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Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy.
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Cistina , Protones , Sistemas de Transporte de Aminoácidos/metabolismo , Cisteína/metabolismo , Cistina/metabolismo , Humanos , Lisosomas/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
A specialized population of mast cells residing within epithelial layers, currently known as intraepithelial mast cells (IEMCs), was originally observed over a century ago, yet their physiological functions have remained enigmatic. In this study, we unveil an unexpected and crucial role of IEMCs in driving gasdermin C-mediated type 2 immunity. During helminth infection, αEß7 integrin-positive IEMCs engaged in extensive intercellular crosstalk with neighboring intestinal epithelial cells (IECs). Through the action of IEMC-derived proteases, gasdermin C proteins intrinsic to the epithelial cells underwent cleavage, leading to the release of a critical type 2 cytokine, interleukin-33 (IL-33). Notably, mast cell deficiency abolished the gasdermin C-mediated immune cascade initiated by epithelium. These findings shed light on the functions of IEMCs, uncover a previously unrecognized phase of type 2 immunity involving mast cell-epithelial cell crosstalk, and advance our understanding of the cellular mechanisms underlying gasdermin C activation.
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Interleucina-33 , Mastocitos , Proteínas de Unión a Fosfato , Proteínas Citotóxicas Formadoras de Poros , Animales , Ratones , Comunicación Celular/inmunología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Interleucina-33/metabolismo , Interleucina-33/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/inmunología , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/inmunología , Proteínas Citotóxicas Formadoras de Poros/metabolismoRESUMEN
Siglecs are cell surface receptors whose functions are tied to the binding of their sialoglycan ligands. Recently, we developed an optimized liposome formulation and used it to investigate the binding of human Siglecs (hSiglec) against a panel of gangliosides. Animal models, more specifically murine models, are used to understand human biology; however, species-specific differences can complicate the interpretation of the results. Herein, we used our optimized liposome formulation to dissect the interactions between murine Siglecs (mSiglecs) and gangliosides to assess the appropriateness of mSiglecs as a proxy to better understand the biological roles of hSiglec-ganglioside interactions. Using our optimized liposome formulation, we found that ganglioside binding is generally conserved between mice and humans with mSiglec-1, -E, -F, and -15 binding multiple gangliosides like their human counterparts. However, in contrast to the hSiglecs, we observed little to no binding between the mSiglecs and ganglioside GM1a. Detailed analysis of mSiglec-1 interacting with GM1a and its structural isomer, GM1b, suggests that mSiglec-1 preferentially binds α2-3-linked sialic acids presented from the terminal galactose residue. The ability of mSiglecs to interact or not interact with gangliosides, particularly GM1a, has implications for using mice to study neurodegenerative diseases, infections, and cancer, where interactions between Siglecs and glycolipids have been proposed to modulate these human diseases.
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Gangliósidos , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Animales , Gangliósidos/metabolismo , Ratones , Humanos , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/genética , Liposomas/metabolismo , Lectinas/metabolismo , Lectinas/química , Unión Proteica , Antígenos CD/metabolismo , Antígenos CD/genéticaRESUMEN
Networks are vital tools for understanding and modeling interactions in complex systems in science and engineering, and direct and indirect interactions are pervasive in all types of networks. However, quantitatively disentangling direct and indirect relationships in networks remains a formidable task. Here, we present a framework, called iDIRECT (Inference of Direct and Indirect Relationships with Effective Copula-based Transitivity), for quantitatively inferring direct dependencies in association networks. Using copula-based transitivity, iDIRECT eliminates/ameliorates several challenging mathematical problems, including ill-conditioning, self-looping, and interaction strength overflow. With simulation data as benchmark examples, iDIRECT showed high prediction accuracies. Application of iDIRECT to reconstruct gene regulatory networks in Escherichia coli also revealed considerably higher prediction power than the best-performing approaches in the DREAM5 (Dialogue on Reverse Engineering Assessment and Methods project, #5) Network Inference Challenge. In addition, applying iDIRECT to highly diverse grassland soil microbial communities in response to climate warming showed that the iDIRECT-processed networks were significantly different from the original networks, with considerably fewer nodes, links, and connectivity, but higher relative modularity. Further analysis revealed that the iDIRECT-processed network was more complex under warming than the control and more robust to both random and target species removal (P < 0.001). As a general approach, iDIRECT has great advantages for network inference, and it should be widely applicable to infer direct relationships in association networks across diverse disciplines in science and engineering.
