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Alternative polyadenylation (APA) is a widespread mechanism of gene regulation that generates mRNA isoforms with alternative 3' untranslated regions (3' UTRs). Our previous study has revealed the global 3' UTR shortening of host mRNAs through APA upon viral infection. However, how the dynamic changes in the APA landscape occur upon viral infection remains largely unknown. Here we further found that, the reduced protein abundance of CPSF6, one of the core 3' processing factors, promotes the usage of proximal poly(A) sites (pPASs) of many immune related genes in macrophages and fibroblasts upon viral infection. Shortening of the 3' UTR of these transcripts may improve their mRNA stability and translation efficiency, leading to the promotion of type I IFN (IFN-I) signalling-based antiviral immune responses. In addition, dysregulated expression of CPSF6 is also observed in many immune related physiological and pathological conditions, especially in various infections and cancers. Thus, the global APA dynamics of immune genes regulated by CPSF6, can fine-tune the antiviral response as well as the responses to other cellular stresses to maintain the tissue homeostasis, which may represent a novel regulatory mechanism for antiviral immunity.
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Poliadenilación , Virosis , Factores de Escisión y Poliadenilación de ARNm , Humanos , Regiones no Traducidas 3'/genética , Regulación hacia Abajo , Inmunidad/genética , Factores de Escisión y Poliadenilación de ARNm/genética , Factores de Escisión y Poliadenilación de ARNm/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Virosis/genética , Ratones , AnimalesRESUMEN
BACKGROUND & AIMS: Putative anion transporter-1 (PAT1, SLC26A6) plays a key role in intestinal oxalate and bicarbonate secretion. PAT1 knockout (PKO) mice exhibit hyperoxaluria and nephrolithiasis. Notably, diseases such as inflammatory bowel disease are also associated with higher risk of hyperoxaluria and nephrolithiasis. However, the potential role of PAT1 deficiency in gut-barrier integrity and susceptibility to colitis is currently elusive. METHODS: Age-matched PKO and wild-type littermates were administered 3.5% dextran sulfate sodium in drinking water for 6 days. Ileum and colon of control and treated mice were harvested. Messenger RNA and protein expression of tight junction proteins were determined by reverse transcription polymerase chain reaction and western blotting. Severity of inflammation was assessed by measuring diarrheal phenotype, cytokine expression, and hematoxylin and eosin staining. Gut microbiome and associated metabolome were analyzed by 16S ribosomal RNA sequencing and mass spectrometry, respectively. RESULTS: PKO mice exhibited significantly higher loss of body weight, gut permeability, colonic inflammation, and diarrhea in response to dextran sulfate sodium treatment. In addition, PKO mice showed microbial dysbiosis and significantly reduced levels of butyrate and butyrate-producing microbes compared with controls. Co-housing wild-type and PKO mice for 4 weeks resulted in PKO-like signatures on the expression of tight junction proteins in the colons of wild-type mice. CONCLUSIONS: Our data demonstrate that loss of PAT1 disrupts gut microbiome and related metabolites, decreases gut-barrier integrity, and increases host susceptibility to intestinal inflammation. These findings, thus, highlight a novel role of the oxalate transporter PAT1 in promoting gut-barrier integrity, and its deficiency appears to contribute to the pathogenesis of inflammatory bowel diseases.
