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Deubiquitinating enzymes (DUBs) regulate antiviral immune response through targeting DNA sensor signaling pathway members. As one of the DNA sensors, interferon (IFN)-γ inducible protein 16 (IFI16) play a major role in response to virus infections through activating the canonical STING/TBK-1/IRF3 signaling pathway. Only a few studies discuss the function of DUBs in IFI16-mediated antiviral response. Ubiquitin-specific protease 12 (USP12), which is one of the major members of the USP family, participates in various biological functions. However, whether USP12 regulates the nucleic acid sensor to modulate antiviral immune responses has not yet been elucidated. In this study, we found that knockout or knockdown of USP12 impaired the HSV-1-induced expressions of IFN-ß, CCL-5, IL-6, and downstream interferon-stimulated genes (ISGs). Moreover, USP12 deficiency increased HSV-1 replication and host susceptibility to HSV-1 infection. Mechanistically, USP12 inhibited the proteasome-dependent degradation of IFI16 through its deubiquitinase activity, thereby maintaining IFI16 stability and promoting IFI16-STING-IRF3- and p65-mediated antiviral signaling. Overall, our findings demonstrate an essential role of USP12 in DNA-sensing signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.
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Herpes Simple , Herpesvirus Humano 1 , Humanos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Herpesvirus Humano 1/fisiología , Interferones/metabolismo , Antivirales/metabolismo , Inmunidad Innata , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1011480.].
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Ubiquitin-specific peptidase 25 (USP25) is one of the best-characterized deubiquitinating enzymes and plays a vital regulatory role in various biological processes, especially in cancer development and immune regulation. However, the exact role of USP25 and its underlying mechanisms in macrophage activation and immunogenicity during Mycobacterium tuberculosis infection remain unclear. In this study, we found that M tuberculosis infection induced USP25 expression in human and mouse macrophages. In particular, USP25 expression is elevated in multiple cell types, especially monocytes, in patients with tuberculosis. Additionally, USP25 deficiency in macrophages and mice resulted in compromised immunity against M tuberculosis infection, accompanied by reduced expressions of various proinflammatory cytokines and chemokines. Mechanistically, USP25 in macrophages promoted the activation of the ERK signaling pathway through deubiquitination and stabilization of B-Raf and C-Raf. These findings collectively suggest the critical roles of USP25 in M tuberculosis infection and its potential as a therapeutic target.
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Nitrogen (N) immobilization (Nim, including microbial N assimilation) and plant N uptake (PNU) are the two most important pathways of N retention in soils. The ratio of Nim to PNU (hereafter Nim:PNU ratio) generally reflects the degree of N limitation for plant growth in terrestrial ecosystems. However, the key factors driving the pattern of Nim:PNU ratio across global ecosystems remain unclear. Here, using a global data set of 1018 observations from 184 studies, we examined the relative importance of mycorrhizal associations, climate, plant, and soil properties on the Nim:PNU ratio across terrestrial ecosystems. Our results show that mycorrhizal fungi type (arbuscular mycorrhizal (AM) or ectomycorrhizal (EM) fungi) in combination with soil inorganic N mainly explain the global variation in the Nim:PNU ratio in terrestrial ecosystems. In AM fungi-associated ecosystems, the relationship between Nim and PNU displays a weaker negative correlation (r = -.06, p < .001), whereas there is a stronger positive correlation (r = .25, p < .001) in EM fungi-associated ecosystems. Our meta-analysis thus suggests that the AM-associated plants display a weak interaction with soil microorganisms for N absorption, while EM-associated plants cooperate with soil microorganisms. Furthermore, we find that the Nim:PNU ratio for both AM- and EM-associated ecosystems gradually converge around a stable value (13.8 ± 0.5 for AM- and 12.1 ± 1.2 for EM-associated ecosystems) under high soil inorganic N conditions. Our findings highlight the dependence of plant-microbial interaction for N absorption on both plant mycorrhizal association and soil inorganic N, with the stable convergence of the Nim:PNU ratio under high soil N conditions.
