RESUMEN
STING is a central adaptor in the innate immune response to DNA viruses. However, the manner in which STING activity is regulated remains unclear. We identified iRhom2 ('inactive rhomboid protein 2') as a positive regulator of DNA-virus-triggered induction of type I interferons. iRhom2 deficiency markedly impaired DNA-virus- and intracellular-DNA-induced signaling in cells, and iRhom2-deficient mice were more susceptible to lethal herpes simplex virus type 1 (HSV-1) infection. iRhom2 was constitutively associated with STING and acted in two distinct processes to regulate STING activity. iRhom2 recruited the translocon-associated protein TRAPß to the STING complex to facilitate trafficking of STING from the endoplasmic reticulum to perinuclear microsomes. iRhom2 also recruited the deubiquitination enzyme EIF3S5 to maintain the stability of STING through removal of its K48-linked polyubiquitin chains. These results suggest that iRhom2 is essential for STING activity, as it regulates TRAPß-mediated translocation and EIF3S5-mediated deubiquitination of STING.
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Proteínas Portadoras/metabolismo , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Proteínas de la Membrana/metabolismo , Microsomas/metabolismo , Animales , Proteínas Portadoras/genética , Células Cultivadas , Factor 3 de Iniciación Eucariótica/metabolismo , Inmunidad Innata , Interferón Tipo I/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Estabilidad Proteica , Transporte de Proteínas/genética , Fosfatasa Ácida Tartratorresistente/metabolismo , UbiquitinaciónRESUMEN
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 58 DEAD Box/metabolismo , Infecciones por Virus ARN/inmunología , Virus ARN/fisiología , ARN Viral/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Proteínas de Unión al ADN/metabolismo , Regulación Viral de la Expresión Génica , Células HEK293 , Humanos , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , ARN Viral/inmunología , Proteínas de Unión al ARN/genética , Células THP-1 , Factores de Transcripción/metabolismo , UbiquitinaciónRESUMEN
FTO demethylates internal N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am; at the cap +1 position) in mRNA, m6A and m6Am in snRNA, and N1-methyladenosine (m1A) in tRNA in vivo, and in vitro evidence supports that it can also demethylate N6-methyldeoxyadenosine (6mA), 3-methylthymine (3mT), and 3-methyluracil (m3U). However, it remains unclear how FTO variously recognizes and catalyzes these diverse substrates. Here we demonstrate-in vitro and in vivo-that FTO has extensive demethylation enzymatic activity on both internal m6A and cap m6Am Considering that 6mA, m6A, and m6Am all share the same nucleobase, we present a crystal structure of human FTO bound to 6mA-modified ssDNA, revealing the molecular basis of the catalytic demethylation of FTO toward multiple RNA substrates. We discovered that (i) N6-methyladenine is the most favorable nucleobase substrate of FTO, (ii) FTO displays the same demethylation activity toward internal m6A and m6Am in the same RNA sequence, suggesting that the substrate specificity of FTO primarily results from the interaction of residues in the catalytic pocket with the nucleobase (rather than the ribose ring), and (iii) the sequence and the tertiary structure of RNA can affect the catalytic activity of FTO. Our findings provide a structural basis for understanding the catalytic mechanism through which FTO demethylates its multiple substrates and pave the way forward for the structure-guided design of selective chemicals for functional studies and potential therapeutic applications.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/química , Epigénesis Genética , ARN Mensajero/química , ARN/química , Adenosina/química , Adenosina/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/química , Catálisis , ADN de Cadena Simple/química , Desmetilación , Desoxiadenosinas/química , Humanos , Conformación de Ácido Nucleico , Conformación Proteica , Estructura Terciaria de Proteína , Especificidad por Sustrato , Timina/análogos & derivados , Timina/química , Uracilo/análogos & derivados , Uracilo/químicaRESUMEN
The epitranscriptomic mark N6-methyladenosine (m6A) can be written, read, and erased via the action of a complex network of proteins. m6A binding proteins read m6A marks and transduce their downstream regulatory effects by altering RNA metabolic processes. The characterization of m6A readers is an essential prerequisite for understanding the roles of m6A in plants, but the identities of m6A readers have been unclear. Here, we characterized the YTH-domain family protein ECT2 as an Arabidopsis thaliana m6A reader whose m6A binding function is required for normal trichome morphology. We developed the formaldehyde cross-linking and immunoprecipitation method to identify ECT2-RNA interaction sites at the transcriptome-wide level. This analysis demonstrated that ECT2 binding sites are strongly enriched in the 3' untranslated regions (3' UTRs) of target genes and led to the identification of a plant-specific m6A motif. Sequencing analysis suggested that ECT2 plays dual roles in regulating 3' UTR processing in the nucleus and facilitating mRNA stability in the cytoplasm. Disruption of ECT2 accelerated the degradation of three ECT2 binding transcripts related to trichome morphogenesis, thereby affecting trichome branching. The results shed light on the underlying mechanisms of the roles of m6A in RNA metabolism, as well as plant development and physiology.