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BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.
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Colitis , Enfermedades Inflamatorias del Intestino , Probióticos , Humanos , Animales , Ratones , Antibacterianos/efectos adversos , Células Th2 , Células Th17 , Colitis/inducido químicamente , Colitis/prevención & control , Probióticos/farmacología , Inflamación , Inmunidad , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: Accumulating evidence from microbial studies have highlighted the modulatory roles of intestinal microbes in numerous human diseases, however, the shared microbial signatures across different diseases remain relatively unclear. METHODS: To consolidate existing knowledge across multiple studies, we performed meta-analyses of 17 disease types, covering 34 case-control datasets of 16S rRNA sequencing data, to identify shared alterations among different diseases. Furthermore, the impact of a microbial species, Lactobacillus salivarius, was established in a dextran sodium sulphate-induced colitis model and a collagen type II-induced arthritis mouse model. RESULTS: Microbial alterations among autoimmune diseases were substantially more consistent compared with that of other diseases (cancer, metabolic disease and nervous system disease), with microbial signatures exhibiting notable discriminative power for disease prediction. Autoimmune diseases were characterized by the enrichment of Enterococcus, Veillonella, Streptococcus and Lactobacillus and the depletion of Ruminococcus, Gemmiger, Oscillibacter, Faecalibacterium, Lachnospiracea incertae sedis, Anaerostipes, Coprococcus, Alistipes, Roseburia, Bilophila, Barnesiella, Dorea, Ruminococcus2, Butyricicoccus, Phascolarctobacterium, Parabacteroides and Odoribacter, among others. Functional investigation of L. salivarius, whose genus was commonly enriched in numerous autoimmune diseases, demonstrated protective roles in two separate inflammatory mouse models. CONCLUSION: Our study highlights a strong link between autoimmune diseases and the gut microbiota, with notably consistent microbial alterations compared with that of other diseases, indicating that therapeutic strategies that target the gut microbiome may be transferable across different autoimmune diseases. Functional validation of L. salivarius highlighted that bacterial genera associated with disease may not always be antagonistic, but may represent protective or adaptive responses to disease.
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Artritis Experimental , Enfermedades Autoinmunes , Microbioma Gastrointestinal , Animales , Ratones , Humanos , ARN Ribosómico 16S , Clostridiales , Modelos Animales de EnfermedadRESUMEN
In this work, carbon-coated bimetallic tin-nickel selenide heterostructures loaded on reduced graphene oxide composites were prepared through a metal-organic framework-assisted strategy. The carbon coating mitigates the volume expansion and maintains the structural stability, while the introduction of reduced graphene oxide and heterojunction enhances electrical conductivity and reaction kinetics, thereby together contributing to the enhanced lithium-ion storage performance. As expected, the optimal material delivers excellent lithium-ion storage performance in terms of a high reversible capacity of 1033.4 mAh g-1 at 0.2 A g-1, outstanding rate capability, and long-term cyclability with the capacity of 726.2 mAh g-1 after 500 cycles at 1.0 A g-1 and 452.4 mAh g-1 after 1000 cycles at 2.0 A g-1. Furthermore, the electrochemical reaction mechanism of the composite is analyzed.