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Micorrizas , Nitrógeno , Microbiología del Suelo , Suelo , Micorrizas/fisiología , Micorrizas/metabolismo , Nitrógeno/metabolismo , Suelo/química , Plantas/metabolismo , Plantas/microbiología , EcosistemaRESUMEN
NOD-like receptor (NLR) family CARD domain containing 3 (NLRC3), an intracellular member of NLR family, is a negative regulator of inflammatory signaling pathways in innate and adaptive immune cells. Previous reports have shown that NLRC3 is expressed in dendritic cells (DCs). However, the role of NLRC3 in DC activation and immunogenicity is unclear. In the present study, we find that NLRC3 attenuates the antigen-presenting function of DCs and their ability to activate and polarize CD4+ T cells into Th1 and Th17 subsets. Loss of NLRC3 promotes pathogenic Th1 and Th17 responses and enhanced experimental autoimmune encephalomyelitis (EAE) development. NLRC3 negatively regulates the antigen-presenting function of DCs via p38 signaling pathway. Vaccination with NLRC3-overexpressed DCs reduces EAE progression. Our findings support that NLRC3 serves as a potential target for treating adaptive immune responses driving multiple sclerosis and other autoimmune disorders.
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Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Animales , Presentación de Antígeno , Autoinmunidad , Linfocitos T CD4-Positivos/trasplante , Polaridad Celular , Células Cultivadas , Células Dendríticas/citología , Encefalomielitis Autoinmune Experimental/terapia , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Transducción de Señal , Células TH1/citología , Células TH1/metabolismo , Células Th17/citología , Células Th17/metabolismo , VacunaciónRESUMEN
Root exudates are an important pathway for plant-microbial interactions and are highly sensitive to climate change. However, how extreme drought affects root exudates and the main components, as well as species-specific differences in response magnitude and direction, are poorly understood. In this study, root exudation rates of total carbon (C) and its components (e.g., sugar, organic acid, and amino acid) were measured under the control and extreme drought treatments (i.e., 70% throughfall reduction) by in situ collection of four tree species with different growth rates in a subtropical forest. We also quantified soil properties, root morphological traits, and mycorrhizal infection rates to examine the driving factors underlying variations in root exudation. Our results showed that extreme drought significantly decreased root exudation rates of total C, sugar, and amino acid by 17.8%, 30.8%, and 35.0%, respectively, but increased root exudation rate of organic acid by 38.6%, which were largely associated with drought-induced changes in tree growth rates, root morphological traits, and mycorrhizal infection rates. Specifically, trees with relatively high growth rates were more responsive to drought for root exudation rates compared with those with relatively low growth rates, which were closely related to root morphological traits and mycorrhizal infection rates. These findings highlight the importance of plant growth strategy in mediating drought-induced changes in root exudation rates. The coordinations among root exudation rates, root morphological traits, and mycorrhizal symbioses in response to drought could be incorporated into land surface models to improve the prediction of climate change impacts on rhizosphere C dynamics in forest ecosystems.
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Ecosistema , Micorrizas , Raíces de Plantas/metabolismo , Sequías , Bosques , Micorrizas/metabolismo , Árboles , Exudados y Transudados/metabolismo , Compuestos Orgánicos/análisis , Aminoácidos/análisis , Aminoácidos/metabolismo , Suelo/química , Azúcares/análisis , Azúcares/metabolismo , Exudados de Plantas/análisis , Exudados de Plantas/metabolismoRESUMEN
Mycobacterium tuberculosis, the pathogen that causes tuberculosis, exhibits complex host-pathogen interactions. Pattern recognition receptors and their downstream signaling pathways play crucial roles in determining the outcome of infection. In particular, the scaffold protein ß-arrestin 2 mediates downstream signaling of G protein-coupled receptors. However, the role of ß-arrestin 2 in conferring immunity against M. tuberculosis has not yet been explored. We found that ß-arrestin 2 was upregulated in the lesioned regions of lung tissues in patients with tuberculosis. M. tuberculosis infection upregulated ß-arrestin 2 expression in human macrophages, and silencing of ß-arrestin 2 significantly enhanced bactericidal activity by enhancing the expression of proinflammatory cytokines such as TNF-α. ß-Arrestin 2 was shown to inhibit the activation of the TLR2/ERK1/2 pathway and its transcriptional regulation activity upon M. tuberculosis infection. Furthermore, ß-arrestin 2 transcriptionally regulates TNF-α by binding to CREB1. These observations revealed that the upregulation of ß-arrestin 2 is critical for M. tuberculosis to escape immune surveillance through an unknown mechanism. Our research offers a novel interference modality to enhance the immune response against tuberculosis by targeting ß-arrestin 2 to modulate the TLR2-ß-arrestin 2-ERK1/2-CREB1-TNF-α regulatory axis.