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Colitis , Colon , Sulfato de Dextran , Disbiosis , Microbioma Gastrointestinal , Ratones Noqueados , Permeabilidad , Transportadores de Sulfato , Animales , Transportadores de Sulfato/genética , Transportadores de Sulfato/metabolismo , Sulfato de Dextran/toxicidad , Colitis/microbiología , Colitis/metabolismo , Colitis/inducido químicamente , Colitis/patología , Colitis/genética , Ratones , Colon/microbiología , Colon/patología , Colon/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Modelos Animales de Enfermedad , Íleon/patología , Íleon/microbiología , Íleon/metabolismo , Diarrea/microbiología , Diarrea/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Proteínas de Uniones Estrechas/genética , Ratones Endogámicos C57BL , Masculino , Antiportadores/genética , Antiportadores/metabolismo , Antiportadores/deficienciaRESUMEN
AIM: To evaluate the effect of different oral irrigators on the sub-gingival microbiome composition in patients with naturally occurring plaque-induced gingivitis. MATERIALS AND METHODS: Sub-gingival plaque was collected from adults participating in a clinical trial assessing the efficacy of oral hygiene with two different oral irrigators (Waterpik Water Flosser [Group 1] and Oral-B Water Flosser [Group 2]) versus dental flossing (Group 3) for microbiome analysis. Plaque samples were reflective of naturally occurring plaque-induced gingivitis at baseline and of gingival health at the endpoint (4 weeks). Clinical measures of gingival inflammation were collected, and the sub-gingival microbiome was analysed by 16S rRNA sequencing to identify amplicon sequence variants. RESULTS: Oral hygiene instruction with self-performed manual toothbrushing and water-jet irrigation led to significant reductions in inflammation for all groups; both oral irrigators outperformed flossing in bleeding-on-probing reduction (p < .001). Microbiome diversity of sub-gingival plaque remained relatively stable over time, but significant changes were noted in certain taxa, consistent with increases in the relative abundance of commensals and reductions in late colonizers and periodontal pathogens in the water-jet groups. CONCLUSIONS: Reduction in gingival inflammation at 4 weeks within the water-jet groups is accompanied by slight but critical changes in microbiome composition. Although biodiversity does not substantially change within 4 weeks during the resolution of naturally induced gingivitis, significant relative increases in commensal early colonizers such as Streptococcus, Veillonella and Fusobacterium were accompanied by a shift towards a less anaerobic microbiota associated with return to health. These changes were contingent upon the type of interdental hygiene, with Group 1 exhibiting more significant alterations in microbiome composition towards a periodontal-health-compatible community.
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Placa Dental , Gingivitis , Adulto , Humanos , Higiene Bucal , Dispositivos para el Autocuidado Bucal , Análisis de Datos Secundarios , ARN Ribosómico 16S , Índice de Placa Dental , Cepillado Dental , Gingivitis/prevención & control , Placa Dental/prevención & control , Inflamación , Agua , Método Simple CiegoRESUMEN
BACKGROUND: In various surgical specialties, preoperative surgical warm-up has been demonstrated to affect a surgeon's performance and the perioperative outcomes for patients. However, the influence of warm-up activities on video-assisted thoracoscopic surgery lobectomy (VATSL) remains largely unexplored. This study aims to investigate the potential effects of preoperative surgical warm-up on VATSL. METHODS: A cohort of 364 patients diagnosed with lung cancer through pathology and undergoing VATSL at the Thoracic Surgery Department of Xuzhou Medical University from January 2018 to September 2022 were included. Patients were categorized into two groups: the warm-up group, comprising 172 patients undergoing their first VATSL of the day, and the warm-up effect group, consisting of 192 patients undergoing their second VATSL on the same day. Propensity score matching was employed to compare operation times and postoperative complications between the two groups, resulting in 159 matched cases in each group. RESULTS: There were no statistically significant differences in operation time (154.5 ± 54.9 vs. 147.2 ± 54.4 min, p = 0.239) and postoperative complications (including pulmonary infection, atelectasis, long-term pulmonary air leakage requiring incision suture in the operating room, and postoperative pleural effusion) (14:22 cases, p = 0.157) between the warm-up and warm-up effect groups. CONCLUSION: The findings suggest that preoperative surgical warm-up does not significantly affect the perioperative outcomes of VATSL.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Cirujanos , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Cirugía Torácica Asistida por Video/métodos , Neumonectomía/métodos , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Complicaciones Posoperatorias/etiología , Estudios RetrospectivosRESUMEN