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Manure application is a global approach for enhancing soil organic carbon (SOC) sequestration. However, the response of SOC decomposition in manure-applied soil to abrupt warming, often occurring during diurnal temperature fluctuations, remains poorly understood. We examined the effects of long-term (23 years) continuous application of manure on SOC chemical composition, soil respiration, and microbial communities under temperature shifts (15 vs 25 °C) in the presence of plant residues. Compared to soil without fertilizer, manure application reduced SOC recalcitrance indexes (i.e., aliphaticity and aromaticity) by 17.45 and 21.77%, and also reduced temperature sensitivity (Q10) of native SOC decomposition, plant residue decomposition, and priming effect by 12.98, 15.98, and 52.83%, respectively. The relative abundances of warm-stimulated chemoheterotrophic bacteria and fungi were lower in the manure-applied soil, whereas those of chemoautotrophic Thaumarchaeota were higher. In addition, the microbial network of the manure-applied soil was more interconnected, with more negative connections with the warm-stimulated taxa than soils without fertilizer or with chemical fertilizer applied. In conclusion, our study demonstrated that the reduced loss of SOC to abrupt warming by manure application arises from C chemistry modification, less warm-stimulated microorganisms, a more complex microbial community, and the higher CO2 intercepting capability by Thaumarchaeota.
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Carbono , Estiércol , Microbiota , Microbiología del Suelo , Suelo , Suelo/química , Fertilizantes , TemperaturaRESUMEN
19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H1-H19) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J1-J5) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the ß2-adrenergic receptor (ß2AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at ß2AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against ß2AR than Cmpd-15, the first reported ß2AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for ß2AR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd-15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of ß2AR NAM.
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Receptores Adrenérgicos beta 2 , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/química , Regulación Alostérica/efectos de los fármacos , Humanos , Relación Estructura-Actividad , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Estructura Molecular , Antagonistas de Receptores Adrenérgicos beta 2/farmacología , Antagonistas de Receptores Adrenérgicos beta 2/química , Antagonistas de Receptores Adrenérgicos beta 2/síntesis químicaRESUMEN
BACKGROUND: Stroke and thromboembolism in nonvalvular atrial fibrillation (NVAF) primarily arise from thrombi or sludge in the left atrial appendage (LAA). Comprehensive insight into the characteristics of these formations is essential for effective risk assessment and management. METHODS: We conducted a single-center retrospective observational of 176 consecutive NVAF patients with confirmed atrial/appendage thrombus or sludge determined by a pre-ablation transesophageal echocardiogram (TEE) from December 2017 to April 2019. We obtained clinical and echocardiographic characteristics, including left atrial appendage emptying velocity (LAAeV) and filling velocity (LAAfV). Data analysis focused on identifying the morphology and location of thrombus or sludge. Patients were divided into the solid thrombus and sludge groups, and the correlation between clinical and echocardiographic variables and thrombotic status was analyzed. RESULTS: Morphological classification: In total, thrombi were identified in 78 patients, including 71 (40.3%) mass and 7 (4.0%) lamellar, while sludge was noted in 98 (55.7%). Location classification: 92.3% (72/78) of patients had thrombus confined to the LAA; 3.8% (3/78) had both LA and LAA involvement; 2.7% (2/78) had LA, LAA and RAA extended into the RA, the remained 1.2%(1/78) was isolated to RAA. 98.0% (96/98) of patients had sludge confined to the LAA; the remaining 2.0% (2/98) were present in the atrial septal aneurysm, which protrusion of interatrial septum into the RA. The thrombus and sludge groups showed low LAAeV (19.43 ± 9.59 cm/s) or LAAfV (17.40 ± 10.09 cm/s). Only LA dimension ≥ 40 mm was independently associated with the thrombus state in the multivariable model. CONCLUSION: This cohort study identified rare thrombus morphology and systematically summarized the classification of thrombus morphology. The distribution of thrombus and sludge outside limited to LAA was updated, including bilateral atrial and appendage involvement and rare atrial septal aneurysm sludge. LAAeV and LAAfV were of limited value in distinguishing solid thrombus from sludge. CLINICAL TRIAL NUMBER: ChiCTR-OCH-13,003,729.