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Arabidopsis/metabolismo , Tricomas/genética , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Sitios de Unión , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Unión Proteica , Estabilidad del ARN/genética , Estabilidad del ARN/fisiologíaRESUMEN
In order to provide a thorough summary and analysis over sperm toxicity evaluation of medical devices for human in vitro assisted reproductive technology, as well as to forecast its future direction, currently available test methods and evaluation indicators related to human sperm were elaborated here. Furthermore, their weakness and risk points were analyzed and possible ways for further improvement were also provided.
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Técnicas Reproductivas Asistidas , Espermatozoides , Humanos , Masculino , Pruebas de ToxicidadRESUMEN
MITA (also called STING) is a central adaptor protein in innate immune response to cytosolic DNA. Cellular trafficking of MITA from the ER to perinuclear microsomes after DNA virus infection is critical for MITA activation and onset of innate antiviral response. Here we found that SNX8 is a component of DNA-triggered induction of downstream effector genes and innate immune response. Snx8-/- mice infected with the DNA virus HSV-1 exhibited lower serum cytokine levels and higher viral titers in the brains, resulting in higher lethality. Mechanistically, SNX8 recruited the class III phosphatylinositol 3-kinase VPS34 to MITA, which is required for trafficking of MITA from the ER to perinuclear microsomes. Our findings suggest that SNX8 is a critical component in innate immune response to cytosolic DNA and DNA virus.
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Encéfalo/inmunología , Infecciones por Virus ADN/inmunología , Virus ADN/patogenicidad , Inmunidad Innata/inmunología , Proteínas de la Membrana/metabolismo , Nexinas de Clasificación/fisiología , Animales , Encéfalo/patología , Encéfalo/virología , Citocinas/metabolismo , Infecciones por Virus ADN/metabolismo , Infecciones por Virus ADN/virología , Virus ADN/inmunología , Células HEK293 , Células HeLa , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transporte de Proteínas , Carga ViralRESUMEN
N6-methyladenosine (m6A) is the most abundant, internal, posttranscriptional modification in mRNA among all higher eukaryotes. In mammals, this modification is reversible and plays broad roles in the regulation of mRNA metabolism and processing. Despite its importance, previous studies on the role and mechanism of m6A methylation in Arabidopsis thaliana have been limited. Here, we report that ALKBH10B is a demethylase that oxidatively reverses m6A methylation in mRNA in vitro and in vivo. Depletion of ALKBH10B in the alkbh10b mutant delays flowering and represses vegetative growth. Complementation with wild-type ALKBH10B, but not a catalytically inactive mutant (ALKBH10B H366A/E368A), rescues these effects in alkbh10b-1 mutant plants, suggesting the observed phenotypes are controlled by the catalytic action of ALKBH10B We show that ALKBH10B-mediated mRNA demethylation affects the stability of target transcripts, thereby influencing floral transition. We identified 1190 m6A hypermethylated transcripts in the alkbh10b-1 mutant involved in plant development. The discovery and characterization of the archetypical RNA demethylase in Arabidopsis sheds light on the occurrence and functional role(s) of reversible mRNA methylation in plants and defines the role of m6A RNA modification in Arabidopsis floral transition.