Timely and precise detection of emerging infections is imperative for effective outbreak management and disease control. Human mobility significantly influences the spatial transmission dynamics of infectious diseases. Spatial sampling, integrating the spatial structure of the target, holds promise as an approach for testing allocation in detecting infections, and leveraging information on individuals' movement and contact behavior can enhance targeting precision. This study introduces a spatial sampling framework informed by spatiotemporal analysis of human mobility data, aiming to optimize the allocation of testing resources for detecting emerging infections. Mobility patterns, derived from clustering point-of-interest and travel data, are integrated into four spatial sampling approaches at the community level. We evaluate the proposed mobility-based spatial sampling by analyzing both actual and simulated outbreaks, considering scenarios of transmissibility, intervention timing, and population density in cities. Results indicate that leveraging inter-community movement data and initial case locations, the proposed Case Flow Intensity (CFI) and Case Transmission Intensity (CTI)-informed spatial sampling enhances community-level testing efficiency by reducing the number of individuals screened while maintaining a high accuracy rate in infection identification. Furthermore, the prompt application of CFI and CTI within cities is crucial for effective detection, especially in highly contagious infections within densely populated areas. With the widespread use of human mobility data for infectious disease responses, the proposed theoretical framework extends spatiotemporal data analysis of mobility patterns into spatial sampling, providing a cost-effective solution to optimize testing resource deployment for containing emerging infectious diseases.
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BACKGROUND: Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine kinase whose activity propagates inflammatory signaling through its association with pattern recognition receptors (PRRs) and subsequent TAK1, NF-κB, and MAPK pathway activation. After stroke, dead and dying cells release a host of damage-associated molecular patterns (DAMPs) that activate PRRs and initiate a robust inflammatory response. We hypothesize that RIPK2 plays a damaging role in the progression of stroke injury by enhancing the neuroinflammatory response to stroke and that global genetic deletion or microglia-specific conditional deletion of Ripk2 will be protective following ischemic stroke. METHODS: Adult (3-6 months) male mice were subjected to 45 min of transient middle cerebral artery occlusion (tMCAO) followed by 24 h, 48 h, or 28 days of reperfusion. Aged male and female mice (18-24 months) were subjected to permanent ischemic stroke and sacrificed 48 h later. Infarct volumes were calculated using TTC staining (24-48 h) or Cresyl violet staining (28d). Sensorimotor tests (weight grip, vertical grid, and open field) were performed at indicated timepoints. Blood-brain barrier (BBB) damage, tight junction proteins, matrix metalloproteinase-9 (MMP-9), and neuroinflammatory markers were assessed via immunoblotting, ELISA, immunohistochemistry, and RT-qPCR. Differential gene expression profiles were generated through bulk RNA sequencing and nanoString®. RESULTS: Global genetic deletion of Ripk2 resulted in decreased infarct sizes and reduced neuroinflammatory markers 24 h after stroke compared to wild-type controls. Ripk2 global deletion also improved both acute and long-term behavioral outcomes with powerful effects on reducing infarct volume and mortality at 28d post-stroke. Conditional deletion of microglial Ripk2 (mKO) partially recapitulated our results in global Ripk2 deficient mice, showing reductive effects on infarct volume and improved behavioral outcomes within 48 h of injury. Finally, bulk transcriptomic profiling and nanoString data demonstrated that Ripk2 deficiency in microglia decreases genes associated with MAPK and NF-κB signaling, dampening the neuroinflammatory response after stroke injury by reducing immune cell activation and peripheral immune cell invasion. CONCLUSIONS: These results reveal a hitherto unknown role for RIPK2 in the pathogenesis of ischemic stroke injury, with microglia playing a distinct role. This study identifies RIPK2 as a potent propagator of neuroinflammatory signaling, highlighting its potential as a therapeutic target for post-stroke intervention.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Femenino , Ratones , Masculino , Animales , Microglía/metabolismo , Enfermedades Neuroinflamatorias , FN-kappa B/metabolismo , Accidente Cerebrovascular/patología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/metabolismo , Inflamación/metabolismo , Infarto , Accidente Cerebrovascular Isquémico/metabolismo , Proteínas Quinasas/metabolismo , Isquemia Encefálica/metabolismoRESUMEN
