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Monitoring the effector function of cytotoxic T lymphocytes (CTLs) in vivo remains a great challenge. Here, we develop a chemistry-enabled enzymatic labeling approach to evaluate the tumor-specific immune response of CTLs by precisely monitoring the interaction between CTLs and tumor cells. Staphylococcus aureus sortase A (SrtA) is linked to the CTL surface through bioconjugate chemistry and then catalyzes the transfer of fluorescent-labeled substrate, 5-Tamra-LPETG, to CTLs. Meanwhile, the tumor cells are specifically decorated with N-terminal glycine residues (G5 peptide) through the inherent glycolmetabolism of cathepsin B-specific cleavable triacetylated N-azidoacetyl-d-mannosamine (CB-Ac3ManNAz) and click chemistry. After the infiltration of engineered CTLs into the tumor tissues, the immune-synapse-mediated specific interaction of CTLs and tumor cells leads to the accurate fluorescent labeling of tumor cells through the SrtA-catalyzed 5-Tamra-LPETG transfer. Therefore, the immune effect of CTLs as well as the performance of immune drugs can be determined, providing a novel strategy for pushing ahead immunotherapy.
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BACKGROUND: Hulless barley (Hordeum vulgare L. var. nudum Hook. f.) is a significant cereal crop and a substantial source of forage for livestock. Long non-coding RNAs (lncRNAs) and metabolites play crucial roles in the nutrient accumulation and regeneration of hulless barley plants following mowing. The study aimed to identify differentially expressed lncRNAs and metabolites in hulless barley plants by analyzing transcriptomic and metabolomic datasets at 2 h, 24 h, and 72 h following mowing. RESULTS: The study revealed that 190, 90, and 438 lncRNA genes were differentially expressed at the 2 h, 24 h, and 72 h time points compared to the non-mowing control. We identified 14 lncRNA genes-11 downregulated and 3 upregulated-showing consistently significant differential expression across all time points after mowing. These differentially expressed lncRNAs target genes involved in critical processes such as cytokinin signaling, cell wall degradation, storage protein accumulation, and biomass increase. In addition, we identified ten differentially expressed metabolites targeting diverse metabolic pathways, including plant hormones, alkaloids, and flavonoids, before and after mowing at various time points. Endogenous hormone analysis revealed that cytokinin most likely played a crucial role in the regeneration of hulless barley after mowing. CONCLUSIONS: This study created a comprehensive dataset of lncRNAs, metabolites, and hormones in hulless barley after mowing, revealing valuable insights into the functional characteristics of lncRNAs, metabolites, and hormones in regulating plant regeneration. The results indicated that cytokinin plays a significant role in facilitating the regeneration process of hulless barley after mowing. This comprehensive dataset is an invaluable resource for better understanding the complex mechanisms that underlie plant regeneration, with significant implications for crop improvement.
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Hordeum , ARN Largo no Codificante , Hordeum/genética , Hordeum/metabolismo , Hordeum/fisiología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Regulación de la Expresión Génica de las Plantas , Transcriptoma , ARN de Planta/genética , Perfilación de la Expresión Génica , MetabolomaRESUMEN
The potential mechanisms by which drought restricts cotton fiber cell wall synthesis and fiber strength are still not fully understood. Herein, drought experiments were conducted using two cultivars of upland cotton (Gossypium hirsutum), Dexiamian 1 (drought-tolerant) and Yuzaomian 9110 (drought-sensitive). Results showed that drought notably reduced sucrose efflux from cottonseed coats to fibers by down-regulating the expression of GhSWEET10 and GhSWEET15 in outer cottonseed coats, leading to enhanced sucrose accumulation in cottonseed coats but decreased sucrose accumulation in fibers. Within cotton fibers, drought restricted the hydrolysis of sucrose to uridine-5'-diphosphoglucose by suppressing sucrose synthase activity, and drought favored the conversion of uridine-5'-diphosphoglucose to ß-1,3-glucan rather than cellulose by up-regulating GhCALS5. Hence, cellulose content was reduced, which was the main reason for the decreased fiber strength under drought. Moreover, drought promoted lignin synthesis by up-regulating the expression of Gh4CL4, GhPAL9, GhCCR5, GhCAD11, and GhCOMT6, which partly offset the negative influence of reduced cellulose content on fiber strength. Compared with Yuzaomian 9110, the drought-tolerance of Dexiamian 1 was evidenced by the following under drought conditions: (i) greater sucrose flow from seedcoat to fiber, (ii) less ß-1,3-glucan accumulation, and (iii) more lignin biosynthesis. Overall, this study provides new insights into the mechanism of reduced cotton fiber strength induced by drought.