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Adenosina/análogos & derivados , Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimología , Arabidopsis/fisiología , Flores/enzimología , Flores/fisiología , Oxidorreductasas N-Desmetilantes/metabolismo , ARN de Planta/metabolismo , Proteínas de Unión al ARN/metabolismo , Adenosina/química , Adenosina/metabolismo , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Proteínas de Arabidopsis/genética , Desmetilación , Flores/genética , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Metilación , Mutación/genética , Oxidorreductasas N-Desmetilantes/genética , Estabilidad Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Especificidad por Sustrato , Regulación hacia Arriba/genéticaRESUMEN
IFNγ is a cytokine that plays a key role in host defense against intracellular pathogens. In addition to the canonical JAK-STAT1 pathway, IFNγ also activates an IKKß-mediated noncanonical signaling pathway that is essential for induction of a subset of downstream effector genes. The molecular mechanisms and functional significance of this IFNγ-triggered noncanonical pathway remains enigmatic. Here, we identified sorting nexin 8 (SNX8) as an important component of the IFNγ-triggered noncanonical signaling pathway. SNX8-deficiency impaired IFNγ-triggered induction of a subset of downstream genes. Snx8-/- mice infected with Listeria monocytogenes exhibited lower serum cytokine levels and higher bacterial loads in the livers and spleens, resulting in higher lethality. Mechanistically, SNX8 interacted with JAK1 and IKKß and promoted their association. IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKß to the JAK1 complex. SNX8-deficiency impaired IFNγ-induced oligomerization and autophosphorylation of IKKß at Ser177, which is critical for selective induction of downstream genes. Our findings suggest that SNX8 acts as a link for IFNγ-triggered noncanonical signaling pathway, which induces a subset of downstream genes important for host defense against L. monocytogenes infection.
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Quinasa I-kappa B/inmunología , Janus Quinasa 1/inmunología , Listeria monocytogenes/patogenicidad , Listeriosis/genética , Nexinas de Clasificación/inmunología , Animales , Carga Bacteriana , Regulación de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Quinasa I-kappa B/deficiencia , Quinasa I-kappa B/genética , Interferón gamma/genética , Interferón gamma/inmunología , Janus Quinasa 1/genética , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Listeriosis/microbiología , Listeriosis/mortalidad , Hígado/inmunología , Hígado/microbiología , Ratones , Ratones Noqueados , Peptidoglicano/administración & dosificación , Fosforilación , Transducción de Señal , Nexinas de Clasificación/deficiencia , Nexinas de Clasificación/genética , Bazo/inmunología , Bazo/microbiología , Análisis de Supervivencia , Células THP-1RESUMEN
VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto-ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Portadoras/inmunología , Degradación Asociada con el Retículo Endoplásmico , Inmunidad Innata , Infecciones por Virus ARN/inmunología , Virus ARN/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteolisis , Infecciones por Virus ARN/genética , Infecciones por Virus ARN/metabolismo , Infecciones por Virus ARN/virología , Virus ARN/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
er to detect the beam quality of the SC200 superconducting cyclotron,measure the beam at the extraction reference and the acceptance of the accelerator is realized.This article mainly introduces the design that use the scintillation screen at the extraction reference to measure the beam profile,position and use the Faraday cup to measure the current intensity with 2.5 level accuracy.The remoted controlling of probes and the acquisition and processing of signal based on LabVIEW and PLC.
