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The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.
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Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Células A549 , Animales , Niño , Preescolar , Femenino , Mutación con Ganancia de Función/genética , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones , Células Madre Embrionarias de Ratones , Mutación/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Transducción de Señal , Dominios Homologos src/genéticaRESUMEN
Infants have a higher risk of developing allergic asthma than adults. However, the underlying mechanism remains unknown. We show here that sensitization of mice with house-dust mites (HDMs) in the presence of low-dose lipopolysaccharide (LPS) prevented T helper 2 (Th2) cell allergic responses in adult, but not infant, mice. Mechanistically, adult CD11b+ migratory dendritic cells (mDCs) upregulated the transcription factor T-bet in response to tumor necrosis factor-α (TNF-α), which was rapidly induced after HDM + LPS sensitization. Consequently, adult CD11b+ mDCs produced interleukin-12 (IL-12), which prevented Th2 cell development by promoting T-bet upregulation in responding T cells. Conversely, infants failed to induce TNF-α after HDM + LPS sensitization. Therefore, CD11b+ mDCs failed to upregulate T-bet and did not secrete IL-12 and Th2 cell responses normally developed in infant mice. Thus, the availability of TNF-α dictates the ability of CD11b+ mDCs to suppress allergic Th2-cell responses upon dose-dependent endotoxin sensitization and is a key mediator governing susceptibility to allergic airway inflammation in infant mice.
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Células Dendríticas/fisiología , Hipersensibilidad/inmunología , Inflamación/inmunología , Células Th2/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Adulto , Animales , Animales Recién Nacidos , Antígenos Dermatofagoides , Diferenciación Celular , Humanos , Inmunización , Lactante , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pyroglyphidae/inmunología , Proteínas de Dominio T Box/metabolismoRESUMEN
We assessed the mechanisms by which nonencapsulated heme, released in the plasma of mice after exposure to chlorine (Cl2) gas, resulted in the initiation and propagation of acute lung injury. We exposed adult male and female C57BL/6 mice to Cl2 (500 ppm for 30 min), returned them to room air, and injected them intramuscularly with either human hemopexin (hHPX; 5 µg/g BW in 50-µL saline) or vehicle at 1 h post-exposure. Upon return to room air, Cl2-exposed mice, injected with vehicle, developed respiratory acidosis, increased concentrations of plasma proteins in the alveolar space, lung mitochondrial DNA injury, increased levels of free plasma heme, and major alterations of their lung proteome. hHPX injection mice mitigated the onset and development of lung and mitochondrial injury and the increase of plasma heme, reversed the Cl2-induced changes in 83 of 237 proteins in the lung proteome at 24 h post-exposure, and improved survival at 15 days post-exposure. Systems biology analysis of the lung global proteomics data showed that hHPX reversed changes in a number of key pathways including elF2 signaling, verified by Western blotting measurements. Recombinant human hemopexin, generated in tobacco plants, injected at 1 h post-Cl2 exposure, was equally effective in reversing acute lung and mtDNA injury. The results of this study offer new insights as to the mechanisms by which exposure to Cl2 results in acute lung injury and the therapeutic effects of hemopexin.NEW & NOTEWORTHY Herein, we demonstrate that exposure of mice to chlorine gas causes significant changes in the lung proteome 24 h post-exposure. Systems biology analysis of the proteomic data is consistent with damage to mitochondria and activation of eIF2, the master regulator of transcription and protein translation. Post-exposure injection of hemopexin, which scavenges free heme, attenuated mtDNA injury, eIF2α phosphorylation, decreased lung injury, and increased survival.
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Lesión Pulmonar Aguda , Cloro , Animales , Ratones , Lesión Pulmonar Aguda/metabolismo , Cloro/efectos adversos , Cloro/metabolismo , ADN Mitocondrial/metabolismo , Hemo , Hemopexina , Pulmón/metabolismo , Ratones Endogámicos C57BL , Mitocondrias , Proteoma/metabolismo , ProteómicaRESUMEN
Lithium-sulfur batteries have garnered significant attention as a promising next-generation battery technology due to their potential for high energy density. However, their practical application is hampered by slow reaction kinetics and the shuttle effect of lithium polysulfide intermediates. In this context, the authors introduce a pioneering solution in the form of a novel porous carbon nanostructure modified with samarium oxide, denoted as Sm2O3/KB. The material has a highly polar surface, allowing lithium polysulfide to be chemisorbed efficiently. The unsaturated sites provided by the oxygen vacancies of Sm2O3 promote Li2S nucleation, lowering the reaction energy barrier and accelerating Li2S dissolution. The porous structure of Ketjen Black provides a highly conductive channel for electron transport and effectively traps polysulfides. Meanwhile, the batteries with Sm2O3/KB/PP spacers exhibited remarkable electrochemical performances, including a low-capacity decay rate of only 0.046 % for 1000 cycles at 2â C and an excellent multiplicative performance of 624â mAh g-1 at 3â C. This work opens up a new avenue for the potential use of rare-earth-based materials in lithium-sulfur batteries.