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Apéndice Atrial , Fibrilación Atrial , Ecocardiografía Transesofágica , Trombosis , Humanos , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/diagnóstico , Estudios Retrospectivos , Masculino , Femenino , Trombosis/diagnóstico por imagen , Trombosis/etiología , Anciano , Persona de Mediana Edad , Apéndice Atrial/diagnóstico por imagen , Apéndice Atrial/fisiopatología , Factores de Riesgo , Valor Predictivo de las Pruebas , Función del Atrio Izquierdo , Cardiopatías/diagnóstico por imagen , Cardiopatías/fisiopatología , Tromboembolia/etiología , Tromboembolia/diagnóstico por imagen , Tromboembolia/diagnósticoRESUMEN
BACKGROUND: Left bundle branch block (LBBB) and atrial fibrillation (AF) are commonly coexisting conditions. The impact of LBBB on catheter ablation of AF has not been well determined. This study aims to explore the long-term outcomes of patients with AF and LBBB after catheter ablation. METHODS: Forty-two patients with LBBB of 11,752 patients who underwent catheter ablation of AF from 2011 to 2020 were enrolled as LBBB group. After propensity score matching in a 1:4 ratio, 168 AF patients without LBBB were enrolled as non-LBBB group. Late recurrence and a composite endpoint of stroke, all-cause mortality, and cardiovascular hospitalization were compared between the two groups. RESULTS: Late recurrence rate was significantly higher in the LBBB group than that in the non-LBBB group (54.8% vs. 31.5%, p = .034). Multivariate analysis showed that LBBB was an independent risk factor for late recurrence after catheter ablation of AF (hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.09-4.40, p = .031). LBBB group was also associated with a significantly higher incidence of the composite endpoint (21.4% vs. 6.5%, HR 3.98, 95% CI 1.64-9.64, p = .002). CONCLUSIONS: LBBB was associated with a higher risk for late recurrence and a higher incidence of composite endpoint in the patients underwent catheter ablation.
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Fibrilación Atrial , Ablación por Catéter , Accidente Cerebrovascular , Humanos , Bloqueo de Rama/etiología , Factores de Riesgo , Accidente Cerebrovascular/etiología , Ablación por Catéter/efectos adversos , Resultado del Tratamiento , RecurrenciaRESUMEN
Dendrobium officinale soft rot is a widespread and destructive disease caused by Fusarium oxysporum that can seriously affect yield and quality. To better understand the fungal infection and colonization, we successfully created an F. oxysporum labeled with green fluorescent protein using the Agrobacterium tumefaciens-mediated transformation method. Transformants had varying fluorescence intensities, but their pathogenicity did not differ from that of the wild type. Fluorescence microscopy revealed that F. oxysporum primarily entered the aboveground portion of D. officinale through the leaf margin, stomata, or by direct penetration of the leaf surface. It then colonized the mesophyll and spread along its vascular bundles. D. officinale exhibited typical symptoms of decay and wilting at 14 days postinoculation, accompanied by a pronounced fluorescence signal in the affected area. The initial colonization of F. oxysporum in the subterranean region primarily involved attachment to the root hair and epidermis, which progressed to the medullary vascular bundle. At 14 days postinoculation, the root vascular bundles of D. officinale exhibited significant colonization by F. oxysporum. Macroconidia were also observed in black rot D. officinale tissue. In particular, the entire root was surrounded by a significant number of chlamydospore-producing F. oxysporum mycelia at 28 days postinoculation. This approach allowed for the visualization of the complete infection process of F. oxysporum and provided a theoretical foundation for the development of field control strategies.
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Agrobacterium tumefaciens , Dendrobium , Fusarium , Proteínas Fluorescentes Verdes , Enfermedades de las Plantas , Hojas de la Planta , Raíces de Plantas , Fusarium/genética , Fusarium/fisiología , Fusarium/patogenicidad , Fusarium/crecimiento & desarrollo , Dendrobium/microbiología , Dendrobium/genética , Proteínas Fluorescentes Verdes/genética , Enfermedades de las Plantas/microbiología , Raíces de Plantas/microbiología , Hojas de la Planta/microbiología , Agrobacterium tumefaciens/genética , Microscopía Fluorescente , Transformación GenéticaRESUMEN
Bamboo leaf extract (BLE) is a pale brown powder extracted from bamboo leaves, and it is listed in the Chinese Standard GB-2760 as a legal and safe food additive. The present study aims to identify and characterize the major flavonoids in BLE. The identification of major flavonoids was carried out using ultra performance liquid chromatography combined with electrospray ionization quadruple time-of-flight tandem mass spectrometry (HPLC/ESI-QTOF-MS/MS). A total of 31 flavonoid compounds were identified and tentatively characterized base on reference standards and MS dissociation mechanisms. HPLC/ESI-QTOF-MS can serve as an important analytical platform to identification structure of bamboo leaf flavonoids (BLF).