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Terapia de Protones , Terapia de Protones/instrumentaciónRESUMEN
Various types of medical devices used in assisted reproductive technologies (ART) should be detected for their safety by strict biological assays. Mouse embryo assay(MEA)has been recognized as one of the most important and standardized methods with the threshold more than 80% of blastocyst formation rate (BR) after 96 h culture of fertilized eggs. The disadvantage using BR for embryonic quality control has been concerned as it is ubiquitously dependent of embryonic morphology and the detailed data including molecular and genetic information is obviously missing and incomplete. This leads to the urgent requirement for more sensitive and efficient assessments for the quality control of ART. This study evaluated the reliability of an immunofluorescent MEA by counting total cell and differential number of the cells in the inner cell mass (ICM) and trophectoderm (TE) in the blastocyst. This method improved the traditional MEA, provided a sensitive and powerful platform to assess embryonic developmental viability and should be suggested as a standard assay to be globally used for the quality control of medical devices and pre-clinical procedures in ART.
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Blastocisto , Seguridad de Equipos , Técnicas Reproductivas Asistidas/instrumentación , Animales , Desarrollo Embrionario , Ratones , Reproducibilidad de los ResultadosRESUMEN
Diabetic nephropathy (DN) is one of the most common microvascular complication of diabetes mellitus (DM) as well as the main reason resulting in chronic renal failure. Transmembrane protein 16A (TMEM16A) plays an important role in multiple physiological actions. Here we found that it was up-regulated in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) amplification, Western blot detection, Periodic Acid Schiff (PAS) staining and immunohistochemical analysis confirmed that TMEM16A deficiency alleviated renal injury in diabetic mice and TMEM16A knockout diabetic mice were protected from the HFD-induced reduction in Nephrin expression. To understand further the molecular mechanism of its function, podocytes treated with high glucose (HG, 30 mmol/L glucose) in vitro was chosen as a model to study its signal transduction pathway. Nephrin expression level in siRNA-TMEM16A group was significantly higher than that of the HG group (also called Model group). Flow cytometric analysis revealed that podocyte apoptosis in siRNA-TMEM16A group was significantly lower than that of the Model group. RT-PCR and Western blot exhibited that apoptosis-related genes including apoptosis-inducing factor (AIF) and cystinylaspartate specific protease-3/-9 (caspase-3/-9) were dramatically down regulated in siRNA-TMEM16A group, compared with Model group. Phosphorylation levels of P38 and JNK in siRNA-TMEM16A group were lower than that of the Model group. Thus, TMEM16A is one of the critical components of a signal transduction pathway that links renal injury to podocyte apoptosis in DN.
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Apoptosis , Canales de Cloruro/metabolismo , Nefropatías Diabéticas/metabolismo , Riñón/metabolismo , Sistema de Señalización de MAP Quinasas , Podocitos/metabolismo , Animales , Anoctamina-1 , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Podocitos/patologíaRESUMEN
IFN-γ (also known as type II IFN) is a cytokine that is critically involved in antiviral and immunomodulatory effects. IFN-γ activates JAK1 and JAK2, which lead to the phosphorylation and activation of the transcription factor STAT1. Whether and how additional molecules are involved in the process are not fully clear. In this study, we identified parafibromin as an important component of the IFN-γ-triggered signaling pathways. Overexpression of parafibromin promoted IFN-γ-triggered phosphorylation of STAT1 at Tyr(701), subsequent expression of downstream genes, and cellular antiviral response, whereas knockdown of parafibromin had opposite effects. Parafibromin interacted with JAK1/2, promoted the interactions of JAK1-JAK2 and JAK1/2-STAT1, and promoted tyrosine phosphorylation of STAT1 by JAKs after IFN-γ stimulation. Our results reveal a previously uncharacterized role of parafibromin in mediating IFN-γ-triggered signaling and cellular effects.