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Fibra de Algodón , Sequías , Gossypium , Sacarosa , Sacarosa/metabolismo , Gossypium/metabolismo , Gossypium/genética , Gossypium/fisiología , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Celulosa/metabolismo , Glucosiltransferasas/metabolismo , Glucosiltransferasas/genéticaRESUMEN
BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) is the most common pathological type in oral tumors. This study intends to construct a novel prognostic nomogram model based on China populations for these resectable OCSCC patients, and then validate these nomograms. METHODS: A total of 607 postoperative patients with OCSCC diagnosed between June 2012 and June 2018 were obtained from two tertiary medical institutions in Xinxiang and Zhengzhou. Then, 70% of all the cases were randomly assigned to the training group and the rest to the validation group. The endpoint time was defined as overall survival (OS) and disease-free survival (DFS). The nomograms for predicting the 3-, and 5-year OS and DFS in postoperative OCSCC patients were established based on the independent prognostic factors, which were identified by the univariate analysis and multivariate analysis. A series of indexes were utilized to assess the performance and net benefit of these two newly constructed nomograms. Finally, the discrimination capability of OS and DFS was compared between the new risk stratification and the American Joint Committee on Cancer (AJCC) stage by Kaplan-Meier curves. RESULTS: 607 postoperative patients with OCSCC were selected and randomly assigned to the training cohort (n = 425) and validation cohort (n = 182). The nomograms for predicting OS and DFS in postoperative OCSCC patients had been established based on the independent prognostic factors. Moreover, dynamic nomograms were also established for more convenient clinical application. The C-index for predicting OS and DFS were 0.691, 0.674 in the training group, and 0.722, 0.680 in the validation group, respectively. Besides, the calibration curve displayed good consistency between the predicted survival probability and actual observations. Finally, the excellent performance of these two nomograms was verified by the NRI, IDI, and DCA curves in comparison to the AJCC stage system. CONCLUSION: The newly established and validated nomograms for predicting OS and DFS in postoperative patients with OCSCC perform well, which can be helpful for clinicians and contribute to clinical decision-making.
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Neoplasias de la Boca , Nomogramas , Humanos , Masculino , Femenino , Persona de Mediana Edad , China/epidemiología , Neoplasias de la Boca/cirugía , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/patología , Pronóstico , Anciano , Periodo Posoperatorio , Adulto , Supervivencia sin Enfermedad , Estimación de Kaplan-Meier , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Estadificación de NeoplasiasRESUMEN
Myocardial fibrosis (MF) is the characteristic pathological feature of various cardiovascular diseases that lead to heart failure (HF) or even fatal outcomes. Alternatively, activated macrophages are involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)-induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild-type mice. Our data suggest that mice with macrophage-specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our in vitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co-culture system, in vitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast-to-myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.
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Cardiopatías , Insuficiencia Cardíaca , Animales , Ratones , Autofagia , Fibrosis , Cardiopatías/metabolismo , Insuficiencia Cardíaca/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Miocardio/metabolismo , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
As the application of molecular dynamics (MD) simulations continues to evolve, the demand for accelerating large-scale simulation systems and handling of enormous simulation tasks is steadily increasing. We propose a parallel acceleration method for large-scale MD simulations based on Sunway heterogeneous many-core processors. This method integrates task scheduling, simulation calculations, and data storage, effectively tackling issues related to large-scale simulations and numerous simulation tasks. The task scheduling strategy flexibly handles tasks on various scales and enables parallel execution of multiple tasks. During the simulation calculations, we ported GROMACS to the Sunway architecture and accelerated the calculation of short-range forces through a heterogeneous processor. Our method achieves approximately 10-fold acceleration and 90% scalability when executing a single simulation task. When handling numerous simulation tasks, our method achieves parallel execution of all of the tasks with 90% scalability. By employing our method, we carried out 50 ns simulations on over 3000 distinct conotoxin structures individually within just 5 h. Additionally, we evaluated more than 200 protein-ligand complexes, and the simulation efficiency significantly exceeded that of midsized to small GPU clusters.
