RESUMO
BACKGROUND: Lipoprotein(a) (Lp[a]) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association has yet to be fully elucidated. OBJECTIVES: This multicenter study aimed to investigate whether association between Lp(a) and MI risk is reinforced by the presence of low-attenuation plaque (LAP) identified by coronary computed tomography angiography (CCTA). METHODS: In a derivation cohort, a total of 5,607 patients with stable chest pain suspected of coronary artery disease who underwent CCTA and Lp(a) measurement were prospectively enrolled. In validation cohort, 1,122 patients were retrospectively collected during the same period. High Lp(a) was defined as Lp(a) ≥50 mg/dL. The primary endpoint was a composite of time to fatal or nonfatal MI. Associations were estimated using multivariable Cox proportional hazard models. RESULTS: During a median follow-up of 8.2 years (Q1-Q3: 7.2-9.3 years), the elevated Lp(a) levels were associated with MI risk (adjusted HR [aHR]: 1.91; 95% CI: 1.46-2.49; P < 0.001). There was a significant interaction between Lp(a) and LAP (Pinteraction <0.001) in relation to MI risk. When stratified by the presence or absence of LAP, Lp(a) was associated with MI in patients with LAP (aHR: 3.03; 95% CI: 1.92-4.76; P < 0.001). Mediation analysis revealed that LAP mediated 73.3% (P < 0.001) for the relationship between Lp(a) and MI. The principal findings remained unchanged in the validation cohort. CONCLUSIONS: Elevated Lp(a) augmented the risk of MI during 8 years of follow-up, especially in patients with LAP identified by CCTA. The presence of LAP could reinforce the relationship between Lp(a) and future MI occurrence.
Assuntos
Angiografia por Tomografia Computadorizada , Lipoproteína(a) , Infarto do Miocárdio , Placa Aterosclerótica , Humanos , Masculino , Feminino , Lipoproteína(a)/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Pessoa de Meia-Idade , Placa Aterosclerótica/sangue , Placa Aterosclerótica/diagnóstico por imagem , Idoso , Angiografia Coronária , Estudos Retrospectivos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Estudos Prospectivos , Seguimentos , Biomarcadores/sangueRESUMO
Influenza viruses and thogotoviruses account for most recognized orthomyxoviruses. Thogotoviruses, exemplified by Thogoto virus (THOV), are capable of infecting humans using ticks as vectors. THOV transcribes mRNA without the extraneous 5' end sequences derived from cap-snatching in influenza virus mRNA. Here, we report cryo-EM structures to characterize THOV polymerase RNA synthesis initiation and elongation. The structures demonstrate that THOV RNA transcription and replication are able to start with short dinucleotide primers and that the polymerase cap-snatching machinery is likely non-functional. Triggered by RNA synthesis, asymmetric THOV polymerase dimers can form without the involvement of host factors. We confirm that, distinctive from influenza viruses, THOV-polymerase RNA synthesis is weakly dependent of the host factors ANP32A/B/E in human cells. This study demonstrates varied mechanisms in RNA synthesis and host factor utilization among orthomyxoviruses, providing insights into the mechanisms behind thogotoviruses' broad-infectivity range.