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Interferón gamma/inmunología , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT1/metabolismo , Proteínas Supresoras de Tumor/genética , Línea Celular , Proteínas de Unión al ADN/metabolismo , Activación Enzimática/inmunología , Células HEK293 , Humanos , Fosforilación , Interferencia de ARN , ARN Interferente Pequeño , Transducción de Señal/inmunologíaRESUMEN
OBJECTIVE: To evaluate the difference of plasma lactate level between dipping and non-dipping hypertension, and to investigate the effects of lactate on subclinical cardiovascular damages in dipping and non-dipping hypertension. METHODS: According to 24 h ambulatory blood pressure monitoring, 236 patients with dipping and 152 with non-dipping hypertension were included. Clinical characteristics were collected and compared between dipping and non-dipping groups. Left ventricle hypertrophy (LVH) and N-terminal pro-B type natriuretic peptide (NT-proBNP) level were used to evaluate subclinical cardiovascular damage. Multivariate regression analysis was performed to evaluate the relationship between lactate and LVH and NT-proBNP elevation. RESULTS: Compared to dipping hypertension, plasma levels of lactate and NT-proBNP in non-dipping hypertension group were significantly higher. Moreover, the value of left ventricle mass index to height (LVMI/height) was also significantly higher in non-dipping group, and the percentage of patient with LVH was also higher in non-dipping group (36.8% vs. 28.9%, P < 0.05). Multivariate regression analysis revealed that in non-dipping group, after fully adjustment, the associations between lactate with LVH and NT-proBNP remained significant, with odds ratio (OR) of 1.18 (95% confidence interval [CI] of 1.13-1.24) in LVH and OR of 1.16 in NT-proBNP (95% CI of 1.10-1.23), respectively. Nonetheless, the associations between lactate with LVH and NT-proBNP elevation in dipping group were diminished to statistical nonsignificance. CONCLUSION: Plasma lactate level in non-dipping hypertension is significantly higher than dipping hypertension, and this difference may be the potential mechanism non-dipping hypertension contributes to greater targeted organ damage.
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Sistema Cardiovascular , Hipertensión , Hipertrofia Ventricular Izquierda , Ácido Láctico/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Adulto , Anciano , Enfermedades Asintomáticas , Monitoreo Ambulatorio de la Presión Arterial/métodos , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Femenino , Humanos , Hipertensión/sangre , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Persona de Mediana Edad , Estadística como AsuntoRESUMEN
BACKGROUND: Lipid metabolism related factors, such as angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like 4 (ANGPTL4), fatty acid-binding protein 4 (FABP4) are newly discovered factors that can affect coronary artery disease (CAD). In this study, we aimed to investigate the relationship between CAD and these lipid metabolism factors. HYPOTHESIS: ANGPTL3, ANGPTL4, and FABP4 may provide a new method for the control of CAD risk factors and the prevention and treatment of CAD. METHODS: We enrolled 284 consecutive inpatients with suspected CAD and divided them into CAD and non-CAD groups based on the coronary angiography results. Serum ANGPTL3, ANGPTL4, FABP4, and tumor necrosis factor-α (TNF-α) levels were estimated using the enzyme-linked immunosorbent assay. Multivariate logistic regression was used to assess the risk factors for CAD. The receiver operating characteristic curve was used to determine the cutoff and diagnostic values. RESULTS: The serum TNF-α, FABP4, ANGPTL3, and ANGPTL4 values showed a significant difference between the CAD and non-CAD groups (p < .05). After adjusting for confounding factors, the FABP4, ANGPTL3, and ANGPTL4 levels were independently associated with CAD (p < .05). The ANGPTL3 expression level was an independent risk factor for CAD in patients with hypertension, but not in those without hypertension. The ANGPTL3 > 67.53 ng/mL, ANGPTL4 > 29.95 ng/mL, and FABP4 > 1421.25 ng/L combination had the highest diagnostic value for CAD. CONCLUSION: ANGPTL3, ANGPTL4, and FABP4 were identified as independent risk factors for CAD and have valuable clinical implications for the diagnosis and treatment of CAD.