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Simulación de Dinámica Molecular , Conotoxinas/química , Proteínas/química , LigandosRESUMEN
Zinc ion capacitors (ZICs) have shown potential for breaking the energy density ceiling of traditional supercapacitors (SCs) via appropriate device design. Nevertheless, a significant challenge remains in advancing ZIC positive electrode materials with excellent conductivity, high specific capacitance, and reliable cycle stability. A highly attractive option for carbon-based electrode materials is reduced graphene oxide (RGO) due to its vast specific surface area, prominent porosity, and 3D cross-linked frame. However, the tight stacking of RGO sheets driven by van der Waals forces can restrict active sites, decrease specific capacitance, and elevate electrochemical impedance. To overcome these challenges, 3D defective RGO (DRGO) hydrogels were prepared by a metal Co cocatalytic gasification reaction. This method produced mesoporous defects on the surface of RGO hydrogels via a low-temperature hydrothermal self-assembly strategy. The surface of the layer has a wide and uniform distribution, which can offer abundant redox active sites, rich ion transfer channels, and fast reaction kinetics. In this work, 3D DRGO//Zn exhibited a wide operating window (0-1.8 V), high specific capacitance (189.39 F g-1 at 1 A g-1), outstanding energy density (85.23 W h kg-1 at 960.31 W kg-1; 52.36 W h kg-1 at 17454.87 W kg-1), and persistent cycling life (98.86% initial capacitance retention after 10 000 cycles at 10 A g-1). This study emphasizes the device design of ZIC and promising prospects of using 3D DRGO hydrogel as a feasible positive electrode for ZIC.
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BACKGROUND: Hyperglycemia-induced vascular endothelial cell dysfunction is a major factor contributing to diabetic lower extremity ischemia. We intend to investigate the role of Dusp2 in hyperglycemia-induced vascular endothelial cell dysfunction and related mechanisms. METHODS: The human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG) as the cell model. Streptozotocin injection was performed to induce diabetes and femoral artery ligation was to induce hind limb ischemia in mice. The levels of Dusp2, p-p38 MAPK, E2F4, and p38 MAPK were evaluated by Western blot or quantitative real-time PCR. The laser Doppler perfusion imaging was conducted to measure blood flow recovery. The cell counting kit-8, transwell, and tube formation assay were performed to evaluate cell proliferation, migration, and angiogenesis, respectively. CD31 immunohistochemical staining was carried out to detect the capillary density of gastrocnemius. The dual-luciferase reporter gene assay and Chromatin immunoprecipitation assay were executed to explore the interaction between E2F4 and Dusp2. RESULTS: Dusp2 was highly expressed in HG-induced HUVECs and diabetic lower extremity ischemia model mice. Interference with Dusp2 promoted cell proliferation, migration, and angiogenesis, as well as alleviated mouse diabetic hindlimb ischemia. Dusp2 knockdown up-regulated p-p38 MAPK levels. We verified the binding between E2F4 and Dusp2. Overexpressing E2F4 suppressed Dusp2 levels and promoted cell proliferation, migration, and angiogenesis, co-overexpression of Dusp2 reversed the results. CONCLUSIONS: Overexpressing E2F4 promotes endothelial cell proliferation, migration, and angiogenesis by inhibiting Dusp2 expression and activating p38 MAPK to alleviate vascular endothelial cell dysfunction under HG stimulation.