PURPOSE: To compare the evaluation metrics for deep learning methods that were developed using imbalanced imaging data in osteoarthritis studies. MATERIALS AND METHODS: This retrospective study utilized 2996 sagittal intermediate-weighted fat-suppressed knee MRIs with MRI Osteoarthritis Knee Score readings from 2467 participants in the Osteoarthritis Initiative study. We obtained probabilities of the presence of bone marrow lesions (BMLs) from MRIs in the testing dataset at the sub-region (15 sub-regions), compartment, and whole-knee levels based on the trained deep learning models. We compared different evaluation metrics (e.g., receiver operating characteristic (ROC) and precision-recall (PR) curves) in the testing dataset with various class ratios (presence of BMLs vs. absence of BMLs) at these three data levels to assess the model's performance. RESULTS: In a subregion with an extremely high imbalance ratio, the model achieved a ROC-AUC of 0.84, a PR-AUC of 0.10, a sensitivity of 0, and a specificity of 1. CONCLUSION: The commonly used ROC curve is not sufficiently informative, especially in the case of imbalanced data. We provide the following practical suggestions based on our data analysis: 1) ROC-AUC is recommended for balanced data, 2) PR-AUC should be used for moderately imbalanced data (i.e., when the proportion of the minor class is above 5% and less than 50%), and 3) for severely imbalanced data (i.e., when the proportion of the minor class is below 5%), it is not practical to apply a deep learning model, even with the application of techniques addressing imbalanced data issues.
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Enfermedades de los Cartílagos , Aprendizaje Profundo , Osteoartritis de la Rodilla , Humanos , Estudios Retrospectivos , Benchmarking , Articulación de la Rodilla/patología , Imagen por Resonancia Magnética/métodos , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/patología , Enfermedades de los Cartílagos/patologíaRESUMEN
For the classification of topological phases of matter, an important consideration is whether a system is spinless or spinful, as these two classes have distinct symmetry algebra that gives rise to fundamentally different topological phases. However, only recently has it been realized theoretically that in the presence of gauge symmetry, the algebraic structure of symmetries can be projectively represented, which possibly enables the switch between spinless and spinful topological phases. Here, we report the experimental demonstration of this idea by realizing spinful topological phases in "spinless" acoustic crystals with projective space-time inversion symmetry. In particular, we realize a one-dimensional topologically gapped phase characterized by a 2Z winding number, which features double-degenerate bands in the entire Brillouin zone and two pairs of degenerate topological boundary modes. Our Letter thus overcomes a fundamental constraint on topological phases by spin classes.
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N6 -methyladenosine (m6 A) is a chemical modification present in multiple RNA species and is most abundant in mRNAs. Studies on m6 A reveal its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. Although some recent discoveries indicate that m6 A can affect the life cycles of numerous viruses as well as the cellular antiviral immune response, the roles of m6 A modification in type I interferon (IFN-I) signaling are still largely unknown. Here, we reveal that WT1-associated protein (WTAP), one of the m6 A "writers", is degraded via the ubiquitination-proteasome pathway upon activation of IFN-I signaling. With the degradation of WTAP, the m6 A levels of IFN-regulatory factor 3 (IRF3) and interferon alpha/beta receptor subunit 1 (IFNAR1) mRNAs are reduced, leading to translational suppression of IRF3 and instability of IFNAR1 mRNA. Thus, the WTAP-IRF3/IFNAR1 axis may serve as negative feedback pathway to fine-tune the activation of IFN-I signaling, which highlights the roles of m6 A in the antiviral response by dictating the fate of mRNAs associated with IFN-I signaling.