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Enfermedad de la Arteria Coronaria , Hipertensión , Humanos , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/metabolismo , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Proteína 4 Similar a la Angiopoyetina/metabolismo , Factor de Necrosis Tumoral alfa , Proteínas de Unión a Ácidos GrasosRESUMEN
PURPOSE: To evaluate the clinical features of patients with Systemic Lupus Erythematosus (SLE) and explore the risk factors of disease activity and renal damage. METHODS: A retrospective study involving 194 patients were performed. Patients were divided into lupus nephritis (LN) group (63.40%) and non-LN group (36.60%), different disease activity group, and different renal function group according to the clinical data. Multivariate logistic regression analysis showed that albumin (ALB), uric acid (UC), total cholesterol (TC), and anti-dsDNA antibodies were the influencing factors of LN in patients with SLE (P < 0.05); ALB, UC, and complement 3(C3) were the influencing factors of lupus disease activity (P < 0.05); UC, C3, and hemoglobin (HB) were the influencing factors of abnormal renal function in SLE patients. RESULTS: The results of the ROC curve showed that ALB, UA, and TC had certain predictive value for combined LN in patients with SLE, and the predictive value of ALB was greater than that of TC (P < 0.05); ALB, UA, and C3 being predictors of the activity of patients with SLE; BUN, UA, and HB all had certain predictive value for the abnormal renal function in patients with LN. SLE patients have the high incidence of renal impairment. CONCLUSION: The results of this study suggest that patients with SLE should regularly monitor the levels of ALB, UA, TC, C3, and HB, as well as pay attention to the intervention of hyperlipidemia and hyperuricemia in patients with SLE to better control disease progression.
RESUMEN
OBJECTIVE: We aimed to investigate the relationship between coronary artery disease (CAD) and systemic inflammation indices and lipid metabolism-related factors and subsequently, discuss the clinical application of these factors in CAD. METHODS: We enrolled 284 consecutive inpatients with suspected CAD and divided them into a CAD group and a non-CAD group according to coronary angiography results. Serum levels of angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), fatty acid-binding protein 4 (FABP4), and tumor necrosis factor-α (TNF-α) levels were assessed using the ELISA and the systemic inflammation indices were calculated. Multivariate logistic regression was used to assess the risk factors of CAD. The receiver operating characteristic curve was used to determine the cutoff and diagnostic values. RESULTS: The neutrophil-to-high density lipoprotein cholesterol ratio (5.04 vs. 3.47), neutrophil-to-lymphocyte ratio (3.25 vs. 2.45), monocyte-to-high density lipoprotein cholesterol ratio (MHR) (0.46 vs. 0.36), monocyte-to-lymphocyte ratio (0.31 vs. 0.26), systemic immune-inflammation index (SII) (696.00 vs. 544.82), serum TNF-α (398.15â ng/l vs. 350.65â ng/l), FABP4 (1644.00â ng/l vs. 1553.00â ng/l), ANGPTL3 (57.60â ng/ml vs. 52.85â ng/ml), and ANGPTL4 (37.35â ng/ml vs. 35.20â ng/ml) values showed a significant difference between the CAD and non-CAD groups ( P â <â 0.05). After adjusting for confounding factors, the following values were obtained: ANGPTL3â >â 67.53â ng/ml [odds ratio (OR)â =â 8.108, 95% confidence interval (CI) (1.022-65.620)]; ANGPTL4â >â 29.95â ng/ml [ORâ =â 5.599, 95% CI (1.809-17.334)]; MHRâ >â 0.47 [ORâ =â 4.872, 95% CI (1.715-13.835)]; SIIâ >â 589.12 [ORâ =â 5.131, 95% CI (1.995-13.200)]. These factors were found to be independently associated with CAD ( P â <â 0.05). Diabetes combined with MHRâ >â 0.47, SIIâ >â 589.12, TNF-α >285.60â ng/l, ANGPTL3â >â 67.53â ng/ml, and ANGPTL4â >â 29.95â ng/l had the highest diagnostic value for CAD [area under the curve: 0.921, 95% CI, (0.881-0.960), Sensitivity: 88.9%, Specificity: 82.2%, P â <â 0.001]. CONCLUSION: MHRâ >â 0.47, SIIâ >â 589.12, TNF-α >285.60â ng/l, ANGPTL3â >â 67.53â ng/ml, and ANGPTL4â >â 29.95â ng/l were identified as independent CAD risk factors and have valuable clinical implications in the diagnosis and treatment of CAD.