Assuntos
Microscopia Crioeletrônica , RNA Viral , Thogotovirus , Transcrição Gênica , Replicação Viral , Humanos , Thogotovirus/genética , Thogotovirus/metabolismo , Thogotovirus/ultraestrutura , RNA Viral/metabolismo , RNA Viral/genética , Replicação Viral/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Proteínas Virais/metabolismo , Proteínas Virais/genética , Proteínas Virais/química , Proteínas Virais/ultraestruturaRESUMO
Mitogen-activated protein kinases (MAPKs) play important roles in plant stress response. As a major member of the MAPK family, MPK3 has been reported to participate in the regulation of chilling stress. However, the regulatory function of wheat (Triticum aestivum ) mitogen-activated protein kinase TaMPK3 in freezing tolerance remains unknown. Dongnongdongmai No.1 (Dn1) is a winter wheat variety with strong freezing tolerance; therefore, it is important to explore the mechanisms underlying this tolerance. In this study, the expression of TaMPK3 in Dn1 was detected under low temperature and hormone treatment. Gene cloning, bioinformatics and subcellular localisation analyses of TaMPK3 in Dn1 were performed. Overexpressed TaMPK3 in Arabidopsis thaliana was obtained, and freezing tolerance phenotype observations, physiological indices and expression levels of ICE-C-repeat binding factor (CBF)-COR -related genes were determined. In addition, the interaction between TaMPK3 and TaICE41 proteins was detected. We found that TaMPK3 expression responds to low temperatures and hormones, and the TaMPK3 protein is localised in the cytoplasm and nucleus. Overexpression of TaMPK3 in Arabidopsis significantly improves freezing tolerance. TaMPK3 interacts with the TaICE41 protein. In conclusion, TaMPK3 is involved in regulating the ICE-CBF-COR cold resistance module through its interaction with TaICE41, thereby improving freezing tolerance in Dn1 wheat.
Assuntos
Arabidopsis , Congelamento , Regulação da Expressão Gênica de Plantas , Triticum , Arabidopsis/genética , Triticum/genética , Triticum/metabolismo , Triticum/enzimologia , Plantas Geneticamente Modificadas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genéticaRESUMO
Infectious bursal disease (IBD) is an acute and fatal immunosuppressive disease caused by infectious bursal disease virus (IBDV). As an obligate intracellular parasite, IBDV infection is strictly regulated by host factors. Knowledge on the antiviral activity and possible mechanism of host factors might provide the theoretical basis for the prevention and control of IBD. In this study, RNA-sequencing results indicated that many host factors were induced by IBDV infection, among which the expression levels of OASL (2´,5´-oligadenylate synthetase-like protein) was significantly upregulated. OASL overexpression significantly inhibited IBDV replication, whereas OASL knockdown promoted IBDV replication. Interestingly, the antiviral ability of OASL was independent of its canonical enzymatic activity, i.e., OASL targeted viral protein VP2 for degradation, depending on the autophagy receptor p62/SQSTM1 in the autophagy pathway. Additionally, the 316 lysine (K) of VP2 was the key site for autophagy degradation, and its replacement with arginine disrupted VP2 degradation induced by OASL and enhanced IBDV replication. Importantly, our results for the first time indicate a unique and potent defense mechanism of OASL against double-stranded RNA virus by interaction with viral proteins, which leads to their degradation. IMPORTANCE: OASL (2´,5´-oligadenylate synthetase-like protein) exhibits broad-spectrum antiviral effects against single-stranded RNA viruses in mammals, potentially serving as a promising target for novel antiviral strategies. However, its role in inhibiting the replication of double-stranded RNA viruses (dsRNA viruses), such as infectious bursal disease virus (IBDV), in avian species remains unclear. Our findings indicated a unique and potent defense mechanism of OASL against dsRNA viruses. It has been previously shown in mammals that OASL inhibits virus replication through increasing interferon production. The groundbreaking aspect of our study is the finding that OASL has the ability to interact with IBDV viral protein VP2 and target it for degradation and thus exerts its antiviral effect. Our results reveal the interaction between avian natural antiviral immune response and IBDV infection. Our study not only enhances our understanding of bird defenses against viral infections but can also inform strategies for poultry disease management.