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Antivirales , Factor 3 Regulador del Interferón , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/metabolismo , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , UbiquitinaciónRESUMEN
In the present study, a series of cycloalkyl[b]thiophenylnicotinamide derivatives against α-glucosidase were synthesized, and evaluated for their in vitro and in vivo anti-diabetic potential. Most of the synthetic analogues exhibited superior α-glucosidase inhibitory effects than the standard drug acarbose (IC50 = 258.5 µM), in which compound 11b with cyclohexyl[b]thiophene core demonstrated the highest activity with an IC50 value of 9.9 µM and showed higher selectivity towards α-glucosidase over α-amylase by 7.4-fold. Fluorescence quenching experiment confirmed the direct binding of 11b with α-glucosidase, kinetics study revealed that 11b was a mixed-type inhibitor, and its binding mode was analyzed using molecular docking. Moreover, analogs compounds 6a-9b, 11b, 12b did not show in vitro cytotoxicity against LO2 and HepG2 cells. Finally, compound 11b exhibited in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-loaded rats.
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Inhibidores de Glicósido Hidrolasas , alfa-Glucosidasas , Animales , Ratas , Inhibidores de Glicósido Hidrolasas/farmacología , Simulación del Acoplamiento Molecular , Hipoglucemiantes/farmacología , AcarbosaRESUMEN
Vitamin B12 (VB12) is a critical micronutrient that controls DNA metabolic pathways to maintain the host genomic stability and tissue homeostasis. We recently reported that the newly discovered commensal Propionibacterium, P. UF1, regulates the intestinal immunity to resist pathogen infection, which may be attributed in part to VB12 produced by this bacterium. Here we demonstrate that VB12 synthesized by P. UF1 is highly dependent on cobA gene-encoding uroporphyrinogen III methyltransferase, and that this vitamin distinctively regulates the cobA operon through its 5' untranslated region (5' UTR). Furthermore, conserved secondary structure and mutagenesis analyses revealed a VB12-riboswitch, cbiMCbl (140 bp), within the 5' UTR that controls the expression of downstream genes. Intriguingly, ablation of the cbiMCbl significantly dysregulates the biosynthesis of VB12, illuminating the significance of this riboswitch for bacterial VB12 biosynthesis. Collectively, our finding is an in-depth report underscoring the regulation of VB12 within the beneficial P. UF1 bacterium, through which the commensal metabolic network may improve gut bacterial cross-feeding and human health.
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Regulación Bacteriana de la Expresión Génica , Propionibacterium/metabolismo , Riboswitch/genética , Vitamina B 12/biosíntesis , Regiones no Traducidas 5'/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Microbioma Gastrointestinal/fisiología , Metiltransferasas/genética , Metiltransferasas/metabolismo , Mutagénesis Sitio-Dirigida , Operón/genética , Probióticos/metabolismo , Propionibacterium/genéticaRESUMEN
BACKGROUND & AIMS: The down-regulated in adenoma (DRA) protein, encoded by SLC26A3, a key intestinal chloride anion exchanger, has recently been identified as a novel susceptibility gene for inflammatory bowel disease (IBD). However, the mechanisms underlying the increased susceptibility to inflammation induced by the loss of DRA remain elusive. Compromised barrier is a key event in IBD pathogenesis. The current studies were undertaken to elucidate the impact of DRA deficiency on epithelial barrier integrity and to define underlying mechanisms. METHODS: Wild-type and DRA-knockout (KO) mice and crypt-derived colonoids were used as models for intestinal epithelial response. Paracellular permeability was measured by using fluorescein isothiocyanate-dextran flux. Immunoblotting, immunofluorescence, immunohistochemistry, and ribonucleoprotein immunoprecipitation assays were performed. Gut microbiome analysis was conducted to investigate the impact of DRA deficiency on gut microbial communities. RESULTS: DRA-KO mice exhibited an increased colonic paracellular permeability with significantly decreased levels of tight junction/adherens junction proteins, including ZO-1, occludin, and E-cadherin. A similar expression pattern of occludin and E-cadherin was observed in colonoids derived from DRA-KO mice and short hairpin RNA-mediated DRA knockdown in Caco-2 cells. Microbial analysis showed gut dysbiosis in DRA-KO mice. However, cohousing studies showed that dysbiosis played only a partial role in maintaining tight junction protein expression. Furthermore, our results showed increased binding of RNA-binding protein CUGBP1 with occludin and E-cadherin genes in DRA-KO mouse colon, suggesting that posttranscriptional mechanisms play a key role in gut barrier dysfunction. CONCLUSIONS: To our knowledge, our studies demonstrate a novel role of DRA in maintaining the intestinal epithelial barrier function and potential implications of its dysregulation in IBD pathogenesis.