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SIGNIFICANCE STATEMENT: African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. BACKGROUND: African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. METHODS: We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. RESULTS: In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. CONCLUSIONS: APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.
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Apolipoproteína L1 , Salud Poblacional , Insuficiencia Renal Crónica , Humanos , Apolipoproteína L1/genética , Apolipoproteínas/genética , Estudios Transversales , Predisposición Genética a la Enfermedad , Genotipo , Canales Iónicos/genética , Insuficiencia Renal Crónica/genética , Negro o Afroamericano/genéticaRESUMEN
Unraveling the chirality transfer mechanism of polymer assemblies and controlling their handedness is beneficial for exploring the origin of hierarchical chirality and developing smart materials with desired chiroptical activities. However, polydisperse polymers often lead to an ambiguous or statistical evaluation of the structure-property relationship, and it remains unclear how the iterative number of repeating units function in the helicity inversion of polymer assemblies. Herein, we report the macroscopic helicity and dynamic manipulation of the chiroptical activity of supramolecular assemblies from discrete azobenzene-containing oligomers (azooligomers), together with the helicity inversion and morphological transition achieved solely by changing the iterative chain lengths. The corresponding assemblies also differ from their polydisperse counterparts in terms of thermodynamic properties, chiroptical activities, and morphological control.
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Breast cancer is the globally most common malignant tumor and the biggest threat to women. Even though the diagnosis and treatment of breast cancer are progressing continually, a large number of breast cancer patients eventually develop a metastatic tumor, especially triple-negative breast cancer (TNBC). Recently, metal ion homeostasis and ion signaling pathway have become important targets for cancer therapy. In this study, We analyzed the effects and mechanisms of isopimaric acid (IPA), an ion channel regulator, on the proliferation and metastasis of breast cancer cells (4 T1, MDA-MB-231and MCF-7) by cell functional assay, flow cytometry, western blot, proteomics and other techniques in vitro and in vivo. Results found that IPA significantly inhibited the proliferation and metastasis of breast cancer cells (especially 4 T1). Further studies on the anti-tumor mechanism of IPA suggested that IPA might affect EMT and Wnt signaling pathways by targeting mitochondria oxidative phosphorylation and Ca2+ signaling pathways, and then inducing breast cancer cell cycle arrest and apoptosis. Our research reveals the therapeutic value of IPA in breast cancer and provides a theoretical basis for the new treatment of breast cancer.
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Calcio , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Calcio/metabolismo , Fosforilación Oxidativa , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Vía de Señalización Wnt , Proliferación Celular , Canales Iónicos/metabolismo , Línea Celular Tumoral , Apoptosis , Movimiento CelularRESUMEN
OBJECTIVES: Lung adenocarcinoma (LUAD) exhibits a higher fatality rate among all cancer types worldwide, yet the precise mechanisms underlying its initiation and progression remain unknown. Mounting evidence suggests that long non-coding RNAs (lncRNAs) exert significant regulatory roles in cancer development and progression. Nevertheless, the precise involvement of lncRNA CYP4A22-AS1 in LUAD remains incompletely comprehended. METHODS: Bioinformatics analyses evaluated the expression level of CYP4A22-AS1 in lung adenocarcinoma and paracancer. The LUAD cell line with a high expression of CYP4A22-AS1 was constructed to evaluate the role of CYP4A22-AS1 in the proliferation and metastasis of LUAD by CCK8, scratch healing, transwell assays, and animal experiments. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. Luciferase reporter gene analyses, west-blotting, and qRT-PCR were carried out to reveal the interaction between CYP4A22-AS1, miR-205-5p/EREG, and miR-34c-5p/BCL-2 axes. RESULTS: CYP4A22-AS1 expression was significantly higher in LUAD tissues than in the adjacent tissues. Furthermore, we constructed a LUAD cell line with a high expression of CYP4A22-AS1 and noted that the high expression of CYP4A22-AS1 significantly enhanced the proliferation and metastasis of LUAD. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. CYP4A22-AS1 increased the expression of EREG and BCL-2 by reducing the expression of miR-205-5p and miR-34-5p and activating the downstream signaling pathway of EGFR and the anti-apoptotic signaling pathway of BCL-2, thereby triggering the proliferation and metastasis of LUAD. The transfection of miR-205-5p and miR-34-5p mimics inhibited the role of CYP4A22-AS1 in enhancing tumor progression. CONCLUSION: This study elucidates the molecular mechanism whereby CYP4A22-AS1 overexpression promotes LUAD progression through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.