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Enfermedad de la Arteria Coronaria , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Factor de Necrosis Tumoral alfa/metabolismo , Metabolismo de los Lípidos , HDL-Colesterol , Proteína 4 Similar a la Angiopoyetina/metabolismo , Proteína 3 Similar a la Angiopoyetina , Inflamación/complicacionesRESUMEN
Cell-intrinsic defences constitute the first line of defence against intracellular pathogens. The guanosine triphosphatase RAB32 orchestrates one such defence response against the bacterial pathogen Salmonella, through delivery of antimicrobial itaconate. Here we show that the Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) orchestrates this defence response by scaffolding a complex between RAB32 and aconitate decarboxylase 1, which synthesizes itaconate from mitochondrial precursors. Itaconate delivery to Salmonella-containing vacuoles was impaired and Salmonella replication increased in LRRK2-deficient cells. Loss of LRRK2 also restored virulence of a Salmonella mutant defective in neutralizing this RAB32-dependent host defence pathway in mice. Cryo-electron tomography revealed tether formation between Salmonella-containing vacuoles and host mitochondria upon Salmonella infection, which was significantly impaired in LRRK2-deficient cells. This positions LRRK2 centrally within a host defence mechanism, which may have favoured selection of a common familial Parkinson's disease mutant allele in the human population.
Asunto(s)
Enfermedad de Parkinson , Infecciones por Salmonella , Humanos , Ratones , Animales , Enfermedad de Parkinson/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Infecciones por Salmonella/microbiología , Salmonella/metabolismoRESUMEN
The preparation of active packaging loaded with antimicrobial, antioxidant, and other functional agents has become a hot topic for food preservation in recent years. In this field, active fiber films based on spinning methods have attracted the interest of researchers owing to their high specific surface area, high porosity, high loading capacity, and good controlled release capacity. In the present work, neatly arranged ethyl cellulose (EC)/polyvinyl-pyrrolidone (PVP) fibrous films loaded with natamycin as an antimicrobial agent were prepared by microfluidic spinning. The encapsulation efficiency of natamycin was more than 90% in each group and the loading increased with increasing natamycin content. According to the characterization results of the natamycin-loaded EC/PVP fibrous films, hydrogen bonding was formed between natamycin and EC and PVP in the fibrous films. Meanwhile, the water contact angle of the fibrous films was increased, suggesting the improved hydrophobicity of the films. In the in vitro bacterial inhibition experiments, the active fiber films loaded with natamycin showed good antimicrobial activity, which could significantly inhibit the growth of gray mold. In conclusion, N-EC/PVP fibrous films with antimicrobial activity prepared by microfluidic spinning showed good potential in the field of active packaging.
RESUMEN
Many positive-strand RNA viruses, including all known coronaviruses, employ programmed -1 ribosomal frameshifting (-1 PRF) to regulate the translation of polycistronic viral RNAs. However, only a few host factors have been shown to regulate -1 PRF. Through a genome-wide CRISPR-Cas9 knockout screen, we have identified host factors that either suppress or enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -1 PRF. Among them, eukaryotic translation initiation factor 2A (eIF2A) specifically and directly enhances -1 PRF independent of changes in initiation. Consistent with the crucial role of efficient -1 PRF in transcriptase/replicase expression, loss of eIF2A reduces SARS-CoV-2 replication in cells. Furthermore, transcriptome-wide analysis shows that eIF2A preferentially binds CG-rich RNA motifs, including a region within 18S ribosomal RNA near the contacts between the SARS-CoV-2 frameshift-stimulatory element (FSE) and the ribosome. Thus, our results indicate a role for eIF2A in modulating the translation of specific RNAs independent of its role during initiation.