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Hiperglucemia , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Humanos , Ratones , Células Cultivadas , Glucosa/farmacología , Glucosa/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Hiperglucemia/metabolismo , Isquemia/genética , Neovascularización Fisiológica , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Esculetin (ESC) is a coumarin-derived phytochemical prevalent in traditional Chinese medicine that exhibits anti-acute ischemic stroke activities. Our previous studies demonstrate that CKLF1 is a potential anti-stroke target for coumarin-derived compound. In this study we investigated whether CKLF1 was involved in the neuroprotective effects of ESC against photothrombotic stroke in mice. The mice were treated with ESC (20, 40 or 80 mg·kg-1·d-1, i.g.) for two weeks. The therapeutic effect of ESC was assessed using MRI, neurological function evaluation, and a range of behavioral tests on D1, 3, 7 and 14 of ESC administration. We showed that oral administration of ESC dose-dependently reduced the cerebral infarction volume within one week after stroke, improved behavioral performance, and alleviated neuropathological damage within two weeks. Functional MRI revealed that ESC significantly enhanced the abnormal low-frequency fluctuation (ALFF) value of the motor cortex and promoted functional connectivity between the supplementary motor area (SMA) and multiple brain regions. We demonstrated that ESC significantly reduced the protein levels of CKLF1 and CCR5, as well as the CKLF1/CCR5 protein complex in the peri-infarcted area. We showed that ESC (0.1-10 µM) dose-dependently blocked CKLF1-induced chemotactic movement of neutrophils in the Transwell assay, reducing the interaction of CKLF1/CCR5 on the surface of neutrophils, thereby reducing neutrophil infiltration, and decreasing the expression of ICAM-1, VCAM-1 and MMP-9 in the peri-infarct tissue. Knockout of CKLF1 reduced brain infarction volume and motor dysfunction after stroke but also negated the anti-stroke efficacy and neutrophil infiltration of ESC. These results suggest that the efficacy of ESC in promoting post-stroke neural repair depends on its inhibition on CKLF1-mediated neutrophil infiltration, which offering novel perspectives for elucidating the therapeutic properties of coumarins.
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BACKGROUND: Blood shortage is a global challenge, impacting elective surgeries with high bleeding risk. Predicting intraoperative blood use, optimizing resource allocation, and ensuring safe elective surgery are vital. This study targets identifying key bleeding risk factors in Aortic Valve Replacement (AVR) through machine learning. METHODS: Data from 702 AVR patients were split into 70% training and 30% test sets. Thirteen models predicted RBC transfusion. SHapley Additive exPlanations (SHAP) analyzed risk factors. RESULTS: Logistic Regression excelled, with Area Under Curve (AUC) 0.872 and 81.0% accuracy on the test set. Notably, female gender, Hemoglobin (HGB) < 131.91 g/L, Hematocrit (HCT) < 0.41L/L, weight < 59.49 kg, age > 54.47 year, Mean Corpuscular Hemoglobin (MCH) < 29.15 pg, Total Protein (TP) > 69.7 g/L, FIB > 2.61 g/L, height < 160 cm, and type of operation is Surgical Aortic Valve Replacement (SAVR) were significant RBC transfusion predictors. CONCLUSIONS: The study's model accurately forecasts AVR-related RBC transfusions. This informs presurgery blood preparations, reducing resource waste and aiding clinicians in optimizing patient care.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Humanos , Femenino , Válvula Aórtica/cirugía , Transfusión de Eritrocitos , Factores de Riesgo , Aprendizaje Automático , Estudios RetrospectivosRESUMEN
Mobile genetic elements such as phages and plasmids have evolved anti-CRISPR proteins (Acrs) to suppress CRISPR-Cas adaptive immune systems. Recently, several phage and non-phage derived Acrs including AcrIIA17 and AcrIIA18 have been reported to inhibit Cas9 through modulation of sgRNA. Here, we show that AcrIIA17 and AcrIIA18 inactivate Cas9 through distinct mechanisms. AcrIIA17 inhibits Cas9 activity through interference with Cas9-sgRNA binary complex formation. In contrast, AcrIIA18 induces the truncation of sgRNA in a Cas9-dependent manner, generating a shortened sgRNA incapable of triggering Cas9 activity. The crystal structure of AcrIIA18, combined with mutagenesis studies, reveals a crucial role of the N-terminal ß-hairpin in AcrIIA18 for sgRNA cleavage. The enzymatic inhibition mechanism of AcrIIA18 is different from those of the other reported type II Acrs. Our results add new insights into the mechanistic understanding of CRISPR-Cas9 inhibition by Acrs, and also provide valuable information in the designs of tools for conditional manipulation of CRISPR-Cas9.