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Moisture content is an important parameter for estimating the quality of pellet feed, which is vital in nutrition, storage, and taste. The ranges of moisture content serve as an index for factors such as safe storage and nutrition stability. A rapid and non-destructive model for the measurement of moisture content in pellet feed was developed. To achieve this, 144 samples of Caragana korshinskii pellet feed from various regions in Inner Mongolia Autonomous Region underwent separate moisture content control, measurement using standard methods, and captured their images using a hyperspectral imaging (HSI) system in the spectral range of 935.5-2539 nm. The Monte Carlo cross validation (MCCV) was used to eliminate abnormal sample data from the spectral data for better model accuracy, and a global model of moisture content was built by using partial least squares regression (PLSR) with seven preprocessing techniques and two spectral feature extraction techniques. The results showed that the regression model developed by PLSR based on second derivative (SD) and competitive adaptive reweighted sampling (CARS) resulted in better performance for moisture content. The model showed predictive abilities for moisture content with a coefficient of determination of 0.9075 and a root mean square error (RMSE) of 0.4828 for the training set; and a coefficient of determination of 0.907 and a root mean square error (RMSE) of 0.5267 for the test set; and a relative prediction error of 3.3 and the standard error of 0.307.
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Caragana , Imágenes Hiperespectrales , China , Método de Montecarlo , Estado NutricionalRESUMEN
In recent years, molecular perovskite energetic materials have attracted more attention because of their simple synthesis processes, high thermal stabilities, excellent performances, and great significance as a design platform for energetic materials. To explore the possibility of the application of molecular perovskite energetic materials in heat-resistant explosives, four silver(I)-based molecular perovskite energetic compounds, (H2A)[Ag(ClO4)3], where H2A = piperazine-1,4-diium (H2pz2+) for PAP-5, 1-methyl-piperazine-1,4-diium (H2mpz2+) for PAP-M5, homopiperazine-1,4-diium (H2hpz2+) for PAP-H5, and 1,4-diazabicyclo[2.2.2]octane-1,4-diium (H2dabco2+) for DAP-5, were synthesized by a one-pot self-assembly strategy and structurally characterized. The single-crystal structures indicated that PAP-5, PAP-M5, and DAP-5 possess cubic perovskite structures while PAP-H5 possesses a hexagonal perovskite structure. Differential thermal analyses showed that their onset decomposition temperatures are >308.3 °C. For PAP-5 and DAP-5, they have not only exceptional calculated detonation parameters (D values of 8.961 and 8.534 km s-1 and P values of 42.4 and 37.9 GPa, respectively) but also the proper mechanical sensitivity (impact sensitivities of ≤10 J for PAP-5 and 3 J for DAP-5 and friction sensitivities of ≤5N for both PAP-5 and DAP-5) and thus are of interest as potential heat-resistant primary explosive components.
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External obstacle detection is a significant task in transmission line inspection and is related to the safe operation of the power transmission grid. In recent years, unmanned aerial vehicles (UAVs) equipped with different devices have been widely used for transmission line inspection. However, because of the complex environment of transmission lines and weak power line textures in the obtained images, most existing methods and systems cannot meet the requirements for real-time and high-accuracy external obstacle detection of transmission lines. In this paper, a novel, to the best of our knowledge, UAV system integrated trinocular vision technology with remote sensing is developed to achieve better external obstacle detection of transmission lines in real time, which is composed of a DJ-Innovations (DJI) UAV equipped with a global positioning system (GPS), angle sensors, trinocular vision including three visible cameras with the same parameters, and a small processor with a pre-implanted software algorithm. In this paper, a new method for external obstacle detection of transmission lines is proposed to satisfy the requirements for real-time and high-accuracy practical inspection applications. First, the original trinocular images need to be rectified. Then, the rectified trinocular images are adopted to achieve three-dimensional reconstruction of power lines. Finally, based on trinocular vision, bag of feature, and GPS, the clearance distance measurement, obstacle classification, and obstacle location are realized. Experimental tests on 220 kV transmission lines reveal that our proposed system can be applied in practical inspection environments and has good performance.