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Inflamación/inmunología , Tuberculosis/inmunología , Arrestina beta 2/inmunología , Adolescente , Células Cultivadas , Femenino , Humanos , Sistema de Señalización de MAP Quinasas/inmunología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: This study was designated to establish a polycystic ovary syndrome (PCOS) rat model with recombinant human insulin-like growth factor-1 (RH-IGF-1). We made assessment on the characteristics of hyperinsulinemia and hyperandrogenism in the rat model. DESIGN: This study performed the characteristics of PCOS upon RH-IGF-1 injection and evaluated the disease process of PCOS syndrome caused by the insulin-resistant pathological condition of IGF-1 based on the comparative study of in vivo test. SETTING: The experiment was conducted in the experimental research center of Yinzhou NO.2 hospital, Ningbo, Zhejiang Province, China. MATERIALS AND METHODS: Thirty-four female Sprague Dawley immature rats aged 21 days were randomly divided into two groups. Those treated with RH-IGF-1 2 mg/100 g daily were in RH-IGF-1 group (n = 20), and those with 0.9% sodium chloride 0.2 mL/100 g daily were in the saline group (n = 14). The experiment was carried out in two stages. In stage I, rats were anesthetized upon the first estrous cycle in the saline group with tissue and blood samples collected (n = 7), and rats in the RH-IGF-1-treated group were anesthetized on the 5th day after vaginal opening (VO) (n = 10). In stage II, rats in the saline group were anesthetized after three complete cycles (n = 7), meanwhile, while on the 15th day after VO (n = 10) for those in the RH-IGF-1 group. RESULTS: We have found that compared with the control group, rats injected with RH-IGF-1 expressed an early VO, disordered estrous cycle, polycystic ovaries, and significantly increased ovarian weight/body weight ratio. And from the perspective of hormone secretion, their androgen increased significantly and the insulin resistance index also elevated distinctly, possessing main characteristics similar to PCOS. LIMITATIONS: In this study, we were limited by the inability to examine IGF-1 in hypothalamus. IGF-1 in hypothalamus and in vitro experiments would be taken into consideration for further study in the future. CONCLUSIONS: These findings suggest that IGF-1 may be a key factor in the pathogenesis of PCOS, and the increase of androgen may be the pathological result, not the cause of PCOS.
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Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Femenino , Humanos , Ratas , Animales , Factor I del Crecimiento Similar a la Insulina , Andrógenos , Ratas Sprague-Dawley , Insulina , FenotipoRESUMEN
Grazing and global change (e.g., warming, nitrogen deposition, and altered precipitation) both contribute to biodiversity loss and alter ecosystem structure and functioning. However, how grazing and global change interactively influence plant diversity and ecosystem productivity, and their relationship remains unclear at the global scale. Here, we synthesized 73 field studies to quantify the individual and/or interactive effects of grazing and global change factors on biodiversity-productivity relationship in grasslands. Our results showed that grazing significantly reduced plant richness by 3.7% and aboveground net primary productivity (ANPP) by 29.1%, but increased belowground net primary productivity (BNPP) by 9.3%. Global change factors, however, decreased richness by 8.0% but increased ANPP and BNPP by 13.4% and 14.9%, respectively. Interestingly, the strength of the change in biodiversity in response to grazing was positively correlated with the strength of the change in BNPP. Yet, global change flipped these relationships from positive to negative even when combined with grazing. These results indicate that the impacts of global change factors are more dominant than grazing on the belowground biodiversity-productivity relationship, which is contrary to the pattern of aboveground one. Therefore, incorporating global change factors with herbivore grazing into Earth system models is necessary to accurately predict climate-grassland carbon cycle feedbacks in the Anthropocene.
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Ecosistema , Pradera , Biodiversidad , Ciclo del Carbono , Cambio Climático , PlantasRESUMEN
Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.
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Interleucina-1/inmunología , Macrófagos/inmunología , Tuberculosis Pulmonar/inmunología , Proteína Wnt-5a/inmunología , Autofagia/inmunología , Humanos , Interleucina-1/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiología , Mycobacterium tuberculosis/inmunología , Transducción de Señal/inmunología , Tuberculosis Pulmonar/metabolismo , Proteína Wnt-5a/metabolismoRESUMEN
Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti-inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti-inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine-1-phosphate (S1P) in a S1P lyase (SPL)-dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro-inflammatory cytokines by suppressing nuclear factor-κB and mitogen-activated protein kinases signalling pathways. Furthermore, vitamin B6-reduced accumulation of S1P by promoting SPL activity. The anti-inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti-inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.
