFV and identifies VIR as an antagonistic factor for ORFV to evade the antiviral response.
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Interacciones Microbiota-Huesped/genética , Virus del Orf/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Virales/genética , Replicación Viral/genética , Animales , Línea Celular , Cricetinae , Ectima Contagioso/virología , Fibroblastos/inmunología , Fibroblastos/virología , Regulación Viral de la Expresión Génica , Cabras , Evasión Inmune/genética , Inmunidad Innata , Riñón/citología , Virus del Orf/fisiología , Ovinos , Piel/citología , Proteínas Virales/metabolismoRESUMEN
Foot-and-mouth disease (FMD) is a severe, highly contagious viral disease of cloven-hoofed animals. In order to establish an infection, the FMD virus (FMDV) needs to counteract host antiviral responses. Tumor progression locus 2 (TPL2), a mitogen-activated protein kinase, can regulate innate and adaptive immunity; however, its exact mechanisms underlying TPL2-mediated regulation of the pathogenesis of FMDV infection remain unknown. In this study, we confirmed that TPL2 could inhibit FMDV replication in vitro and in vivo. The virus replication increased in Tpl2-deficient suckling mice in association with reduced expression of interferon-stimulated genes interferon-α (IFN-α) and myxovirus resistance (MX2) and significantly reduced expression of C-X-C motif chemokine ligand 10 (CXCL10), interferon regulatory factor 3 (IRF3), and IRF7, while the phosphorylation of IRF3 was not detected. Moreover, the interactions between TPL2 and VP1 were also confirmed. The overexpression of TPL2 promoted IRF3-mediated dose-dependent activation of the IFN-ß signaling pathway in association with interactions between IRF3 and TPL2. VP1 also inhibited phosphorylation of TPL2 at Thr290, while Thr290 resulted as the key functional site associated with the TPL2-mediated antiviral response. Taken together, this study indicated that FMDV capsid protein VP1 antagonizes TPL2-mediated activation of the IRF3/IFN-ß signaling pathway for immune escape and facilitated virus replication.
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Proteínas de la Cápside/metabolismo , Virus de la Fiebre Aftosa/inmunología , Virus de la Fiebre Aftosa/fisiología , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/metabolismo , Animales , Artiodáctilos , Proteínas de la Cápside/inmunología , Fiebre Aftosa , Interacciones Huésped-Patógeno , Humanos , Evasión Inmune , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Porcinos , Replicación ViralRESUMEN
Tumor progression locus 2 (TPL2) is a serine/threonine kinase that belongs to the MAP3K family. The activated TPL2 regulates the innate immune-relevant signaling pathways, such as ERK, JNK, and NF-κB, and the differentiation of immune cells, for example, CD4+ T and NK cells. Therefore, TPL2 plays a critical role in regulating the innate immune response. The present review summarizes the recent advancements in the TPL2-regulated innate immune response.