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PURPOSE: The objective of this study was to investigate the efficacy of zolpidem for improving post-operative sleep quality among patients with infective endocarditis (IE) and to identify the potential risk factors for impaired sleep quality at 6 months after surgery. METHODS: Patients with IE who underwent surgical treatment were divided into two groups according to zolpidem usage. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to evaluate patients' sleep quality and daytime sleepiness at baseline, which was the second day after transferal, and at 6 months after surgery. Logistic regression was used to identify potential risk factors. RESULTS: There were 32 patients in the zolpidem group and 42 in the control group. The PSQI and ESS scores at 6 months after surgery were significantly lower than those at baseline in both groups (P = 0.04). Additionally, 9 patients (28%) in the zolpidem group and 22 patients (52%) in the control group suffered poor sleep quality. Multivariate analysis identified age (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 1.12-1.42), baseline PSQI score (OR = 2.66, 95%CI: 1.55-4.65), and no zolpidem usage (OR = 45.48, 95%CI: 3.01-691.23) as independent factors for poor sleep quality. CONCLUSIONS: Poor sleep quality after IE surgery was prevalent among patients even 6 months after IE surgery. Age, baseline PSQI score and no zolpidem usage were independently associated with poor sleep quality. Therefore, zolpidem has the potential to be an effective part of a treatment arsenal for poor sleep quality after surgical treatment for IE.
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Trastornos de Somnolencia Excesiva , Endocarditis , Trastornos del Inicio y del Mantenimiento del Sueño , Trastornos del Sueño-Vigilia , Humanos , Sueño , Calidad del Sueño , ZolpidemRESUMEN
Protein signaling complexes play important roles in prevention of several cancer types and can be used for development of targeted therapy. The roles of signaling complexes of phosphodiesterase 3B (PDE3B) and Rap guanine nucleotide exchange factor 3 (RAPGEF3), which are two important enzymes of cyclic adenosine monophosphate (cAMP) metabolism, in cancer have not been fully explored. In the current study, a natural product Kaempferol-3-O-(3'',4''-di-E-p-coumaroyl)-α-L-rhamnopyranoside designated as KOLR was extracted from Cinnamomum pauciflorum Nees leaves. KOLR exhibited higher cytotoxic effects against BxCP-3 pancreatic cancer cell line. In BxPC-3 cells, the KOLR could enhance the formation of RAPGEF 3/ PDE3B protein complex to inhibit the activation of Rap-1 and PI3K-AKT pathway, thereby promoting cell apoptosis and inhibiting cell metastasis. Mutation of RAPGEF3 G557A or low expression of PDE3B inactivated the binding action of KOLR resulting in KOLR resistance. The findings of this study show that PDE3B/RAPGEF3 complex is a potential therapeutic cancer target.
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Cinnamomum , Fosfatidilinositol 3-Quinasas , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Hojas de la Planta/metabolismoRESUMEN
Wuhan was the first large city where the initial breakout of COVID-19 took numerous lives. A group of social workers and mental health specialists coordinated the "Be Together Program" (BTP), a psychosocial grief intervention program to help a group of Wuhan COVID-19 bereaved people. Under the Dual-process model framework, BTP used the internet and social media as the main tools, combined with group and individual intervention. Additionally, it employed a "Supermarket Mode" with abundant intervention themes and approaches for BTP participants to choose according to their special needs. Additionally, Chinese cultural elements are integrated into the program. At the end of the program, the grief scores of participants in the qualified sample reduced significantly, and the prevalence of the potential Prolonged Grief Disorder diagnosis reduced from 75% to 12%. The study also found that the BTP was especially effective for those who had high levels of grief reaction.
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The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.
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Sustitución de Aminoácidos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Secuencia de Aminoácidos , Dominio Catalítico , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Proteína Tirosina Fosfatasa no Receptora Tipo 11/química , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismoRESUMEN
Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. nonfungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils, and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α, and IL-1ß), neutrophil survival factors (granulocyte colony-stimulating factor), and neutrophil-targeting chemokines (CCL3 and CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5 and IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ and CXCL9) and survival factors (macrophage colony-stimulating factor). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T-cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a nonclassical immunoregulatory mechanism.
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Asma/inmunología , Quimiocina CX3CL1/inmunología , Hongos/inmunología , Pulmón/inmunología , Animales , Asma/genética , Asma/microbiología , Asma/patología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/microbiología , Quimiocina CX3CL1/genética , Eosinófilos/inmunología , Eosinófilos/patología , Femenino , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones , Ratones NoqueadosRESUMEN
The rapid, accurate and noninvasive detection of biomass and plant cell browning can provide timely feedback on cell growth in plant cell culture. In this study, Siraitia grosvenorii suspension cells were taken as an example, a phenotype analysis platform was successfully developed to predict the biomass and the degree of cell browning based on the color changes of cells in computer-aided vision technology. First, a self-made laboratory system was established to obtain images. Then, matrices were prepared from digital images by a self-developed high-throughput image processing tool. Finally, classification models were used to judge different cell types, and then a semi-supervised classification to predict different degrees of cell browning. Meanwhile, regression models were developed to predict the plant cell mass. All models were verified with a good agreement by biological experiments. Therefore, this method can be applied for low-cost biomass estimation and browning degree quantification in plant cell culture.