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Aldehído-Liasas/metabolismo , Inflamación/metabolismo , Lisofosfolípidos/metabolismo , Macrófagos/metabolismo , Esfingosina/análogos & derivados , Vitamina B 6/metabolismo , Animales , Antiinflamatorios/farmacología , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Choque/metabolismo , Transducción de Señal , Esfingosina/metabolismoRESUMEN
NLRC3, a member of the NLR family, has been reported as a negative regulator of inflammatory signaling pathways in innate immune cells. However, the direct role of NLRC3 in modulation of CD4+ T-cell responses in infectious diseases has not been studied. In the present study, we showed that NLRC3 plays an intrinsic role by suppressing the CD4+ T cell phenotype in lung and spleen, including differentiation, activation, and proliferation. NLRC3 deficiency in CD4+ T cells enhanced the protective immune response against Mycobacterium tuberculosis infection. Finally, we demonstrated that NLRC3 deficiency promoted the activation, proliferation, and cytokine production of CD4+ T cells via negatively regulating the NF-κB and MEK-ERK signaling pathways. This study reveals a critical role of NLRC3 as a direct regulator of the adaptive immune response and its protective effects on immunity during M. tuberculosis infection. Our findings also suggested that NLRC3 serves as a potential target for therapeutic intervention against tuberculosis.
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Linfocitos T CD4-Positivos/patología , Inmunidad/genética , Péptidos y Proteínas de Señalización Intercelular/fisiología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Animales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/fisiología , Células Cultivadas , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tuberculosis/genética , Tuberculosis/patologíaRESUMEN
Predicting future carbon (C) dynamics in grassland ecosystems requires knowledge of how grazing and global climate change (e.g., warming, elevated CO2 , increased precipitation, drought, and N fertilization) interact to influence C storage and release. Here, we synthesized data from 223 grassland studies to quantify the individual and interactive effects of herbivores and climate change on ecosystem C pools and soil respiration (Rs). Our results showed that grazing overrode global climate change factors in regulating grassland C storage and release (i.e., Rs). Specifically, grazing significantly decreased aboveground plant C pool (APCP), belowground plant C pool (BPCP), soil C pool (SCP), and Rs by 19.1%, 6.4%, 3.1%, and 4.6%, respectively, while overall effects of all global climate change factors increased APCP, BPCP, and Rs by 6.5%, 15.3%, and 3.4% but had no significant effect on SCP. However, the combined effects of grazing with global climate change factors also significantly decreased APCP, SCP, and Rs by 4.0%, 4.7%, and 2.7%, respectively but had no effect on BPCP. Most of the interactions between grazing and global climate change factors on APCP, BPCP, SCP, and Rs were additive instead of synergistic or antagonistic. Our findings highlight the dominant effects of grazing on C storage and Rs when compared with the suite of global climate change factors. Therefore, incorporating the dominant effect of herbivore grazing into Earth System Models is necessary to accurately predict climate-grassland feedbacks in the Anthropocene.
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Ciclo del Carbono , Cambio Climático/estadística & datos numéricos , Pradera , Herbivoria/fisiología , Ganado/fisiología , Animales , Carbono/análisis , Carbono/metabolismo , Monitoreo del Ambiente , Plantas/metabolismo , Suelo/químicaRESUMEN
A method is presented for electrochemiluminescent (ECL) detection of the food additive curcumin via an energy transfer strategy and by using luminol-doped silica nanoparticles (luminol-NPs). The ECL emission of the luminol-NPs (peaking at 425 nm) is reduced in the presence of curcumin due to spectral overlap. The assay can be performed within 1 min, response is linear in the 0.1 to 100 µM curcumin concentration range, and the limit of detection is 32 nM. The method is selective over many ions, adenosine triphosphate, ascorbic acid, cysteine and folic acid. It was successfully applied to the determination of curcumin in spiked human serum and urine. The average recoveries range from 99.0 to 102.6%. Graphical abstract Electrochemiluminescence (ECL) "turn-off" detection of curcumin at levels as low as 32 nM via energy transfer using luminol-doped silica nanoparticles. No hydrogen peroxide (H2O2) is used in ECL detection which makes the luminol-NPs ECL system more stable than the conventional luminol-H2O2 ECL system.