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Bacteriófagos/genética , Sistemas CRISPR-Cas , Edición Génica/métodos , ARN Guía de Kinetoplastida/metabolismo , Proteínas Virales/metabolismoRESUMEN
BACKGROUND: Lip squamous cell carcinoma (LSCC) was one of the most common cancer types of head and neck tumors. This study aimed to find more predictors of the prognosis in postoperative LSCC patients. METHODS: A total of 147 LSCC patients between June 2012 and June 2018 were collected from two tertiary care institutions. There were 21 clinicopathological factors included and analyzed in our study. The univariate and multivariate Cox regression analyses were performed to find the independent prognostic factors for predicting progression-free survival (PFS) and overall survival (OS) in postoperative LSCC patients. The role of adjuvant radiotherapy in various subgroups was displayed by Kaplan-Meier plots. RESULTS: The 1-, 3-, and 5-year PFS of postoperative LSCC patients were 88.4%, 70.1%, and 57.8%, respectively. Similarly, the 1-, 3-, and 5-year OS of postoperative LSCC patients were 94.6%, 76.9%, and 69.4%, respectively. The results suggested that postoperative LSCC patients with age at diagnosis ≥ 70 years, grade with moderate or poor differentiate, the American Joint Committee on Cancer (AJCC) stage IV, higher systemic immune-inflammation index (SII), surgical margin < 5, and age-adjusted Charlson Comorbidity Index (ACCI) ≥ 5 tend to have a poorer PFS (all P < 0.05). Besides, postoperative LSCC patients with age at diagnosis ≥ 70 years, AJCC stage IV, higher GPS, higher SII, and ACCI ≥ 5 tend to have a worse OS (all P < 0.05). Additionally, postoperative patients with LSCC in the subgroup of ACCI < 5 and AJCC III-IV stage was more likely to benefit from adjuvant radiotherapy, but not for the other subgroups. CONCLUSION: We identified a series of significant immune-inflammation-related and comorbidity-related clinicopathological factors associated with the prognosis of postoperative LSCC patients by local data from two tertiary care institutions in China, which can be helpful for patients and surgeons to pay more attention to nutrition, inflammation, and complications and finally obtained a better prognosis.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Laríngeas , Humanos , Anciano , Pronóstico , Labio , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Inflamación , Neoplasias Laríngeas/patología , Estudios RetrospectivosRESUMEN
The responses of patients to tumor therapies vary due to tumor heterogeneity. Tumor stratification has been attracting increasing attention for accurately distinguishing between responders to treatment and non-responders. Nanoprobes with unique physical and chemical properties have great potential for patient stratification. This review begins by describing the features and design principles of nanoprobes that can visualize specific cell types and biomarkers and release inflammatory factors during or before tumor treatment. Then, we focus on the recent advancements in using nanoprobes to stratify various therapeutic modalities, including chemotherapy, radiotherapy (RT), photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), ferroptosis, and immunotherapy. The main challenges and perspectives of nanoprobes in cancer stratification are also discussed to facilitate probe development and clinical applications.