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In recent years, with sinomenine hydrochloride as the main ingredient, Qingfengteng had been formulated as various dosage forms for clinical treatment. Subsequent findings confirmed a variety of biological roles for sinomenine. Here, 15 H2S-donating sinomenine derivatives were synthesized. Target hybrids a11 displayed substantial cytotoxic effects on cancer cell lines, particularly against K562 cells, with an IC50 value of 1.36 µM. In-depth studies demonstrated that a11 arrested cell cycle at G1 phase, induced apoptosis via both morphological changes in nucleus and membrane potential collapse in mitochondria. These results indicated a11 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.
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BACKGROUND: Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. METHODS: A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. RESULTS: Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05-8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60-184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78-1.04; P = 0.160) and 1.49 (95% CI, 0.95-2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34-50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89-7.92; P = 0.12) and 0.66 (95% CI, 0.03-4.55; P = 0.71), respectively, using ICI monotherapy as reference. CONCLUSIONS: Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.
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Carcinoma de Pulmón de Células no Pequeñas , Enfermedades Pulmonares Intersticiales , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Farmacovigilancia , Inmunoterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Estudios RetrospectivosRESUMEN
BACKGROUND: In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion. OBJECTIVE: This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for the ablation of PeAF. STUDY DESIGN: The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months). CONCLUSIONS: The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation.
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Fibrilación Atrial , Ablación por Catéter , Venas Pulmonares , Humanos , Fibrilación Atrial/cirugía , Venas Pulmonares/cirugía , Estudios Prospectivos , Atrios Cardíacos/cirugía , Etanol , Ablación por Catéter/métodos , Resultado del Tratamiento , RecurrenciaRESUMEN
BACKGROUND: Left ventricular thrombus (LVT) is a common complication of dilated cardiomyopathy (DCM), causing morbidity and mortality. METHODS: This study retrospectively analyzed patients with DCM from January 2002 to August 2020 in Beijing Anzhen Hospital. Clinical characteristics were compared between the LVT group and the age and sex 1:4 matched with the LVT absent group. The receiver operator characteristic (ROC) curve was plotted to evaluate the diagnostic value of D-dimer predicting LVT occurrence in DCM. RESULTS: A total of 3,134 patients were screened, and LVT was detected in 72 (2.3%) patients on echocardiography. The patients with LVT had higher D-dimer, fibrinogen, and lower systolic blood pressure than those without LVT. The ejection fraction (EF) was lower and left ventricular end-systolic diameter was larger in the LVT group. Severe mitral regurgitation (MR) was more common in the LVT absent groups. The prevalence of atrial fibrillation was lower in the LVT group. The ROC curve analysis yielded an optimal cut-off value of 444 ng/mL DDU (D-dimer units) for D-dimer to predict the presence of LVT. Multivariable binary logistic regression analysis revealed that EF (OR = 0.90, 95% CI = 0.86-0.95), severe MR (OR = 0.19, 95% CI = 0.08-0.48), and D-dimer level (OR = 15.4, 95% CI = 7.58-31.4) were independently associated with LVT formation. CONCLUSION: This study suggested that elevated D-dimer levels (>444 ng/mL DDU) and reduced EF were independently associated with increased risk of LVT formation. Severe MR could decrease the incidence of LVT.