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Extreme drought is likely to become more frequent and intense as a result of global climate change, which may significantly impact plant root traits and responses (i.e., morphology, production, turnover, and biomass). However, a comprehensive understanding of how drought affects root traits and responses remains elusive. Here, we synthesized data from 128 published studies under field conditions to examine the responses of 17 variables associated with root traits to drought. Our results showed that drought significantly decreased root length and root length density by 38.29% and 11.12%, respectively, but increased root diameter by 3.49%. However, drought significantly increased root:shoot mass ratio and root cortical aerenchyma by 13.54% and 90.7%, respectively. Our results suggest that drought significantly modified root morphological traits and increased root mortality, and the drought-induced decrease in root biomass was less than shoot biomass, causing higher root:shoot mass ratio. The cascading effects of drought on root traits and responses may need to be incorporated into terrestrial biosphere models to improve prediction of the climate-biosphere feedback.
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Raíces de Plantas/anatomía & histología , Biomasa , Cambio Climático , Deshidratación , Sequías , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/fisiología , Factores de TiempoRESUMEN
Water-dispersed fluorescent silicon nanodots (SiNDs) were synthesized by a one-pot hydrothermal method starting from tetraethyl orthosilicate (TEOS) as silicon source and trisodium citrate as reducing reagent. The method is simple and convenient. The SiNDs, with excitation/emission peaks at 347/440 nm and with fluorescence quantum yield of 18% are shown to be viable fluorescent probes for picric acid (PA). The SiNDs strongly bind PA, and their blue fluorescence is quenched. The distance between the donor and acceptor (R0 value) is calculated from fluorescence data to be 2.1 nm. A fluorometric method was worked out that has a linear response in the 8 nM to 50 µM PA concentration range and a 0.92 nM limit of detection. The method has a fast response (2 min) and is well selective over other nitroaromatic compounds and metal ions. The average recoveries from spiked lake water samples ranged between 98.4 and 100.8%. Graphical abstract Water-dispersed fluorescent silicon nanodots (SiNDs) are synthesized using tetraethyl orthosilicate (TEOS) and trisodium citrate. Based on spectral overlap of fluorescent spectrum of SiNDs and absorption spectrum of picric acid (PA), fluorometric determination of PA at concentrations as low as 0.92 nM is achieved.
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OBJECTIVES: We evaluated inter-reader agreement of the ST-segment between two electrocardiogram (ECG) core laboratories. BACKGROUND: Accurate measurement of the ST-segment is key to diagnosis and management of acute coronary syndromes (ACS). Clinical trials also rely on adherence to the pre-specified ECG eligibility criteria. METHODS: 150 patients (100 ST-segment elevation (STE)-ACS, 50 non-STE-ACS) were selected. An experienced ECG reader from each laboratory measured ST-segment deviation on the baseline ECGs (nearest 0.1mm). RESULTS: ∑ST-segment deviation showed excellent inter-reader agreement (R=0.965, intraclass correlation coefficient (ICC) 0.949, 95% CI (0.930-0.963)). Similar agreement was observed when ∑ST-segment elevation (∑STE) and ∑ST-segment depression (∑STD) were assessed separately. Better agreement was evident in STE-ACS cohort (ICC (95% CI): 0.968 (0.953-0.978, 0.969 (0.954-0.979), 0.931 (0.899-0.953)) compared to NSTE-ACS patients (ICC (95% CI): 0.860 (0.768-0.917), 0.816 (0.699-0.890), 0.753 (0.605-0.851) across measurement of ∑ST-segment deviation, ∑STE, and ∑STD. CONCLUSIONS: We demonstrated excellent agreement on ST-segment measurements between two experienced readers from two ECG core laboratories.