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Ferroptosis , Neoplasias , Fotoquimioterapia , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Inmunoterapia , Imagen MolecularRESUMEN
BACKGROUND: Parotid gland carcinoma (PGC) is a rare malignant tumor. The purpose of this study was to investigate the role of immune-inflammatory-nutrition indicators and age-adjusted Charlson comorbidity index score (ACCI) of PGC and develop the nomogram model for predicting prognosis. METHOD: All patients diagnosed with PGC in two tertiary hospitals, treated with surgical resection, from March 2012 to June 2018 were obtained. Potential prognostic factors were identified by univariate and multivariate Cox regression analyses. The nomogram models were established based on these identified independent prognostic factors. The performance of the developed prognostic model was estimated by related indexes and plots. RESULT: The study population consisted of 344 patients with PGC who underwent surgical resection, 285 patients without smoking (82.8%), and 225 patients (65.4%) with mucoepidermoid carcinoma, with a median age of 50.0 years. American Joint Committee on Cancer (AJCC) stage (p < 0.001), pathology (p = 0.019), tumor location (p < 0.001), extranodal extension (ENE) (p < 0.001), systemic immune-inflammation index (SII) (p = 0.004), prognostic nutrition index (PNI) (p = 0.003), ACCI (p < 0.001), and Glasgow prognostic Score (GPS) (p = 0.001) were independent indicators for disease free survival (DFS). Additionally, the independent prognostic factors for overall survival (OS) including AJCC stage (p = 0.015), pathology (p = 0.004), tumor location (p < 0.001), perineural invasion (p = 0.009), ENE (p < 0.001), systemic immune-inflammation index (SII) (p = 0.001), PNI (p = 0.001), ACCI (p = 0.003), and GPS (p = 0.033). The nomogram models for predicting DFS and OS in PGC patients were generated based on these independent risk factors. All nomogram models show good discriminative capability with area under curves (AUCs) over 0.8 (DFS 0.802, and OS 0.825, respectively). Decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) show good clinical net benefit of the two nomograms in both training and validation cohorts. Kaplan-Meier survival analyses showed superior discrimination of DFS and OS in the new risk stratification system compared with the AJCC stage system. Finally, postoperative patients with PGC who underwent adjuvant radiotherapy had a better prognosis in the high-, and medium-risk subgroups (p < 0.05), but not for the low-risk subgroup. CONCLUSION: The immune-inflammatory-nutrition indicators and ACCI played an important role in both DFS and OS of PGC patients. Adjuvant radiotherapy had no benefit in the low-risk subgroup for PGC patients who underwent surgical resection. The newly established nomogram models perform well and can provide an individualized prognostic reference, which may be helpful for patients and surgeons in proper follow-up strategies.
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Nomogramas , Neoplasias de la Parótida , Humanos , Masculino , Persona de Mediana Edad , Femenino , Neoplasias de la Parótida/cirugía , Neoplasias de la Parótida/patología , Pronóstico , Anciano , Adulto , Comorbilidad , Estudios Retrospectivos , Inflamación , Factores de EdadRESUMEN
Drought stress significantly affects cotton's net photosynthetic rate (A) by restraining stomatal (gs ) and mesophyll conductance (gm ) as well as perturbing its biochemical process, resulting in yield reductions. Despite the significant progress in dissecting effects of drought on photosynthesis, the variability observed in cotton's gm , and the mechanisms contributing to that variability under dynamic drought stress conditions are poorly understood. For that reason, a controlled-environment experiment with two cotton genotypes (Dexiamian 1, Yuzaomian 9110), three water levels (soil relative water content: control [75 ± 5]%, moderate drought [60 ± 5]%, severe drought [45 ± 5]%), and two drought durations (10 and 31 days) were conducted. The results indicated that the cotton boll biomass was significantly decreased under 10-day severe drought and 31-day moderate and severe drought. Decreases in gs were later accompanied by decreases in gm and further combined with reductions in electron transport rate, as drought stress progressed in duration and severity, ultimately resulting in significant reductions in A of subtending leaf. Stomatal and mesophyll conductance constraints were the primary factors limiting photosynthesis, while biochemical constraints decreased, as drought stress progressed. Considering gm , its decline was ascribed to increases in the diffusion resistance of CO2 through cytoplasm (rcyt ), under short- or long-term drought, as well as to increases in leaf dry mass (LMA), and decreases in the chloroplast surface area exposed to intercellular air space (Sc /S), under long-term drought. It was concluded that A could be enhanced, under dynamic drought stress conditions, by increasing gm through increasing Sc /S and reducing LMA and rcyt .