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Antiportadores/deficiencia , Antiportadores de Cloruro-Bicarbonato/deficiencia , Disbiosis/inmunología , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Transportadores de Sulfato/deficiencia , Animales , Antiportadores/genética , Proteínas CELF1/metabolismo , Células CACO-2 , Cadherinas/metabolismo , Antiportadores de Cloruro-Bicarbonato/genética , Modelos Animales de Enfermedad , Disbiosis/microbiología , Disbiosis/patología , Técnicas de Silenciamiento del Gen , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Masculino , Ratones , Ratones Noqueados , Ocludina/metabolismo , Permeabilidad , Transportadores de Sulfato/genética , Uniones Estrechas/patologíaRESUMEN
Dirac cones (DCs) play a pivotal role in various unique phenomena ranging from massless electrons in graphene to robust surface states in topological insulators (TIs). Recent studies have theoretically revealed a full Dirac hierarchy comprising an eightfold bulk DC, a fourfold surface DC, and a twofold hinge DC, associated with a hierarchy of topological phases including first-order to third-order three-dimensional (3D) topological insulators, using the same 3D base lattice. Here, we report the first experimental observation of the Dirac hierarchy in 3D acoustic TIs. Using acoustic measurements, we unambiguously reveal that lifting of multifold DCs in each hierarchy can induce two-dimensional topological surface states with a fourfold DC in a first-order 3D TI, one-dimensional topological hinge states with a twofold DC in a second-order 3D TI, and zero-dimensional topological corner states in a third-order 3D TI. Our Letter not only expands the fundamental research scope of Dirac physics, but also opens up a new route for multidimensional robust wave manipulation.
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OBJECTIVES: To assess the prevalence and characteristics of infections in patients with idiopathic inflammatory myopathies (IIM) and analyse risk factors for infection using clinical presentation and biochemical findings of IIM. METHODS: Retrospective review of the medical records of patients with IIM followed up in a single medical centre from January 2008 to January 2018. RESULTS: Of the 779 patients with IIM, 215 (27.6%) suffered from infections. The prevalence of infection in dermatomyositis (DM) (29.8%) was more than polymyositis (PM) (18.5%). The lung was the most common infection site (66.5%). Multivariate analyses demonstrated that methylprednisolone pulse (MP) (OR=3.22; 95% CI=1.60 - 6.48; p=0.001), age of onset >50 years (OR=1.02; 95% CI=1.00 - 1.03; p=0.011), anti-melanoma differentiation-associated gene 5 (MDA5) antibody (OR=1.93; 95% CI=1.20 - 3.11; p=0.007), lymphocyte count <1200/mm3 (OR=2.85; 95% CI=1.89 - 4.30; p<0.001), and interstitial lung diseases (ILD) (OR=2.03; 95% CI=1.30 - 3.71; p=0.002) are independent risk factors for infection. Survival analysis demonstrated that the three-year survival rate in the infection group was lower than the no-infection group (75.3% vs. 94.7%, p < 0.001). CONCLUSIONS: Among hospitalised individuals with IIM, infection is frequent and the leading cause of mortality. The anti-MDA5 antibody, lymphopenia, ILD, old age, and treatment with MP are contributing factors in the development of infections in patients with IIM.