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Electrocardiografía/métodos , Electrocardiografía/estadística & datos numéricos , Laboratorios de Hospital/estadística & datos numéricos , Infarto del Miocardio/diagnóstico , Variaciones Dependientes del Observador , Anciano , Alberta , Femenino , Humanos , Masculino , Persona de Mediana Edad , Missouri , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: To evaluate quantitative relationships between baseline Q-wave width and 90-day outcomes in ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Baseline Q-waves are useful in predicting clinical outcomes after MI. METHODS: 3589 STEMI patients were assessed from a multi-centre study. RESULTS: 1156 patients of the overall cohort had pathologic Q-waves. The 90-day mortality and the composite of mortality, congestive heart failure (CHF), or cardiogenic shock (p<0.001 for both outcomes) rose as Q-wave width increased. After adapting a threshold ≥40ms for inferior and ≥20ms for lateral/apical MI in all patients (n=3065) with any measureable Q-wave we found hazard ratios (HR) for mortality (HR: 2.44, 95% confidence interval (CI) (1.54-3.85), p<0.001) and the composite (HR: 2.32, 95% CI (1.70-3.16), p<0.001). This improved reclassification of patients experiencing the composite endpoint versus the conventional definition (net reclassification index (NRI): 0.23, 95% CI (0.09-0.36), p<0.001) and universal MI definition (NRI: 0.15, 95% CI (0.02-0.29), p=0.027). CONCLUSIONS: The width of the baseline Q-wave in STEMI adds prognostic value in predicting 90-day clinical outcomes. A threshold of ≥40ms in inferior and ≥20ms for lateral/apical MI enhances prognostic insight beyond current criteria.
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Electrocardiografía/métodos , Insuficiencia Cardíaca/mortalidad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Choque Cardiogénico/mortalidad , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Comorbilidad , Método Doble Ciego , Electrocardiografía/estadística & datos numéricos , Femenino , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Pronóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Anticuerpos de Cadena Única/uso terapéutico , Tasa de SupervivenciaRESUMEN
Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in multiple sclerosis (MS) and in other neuroinflammatory autoimmune diseases. Ubiquitination is a posttranslational protein modification involved in regulating a variety of cellular processes, including CD4+ T cell differentiation and function. However, only a limited number of E3 ubiquitin ligases have been characterized in terms of their biological functions, particularly in CD4+ T cell differentiation and function. In this study, we found that the RING finger protein 213 (RNF213) specifically promoted regulatory T (Treg) cell differentiation in CD4+ T cells and attenuated autoimmune disease development in an FOXO1-dependent manner. Mechanistically, RNF213 interacts with Forkhead Box Protein O1 (FOXO1) and promotes nuclear translocation of FOXO1 by K63-linked ubiquitination. Notably, RNF213 expression in CD4+ T cells was induced by IFN-ß and exerts a crucial role in the therapeutic efficacy of IFN-ß for MS. Together, our study findings collectively emphasize the pivotal role of RNF213 in modulating adaptive immune responses. RNF213 holds potential as a promising therapeutic target for addressing disorders associated with Treg cells.
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Diferenciación Celular , Proteína Forkhead Box O1 , Interferón beta , Linfocitos T Reguladores , Ubiquitina-Proteína Ligasas , Ubiquitinación , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Ratones , Humanos , Interferón beta/metabolismo , Ratones Endogámicos C57BL , Núcleo Celular/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Transporte Activo de Núcleo Celular , Femenino , Ratones Noqueados , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Células HEK293RESUMEN
Ecological succession and restoration rapidly promote multiple dimensions of ecosystem functions and mitigate global climate change. However, the factors governing the limited capacity to sequester soil organic carbon (SOC) in old forests are poorly understood. Ecological theory predicts that plants and microorganisms jointly evolve into a more mutualistic relationship to accelerate detritus decomposition and nutrient regeneration in old than young forests, likely explaining the changes in C sinks across forest succession or rewilding. To test this hypothesis, we conducted a field experiment of root-mycorrhizal exclusion in successional subtropical forests to investigate plant-decomposer interactions and their effects on SOC sequestration. Our results showed that SOC accrual rate at the 0-10 cm soil layer was 1.26 mg g-1 yr-1 in early-successional arbuscular mycorrhizal (AM) forests, which was higher than that in the late-successional ectomycorrhizal (EcM) forests with non-significant change. A transition from early-successional AM to late-successional EcM forests increase fungal diversity, especially EcM fungi. In the late-successional forests, the presence of ectomycorrhizal hyphae promotes SOC decomposition and nutrient cycle by increasing soil nitrogen and phosphorus degrading enzyme activity as well as saprotrophic microbial richness. Across early- to late-successional forests, mycorrhizal priming effects on SOC decomposition explain a slow-down in the capacity of older forests to sequester soil C. Our findings suggest that a transition from AM to EcM forests supporting greater C decomposition can halt the capacity of forests to provide nature-based global climate change solutions.