Assuntos
2',5'-Oligoadenilato Sintetase , Autofagia , Infecções por Birnaviridae , Galinhas , Vírus da Doença Infecciosa da Bursa , Proteínas Estruturais Virais , Replicação Viral , Vírus da Doença Infecciosa da Bursa/fisiologia , Animais , Infecções por Birnaviridae/virologia , Infecções por Birnaviridae/metabolismo , Proteínas Estruturais Virais/metabolismo , Proteínas Estruturais Virais/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , Doenças das Aves Domésticas/virologia , Doenças das Aves Domésticas/metabolismo , Interações Hospedeiro-Patógeno , Células HEK293 , Humanos , Linhagem CelularRESUMO
The subgroup J avian leukosis virus (ALV-J), a retrovirus, uses its gp85 protein to bind to the receptor, the chicken sodium hydrogen exchanger isoform 1 (chNHE1), facilitating viral invasion. ALV-J is the main epidemic subgroup and shows noteworthy mutations within the receptor-binding domain (RBD) region of gp85, especially in ALV-J layer strains in China. However, the implications of these mutations on viral replication and transmission remain elusive. In this study, the ALV-J layer strain JL08CH3-1 exhibited a more robust replication ability than the prototype strain HPRS103, which is related to variations in the gp85 protein. Notably, the gp85 of JL08CH3-1 demonstrated a heightened binding capacity to chNHE1 compared to HPRS103-gp85 binding. Furthermore, we showed that the specific N123I mutation within gp85 contributed to the enhanced binding capacity of the gp85 protein to chNHE1. Structural analysis indicated that the N123I mutation primarily enhanced the stability of gp85, expanded the interaction interface, and increased the number of hydrogen bonds at the interaction interface to increase the binding capacity between gp85 and chNHE1. We found that the N123I mutation not only improved the viral replication ability of ALV-J but also promoted viral shedding in vivo. These comprehensive data underscore the notion that the N123I mutation increases receptor binding and intensifies viral replication.
Assuntos
Vírus da Leucose Aviária , Leucose Aviária , Doenças das Aves Domésticas , Animais , Vírus da Leucose Aviária/genética , Vírus da Leucose Aviária/química , Mutação , Galinhas , Isoformas de Proteínas/genética , Proteínas do Envelope Viral/genéticaRESUMO
A 65-year-old man presented with asymptomatic retroperitoneal mass that had been detected on ultrasonography performed during a physical screening. He had no hematochezia, hematuria or any other symptoms. Tumor markers were normal, including alpha fetoprotein, carcinoembryonic antigen, neuron-specific enolase and cancer antigen 199. Abdominal CT demonstrated a retroperitoneal mass (white arrow) accompanied by significant thickening of the jejunal wall, involving the left kidney. After enhancement, the mass showed rapid enhancement at arterial phase and venous phase, showed washout at delayed phase. Multi-planar reformation revealed the mass involving the pancreatic tail and the left renal pelvis. Surgical resection was performed and pathological examination confirmed clear cell renal cell carcinoma involving pancreas and jejunum, with immunohistochemical results as follows: CK (partly +), Vimentin (partly +), Pax-8 (+), CD10 (+), P505s (partly +), CA-IX (+), TFE-3 (-), Syn (-), CgA (-), CD56 (+), S-100 (-), SOX-10 (-), HMB-45 (-), Desmin (-),CD117 (-), DOG-1 (-), Melan-A (-), SMA (-), CD34 (+), CD31 (+), CD68 (+), Ki67 (5%+). Discussion.
RESUMO
Species-specific differences in acidic nuclear phosphoprotein 32 family member A (ANP32A) determine the restriction of avian-signature polymerase in mammalian cells. Mutations that evade this restriction, such as PB2-E627K, are frequently acquired when avian influenza A viruses jump from avian hosts to mammalian hosts. However, the mechanism underlying this adaptation process is still unclear. Here, we report that host factor ANP32 proteins can be incorporated into influenza viral particles through combination with the viral RNA polymerase (vPol) and then transferred into targeted cells where they support virus replication. The packaging of the ANP32 proteins into influenza viruses is dependent on their affinity with the vPol. Avian ANP32A (avANP32A) delivered by avian influenza A virions primes early viral replication in mammalian cells, thereby favoring the downstream interspecies transmission event by increasing the total amount of virus carrying adaptive mutations. Our study clarifies one role of avANP32A where it is used by avian influenza virus to help counteract the restriction barrier in mammals.