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Dermatomiositis , Enfermedades Pulmonares Intersticiales , Miositis , Polimiositis , Autoanticuerpos , Dermatomiositis/diagnóstico , Dermatomiositis/epidemiología , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/epidemiología , Persona de Mediana Edad , Miositis/diagnóstico , Miositis/epidemiología , Polimiositis/diagnóstico , Polimiositis/epidemiología , Estudios RetrospectivosRESUMEN
OBJECTIVES: This study aimed to analyse the clinical features of anti-isoleucyl-tRNA synthetase (OJ) antibodies in Chinese patients and to compare with previously published cohorts. We reviewed the clinical data of anti-OJ antibody positive patients, including their long-term follow-up. RESULTS: Anti-OJ antibodies were present in 10 of 1269 (0.8%) patients with idiopathic inflammatory myopathies (IIMs), and 10/320 (3.1%) patients with anti-synthetase syndrome (ASS). Of the anti-OJ antibody-positive patients, 90% had interstitial lung disease (ILD), of whom three (30%) developed rapidly progressive ILD (RP-ILD). Half (50%) of the patients were febrile and developed myocardial involvement; 40% of patients experienced myositis, mechanic's hands and arthritis. Compared to the anti-Jo-1 group, the levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in the anti-OJ antibody-positive group were higher (p<0.05). From a review of the literature regarding the clinical features of anti-OJ, fever was more common in the eastern cohort (41.7% vs. 8.3%, p=0.002), whereas patients in western countries were more likely to develop arthritis (20.9% vs. 58.1%, p=0.001). With complete follow-up of the present cohort, 80% improved with treatment, including one patient who underwent lung transplant. CONCLUSIONS: The anti-OJ antibody occurred infrequently in Chinese patients, ILD was the major clinical feature, but myocardial injury was also a prominent associated complication. Anti-OJ positive patients were responsive to treatment.
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Enfermedades Pulmonares Intersticiales , Miositis , Autoanticuerpos , Estudios de Cohortes , Humanos , Isoleucina-ARNt LigasaRESUMEN
Inhibition of oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial cell (VEC) injury is one of the effective strategies for treating atherosclerosis. In the present study, a series of novel marine phidianidine-inspired indole-1,2,4-oxadiazoles was designed, synthesized, and evaluated for their effects against oxLDL-induced injury in VECs. Among them, compound D-6, displaying the most effective protective activity, was found to inhibit oxLDL-induced apoptosis and the expression of ICAM-1 and VCAM-1 in VECs. Mechanistic studies showed that D-6 could trigger Nrf2 nuclear translocation, subsequently resulting in increased expression of Nrf2 target gene HO-1. Meanwhile, D-6 suppressed the increase of ROS level and nuclear translocation of NF-κB induced by oxLDL. Importantly, Nrf2 knockdown attenuated the inhibition effects of D-6 on oxLDL-induced apoptosis, ROS production and NF-κB nuclear translocation. Collectively, our studies demonstrated that compound D-6 protected against oxLDL-induced endothelial injury by activating Nrf2/HO-1 anti-oxidation pathway.
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Factor 2 Relacionado con NF-E2 , FN-kappa B , Lipoproteínas LDL/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Intestinal innate lymphoid cells (ILCs) contribute to the protective immunity and homeostasis of the gut, and the microbiota are critically involved in shaping ILC function. However, the role of the gut microbiota in regulating ILC development and maintenance still remains elusive. Here, we identified opposing effects on ILCs by two Helicobacter species, Helicobacter apodemus and Helicobacter typhlonius, isolated from immunocompromised mice. We demonstrated that the introduction of both Helicobacter species activated ILCs and induced gut inflammation; however, these Helicobacter species negatively regulated RORγt+ group 3 ILCs (ILC3s), especially T-bet+ ILC3s, and diminished their proliferative capacity. Thus, these findings underscore a previously unknown dichotomous regulation of ILC3s by Helicobacter species, and may serve as a model for further investigations to elucidate the host-microbe interactions that critically sustain the maintenance of intestinal ILC3s.