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Sequías , Hojas de la Planta , Dióxido de Carbono , Cloroplastos , Células del Mesófilo , Fotosíntesis , AguaRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. METHODS: VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. RESULTS: We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. CONCLUSIONS: Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.
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Permeabilidad Capilar , Hipertensión Pulmonar , Factor A de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Animales , Ratones , Permeabilidad Capilar/fisiología , Células Endoteliales/metabolismo , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipoxia/complicaciones , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Acute kidney injury (AKI) is a common clinical problem and an efficacious treatment is lacking. Ferroptosis, a newly discovered type of programmed cell death, has been reported to alleviate renal tubular injury in ischemia/reperfusion-induced acute kidney injury (I/R-AKI). Entacapone is a specific inhibitor of catechol-O-methyltransferase, which is used as an adjuvant drug against Parkinson's disease. We demonstrated that entacapone prevents renal I/R injury by inhibiting ferroptosis. Compared with a sham group, entacapone treatment mitigated I/R-induced pathological alterations, improved renal function, and inhibited ferroptosis. In HK-2 cells, entacapone treatment significantly reduced the lipid peroxidation and iron accumulation induced by the ferroptosis inducers erastin and RSL3, and significantly regulated expression of ferroptosis-related proteins. Entacapone upregulates p62 expression and affects the p62-KEAP1-NRF2 pathway, thereby upregulating nuclear translocation of NRF2. This action results in increased expression of the downstream SLC7A11, and significant suppression of oxidative stress and ferroptosis. Our results identify entacapone as a ferroptosis inhibitor that enhances antioxidant capacity. Entacapone may serve as a novel strategy to improve treatment of, and recovery from, I/R-AKI.
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Lesión Renal Aguda , Ferroptosis , Daño por Reperfusión , Lesión Renal Aguda/metabolismo , Catecol O-Metiltransferasa/metabolismo , Catecol O-Metiltransferasa/uso terapéutico , Catecoles , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Nitrilos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismoRESUMEN
Sugar and nitrogen metabolisms help plants maintain cellular homeostasis, stress tolerance, and sustainable growth in drought conditions. Melatonin, a potent antioxidant and signaling molecule, appears to mitigate the negative impacts of drought on plants. This study aimed to investigate the potential role of foliar-applied melatonin in ameliorating drought-induced alterations in leaf sugar and nitrogen metabolisms' enzyme activities during cotton flowering and boll formation. To date, no study has examined drought-induced sugar and nitrogen metabolisms' enzyme activity changes in cotton treated with foliar melatonin. Drought levels (FC1 = 75 ± 5%, FC2 = 60 ± 5%, and FC3 = 45 ± 5%) were maintained between 3 and 35 days after flowering (DAF), and melatonin (M) concentrations (0, 25, 50, and 100 µmol L-1 ) were applied at 3 and 21 DAF in a completely randomized design. M100 concentrations at low FC levels significantly enhanced leaf sugar and N-metabolic enzyme activities, such as sucrose synthase (65.56%) and glutamine synthetase (55.24%), compared to plants not treated with melatonin; peaking between 7 and 21 DAF and declining gradually with crop growth. Moreover, the M100 concentrations at all FC levels, particularly FC3, significantly increased the relative expression of GhSusB, GhSusC, SPS1, and SPS3 genes, indicating that melatonin improves leaf sugar and N-metabolism enzymatic activities under drought stress. Therefore, applying M100 concentrations to cotton foliage under FC3 conditions during reproductive stages improves leaf water status, sugar, and N-metabolism enzyme activities, demonstrating melatonin's potent anti-stress, osmoregulatory, and growth-promoting properties in overcoming drought stress in cotton crops. Future research into the molecular mechanisms of melatonin-mediated sugar and nitrogen metabolism enzyme activities in cotton leaves may lead to biotechnological methods to improve drought resilience in cotton and other crops.