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Cardiomiopatía Dilatada , Trombosis , Humanos , Estudios Retrospectivos , Cardiomiopatía Dilatada/complicaciones , Factores de RiesgoRESUMEN
Polio cases can be missed by acute flaccid paralysis (AFP) case surveillance alone, emphasizing the importance of environmental surveillance (ES). In this study, to investigate the serotype distribution and epidemiological trends of poliovirus (PV), we characterized PV isolated from domestic sewage in Guangzhou City, Guangdong Province, China from 2009 to 2021. A total of 624 sewage samples were collected from the Liede Sewage Treatment Plant, and the positive rates of PV and non-polio enteroviruses were 66.67% (416/624) and 78.37% (489/624), respectively. After sewage sample treatment, each sewage sample was inoculated in six replicate tubes of three cell lines, and 3370 viruses were isolated during the 13-year surveillance period. Among these, 1086 isolates were identified as PV, including type 1 PV (21.36%), type 2 PV (29.19%), and type 3 PV (49.48%). Based on VP1 sequences, 1057 strains were identified as Sabin-like, 21 strains were high-mutant vaccines, and eight strains were vaccine-derived poliovirus (VDPV). The numbers and serotypes of PV isolates in sewage were influenced by the vaccine switch strategy. After type 2 OPV was removed from the trivalent oral PV (OPV) vaccine and a bivalent OPV (bOPV) was adopted in May 2016, the last type 2 PV strain was isolated from sewage, with no detection thereafter. Type 3 PV isolates increased significantly and became the dominant serotype. Before and after the second vaccine switch in January 2020, that is, from the first dose of IPV and second-fourth doses of bOPV to the first two doses of IPV and third-fourth doses of bOPV, there was also a statistical difference in PV positivity rates in sewage samples. Seven type 2 VDPVs and one type 3 VDPV were identified in sewage samples in 2009-2021, and phylogenetic analysis indicated that all VDPVs isolated from ES in Guangdong are newly discovered VDPVs, different from VDPV previously discovered in China, and were classified as ambiguous VDPV. It is noteworthy that no VDPV cases were reported in AFP case surveillance in the same period. In conclusion, continued PV ES in Guangzhou since April 2008 has been a useful supplement to AFP case surveillance, providing an important basis for evaluating the effectiveness of vaccine immunization strategies. ES improves early detection, prevention, and control; accordingly, this strategy can curb the circulation of VDPVs and provide a strong laboratory basis for maintaining a polio-free status.
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Poliomielitis , Poliovirus , Humanos , Aguas del Alcantarillado , Filogenia , alfa-Fetoproteínas , Vacuna Antipolio Oral , Poliomielitis/epidemiología , Poliomielitis/prevención & control , Monitoreo del AmbienteRESUMEN
Global climate models predict that the frequency and intensity of precipitation events will increase in many regions across the world. However, the biosphere-climate feedback to elevated precipitation (eP) remains elusive. Here, we report a study on one of the longest field experiments assessing the effects of eP, alone or in combination with other climate change drivers such as elevated CO2 (eCO2 ), warming and nitrogen deposition. Soil total carbon (C) decreased after a decade of eP treatment, while plant root production decreased after 2 years. To explain this asynchrony, we found that the relative abundances of fungal genes associated with chitin and protein degradation increased and were positively correlated with bacteriophage genes, suggesting a potential viral shunt in C degradation. In addition, eP increased the relative abundances of microbial stress tolerance genes, which are essential for coping with environmental stressors. Microbial responses to eP were phylogenetically conserved. The effects of eP on soil total C, root production, and microbes were interactively affected by eCO2 . Collectively, we demonstrate that long-term eP induces soil C loss, owing to changes in microbial community composition, functional traits, root production, and soil moisture. Our study unveils an important, previously unknown biosphere-climate feedback in Mediterranean-type water-limited ecosystems, namely how eP induces soil C loss via microbe-plant-soil interplay.
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Pradera , Microbiota , Carbono , Cambio Climático , NitrógenoRESUMEN
In this work, a photonic thermal switch is proposed based on the phase-change material vanadium dioxide (VO2) within the framework of near-field radiative heat transfer (NFRHT). The switch consists of two metamaterials filled with core-shell nanoparticles, with the shell made of VO2. Compared to traditional VO2 slabs, the proposed switch exhibits a more than two times increase in the switching ratio, reaching as high as 90.29% with a 100â nm vacuum gap. The improved switching effect is attributed to the capability of the VO2 shell to couple with the core, greatly enhancing heat transfer with the insulating VO2, while blocking the motivation of the core in the metallic state of VO2. The proposed switch opens pathways for active control of NFRHT and holds practical significance for developing thermal photon-based logic circuits.