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Colitis/inmunología , Infecciones por Enterobacteriaceae/inmunología , Microbioma Gastrointestinal/inmunología , Helicobacter/inmunología , Mucosa Intestinal/inmunología , Linfocitos/inmunología , Animales , Citrobacter rodentium/inmunología , Citrobacter rodentium/patogenicidad , Colitis/inducido químicamente , Colitis/microbiología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/microbiología , Femenino , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Interacciones Microbiota-Huesped/inmunología , Humanos , Tolerancia Inmunológica , Inmunidad Innata , Inmunidad Mucosa , Mucosa Intestinal/citología , Mucosa Intestinal/microbiología , Linfocitos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteínas de Dominio T Box/inmunología , Proteínas de Dominio T Box/metabolismoRESUMEN
Governments worldwide have rapidly deployed non-pharmaceutical interventions (NPIs) to mitigate the COVID-19 pandemic. However, the effect of these individual NPI measures across space and time has yet to be sufficiently assessed, especially with the increase of policy fatigue and the urge for NPI relaxation in the vaccination era. Using the decay ratio in the suppression of COVID-19 infections and multi-source big data, we investigated the changing performance of different NPIs across waves from global and regional levels (in 133 countries) to national and subnational (in the United States of America [USA]) scales before the implementation of mass vaccination. The synergistic effectiveness of all NPIs for reducing COVID-19 infections declined along waves, from 95.4% in the first wave to 56.0% in the third wave recently at the global level and similarly from 83.3% to 58.7% at the USA national level, while it had fluctuating performance across waves on regional and subnational scales. Regardless of geographical scale, gathering restrictions and facial coverings played significant roles in epidemic mitigation before the vaccine rollout. Our findings have important implications for continued tailoring and implementation of NPI strategies, together with vaccination, to mitigate future COVID-19 waves, caused by new variants, and other emerging respiratory infectious diseases.
RESUMEN
Based on UPLC characteristic chromatogram and quantitative analysis of multi-components by single marker(QAMS), the content of seven types of ginsenosides in Ginseng Radix et Rhizoma was simultaneously determined, and the quality of Ginseng Radix et Rhizoma was evaluated by the principal component analysis(PCA). The chromatographic separation was performed on the Acquity UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 µm) with the mobile phase of acetonitrile-water for gradient elution at the flow rate of 0.3 mL·min~(-1), the column temperature of 30 â, the detection wavelength of 203 nm, and the injection volume of 2 µL. The UPLC chromatogram was established with 19 batches of Ginseng Radix et Rhizoma samples from three producing areas by Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine(version 2012). Thirteen characteristic peaks were determined and seven components were identified. SPSS 26.0 was used to conduct PCA on the characteristic peak areas. With the peak of ginsenoside Rb_1 as reference peak S, ginsenoside Rb_1 showed good durability of relative correction factor as compared with other ginsenosides. The QAMS method for the determination of seven ginsenosides in Ginseng Radix et Rhizoma was established. There was no significant difference in results between the QAMS method and the external standard method. As revealed by the results of PCA and the determination of the total content of seven ginsenosides, the four batches of Ginseng Radix et Rhizoma numbered S19, S18, S1, and S2 were of superior quality. The characteristic chromatogram and QAMS method for the determination of seven ginsenosides in this study were convenient and accurate, which greatly shortened the analysis time and improved the analysis efficiency. The findings of this study are expected to provide a basis for the overall quality evaluation of Ginseng Radix et Rhizoma.