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Melatonina , Melatonina/farmacología , Azúcares , Sequías , Carbohidratos , Hojas de la Planta , NitrógenoRESUMEN
BACKGROUND: Conventional right ventricular pacing combined with coronary venous pacing (CVP) is a mainstay for cardiac resynchronization therapy (CRT). However, QRS duration of conventional CRT may be frequently more than 130 ms. This study aimed to evaluate the effectiveness of QRS narrowing by bilateral septal pacing (BSP) in combination with CVP for CRT (BSP-CRT). METHODS: Fourteen patients with QRS > 130 ms of conventional CRT after failure of physiological conduction system pacing were enrolled. Electrophysiologic characteristics were compared among different modes of CRT during procedure. BSP which was defined as capture of both sides of interventricular septum manifested as shortened R wave peak time without a right bundle branch block QRS pattern. RESULTS: BSP-CRT were successfully achieved in 85.7% (12/14) patients. QRS duration at baseline was 185 ± 13 ms and significantly narrowed to 156 ± 9 ms during conventional CRT (n = 14, P < .001), to 143 ± 7 ms during left ventricular septal pacing (LVSP) in combination with CVP for CRT (LVSP-CRT) (n = 9, P < .001), and further to 122 ± 10 ms during BSP-CRT (n = 12, P < .001). Notably, among 7 patients in whom both LVSP and BSP were achieved, BSP-CRT outperformed LVSP-CRT at QRS narrowing by 16% (P < .001). At 3-month follow-up, left ventricular ejection fraction improved from 29 ± 6% to 41 ± 8% (P < .001). CONCLUSIONS: BSP-CRT resulted in superior acute electrical synchronization to conventional CRT and might be considered as an alternative to conventional CRT with QRS more than 130 ms.
Asunto(s)
Terapia de Resincronización Cardíaca , Insuficiencia Cardíaca , Humanos , Terapia de Resincronización Cardíaca/métodos , Electrocardiografía/métodos , Insuficiencia Cardíaca/terapia , Volumen Sistólico , Resultado del Tratamiento , Función Ventricular Izquierda , Tabiques Cardíacos , Vasos CoronariosRESUMEN
OBJECTIVES: Pseudomonas aeruginosa has intrinsic antibiotic resistance and the strong ability to acquire additional resistance genes. However, a limited number of investigations provide detailed modular structure dissection and evolutionary analysis of accessory genetic elements (AGEs) and associated resistance genes (ARGs) in P. aeruginosa isolates. The objective of this study is to reveal the prevalence and transmission characteristics of ARGs by epidemiological investigation and bioinformatics analysis of AGEs of P. aeruginosa isolates taken from a Chinese hospital. METHODS: Draft-genome sequencing was conducted for P. aeruginosa clinical isolates (n = 48) collected from a single Chinese hospital between 2019 and 2021. The clones of P. aeruginosa isolates, type 3 secretion system (T3SS)-related virulotypes, and the resistance spectrum were identified using multilocus sequence typing (MLST), polymerase chain reaction (PCR), and antimicrobial susceptibility tests. In addition, 17 of the 48 isolates were fully sequenced. An extensive modular structure dissection and genetic comparison was applied to AGEs of the 17 sequenced P. aeruginosa isolates. RESULTS: From the draft-genome sequencing, 13 STs were identified, showing high genetic diversity. BLAST search and PCR detection of T3SS genes (exoT, exoY, exoS, and exoU) revealed that the exoS+/exoU- virulotype dominated. At least 69 kinds of acquired ARGs, involved in resistance to 10 different categories of antimicrobials, were identified in the 48 P. aeruginosa isolates. Detailed genetic dissection and sequence comparisons were applied to 25 AGEs from the 17 isolates, together with five additional prototype AGEs from GenBank. These 30 AGEs were classified into five groups -- integrative and conjugative elements (ICEs), unit transposons, IncpPBL16 plasmids, Incp60512-IMP plasmids, and IncpPA7790 plasmids. CONCLUSION: This study provides a broad-scale and deeper genomics understanding of P. aeruginosa isolates taken from a single Chinese hospital. The isolates collected are characterized by high genetic diversity, high virulence, and multiple drug resistance. The AGEs in P. aeruginosa chromosomes and plasmids, as important genetic platforms for the spread of ARGs, contribute to enhancing the adaptability of P. aeruginosa in hospital settings.