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Técnicas de Cultivo de Célula , Cucurbitaceae/citología , Cucurbitaceae/metabolismo , Procesamiento de Imagen Asistido por Computador , Aprendizaje Automático , Células Vegetales/metabolismoRESUMEN
BACKGROUND The aim of this study was to measure sleep quality among patients who underwent infective endocarditis (IE) surgery and identify the risk factors involved in sleep disorders. MATERIAL AND METHODS In this study, we used actigraphy, the Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleep Scale (ESS) to determine the clinical characteristics of sleep disorders in 116 patients with IE who were in rehabilitation after surgery. RESULTS Our results showed that 46 (39.7%) patients had sleep efficiency over 85%, while 70 (60.3%) patients had sleep efficiency below 85%. The correlation analysis showed that sleep efficiency was related to the duration of the disease, with a longer duration leading to lower sleep efficiency (P=0.031). The sleep efficiency of patients with IE following surgery was also affected by alcohol consumption; however, surprisingly, patients with "heavy" alcohol consumption had higher sleep efficiency (P=0.030). We found a significant correlation between sleep efficiency and postoperative interleukin-6 (IL) levels, C-reactive protein (CRP) levels, and preoperative erythrocyte sedimentation rate (P<0.05). No significant correlation was found between brain natriuretic peptide levels and sleep efficiency, PSQI score, or ESS score. Postoperative hemoglobin (Hb) level was associated with sleep efficiency (R=0.194, P=0.036), but there was no statistically significant correlation between the PSQI and ESS scores. Postoperative alanine transaminase (ALT) showed a significant negative correlation with sleep efficiency (R=-0.27, P=0.003). CONCLUSIONS We found a high prevalence of sleep disorders in patients with IE along with an increase in inflammatory factors, including postoperative IL-6, CRP, ALT, and Hb levels.
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Válvula Aórtica/cirugía , Cateterismo Cardíaco/efectos adversos , Endocarditis/cirugía , Prótesis Valvulares Cardíacas/efectos adversos , Complicaciones Posoperatorias/patología , Trastornos del Sueño-Vigilia/patología , Adulto , Válvula Aórtica/lesiones , Endocarditis/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Trastornos del Sueño-Vigilia/etiología , Encuestas y CuestionariosRESUMEN
We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization (Vm Air: 62 ± 3 mV; 3 h post Br2:-45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.
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Bloqueadores de los Canales de Calcio/farmacología , Calcio/metabolismo , Ácido Hialurónico/farmacología , Músculo Liso/efectos de los fármacos , Receptores Sensibles al Calcio/metabolismo , Hipersensibilidad Respiratoria/tratamiento farmacológico , Viscosuplementos/farmacología , Animales , Bromo/toxicidad , Células Cultivadas , Cloruros/toxicidad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Peso Molecular , Músculo Liso/metabolismo , Receptores Sensibles al Calcio/antagonistas & inhibidores , Receptores Sensibles al Calcio/genética , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patologíaRESUMEN
Recent studies have indicated that Macrophage migration inhibitory factor (MIF) plays an important role in the prevention and treatment of asthma. However the role of MIF in airway inflammation and airway epithelial barrier disruption in house dust mite (HDM)-induced asthma has not been addressed. We hypothesized that MIF contributed to HDM-induced the production of Th2-associated cytokines and E-cadherin dysfunction in asthmatic mice and 16HBE cells. In vivo, a HDM-induced asthma mouse model was set up and mice treated with MIF antagonist ISO-1 after HDM. The mice treated with the ISO-1 ameliorated airway hyper-reactivity, airway inflammation, increased serum IgE levels, the aberrant arrangement of E-cadherin as well as the release of Th2 cytokines induced by HDM. In vitro, the exposure of 16HBE cells to HDM and rhMIF resulted in airway epithelial barrier disruption, inflammatory cytokine production and enhanced glycolytic flux. While these changes were attenuated by MIF siRNA treatment. Sequentially, treatment of 16HBE cells with PFKFB3 antagonist PFK15 significantly lowered rhMIF-induced these changes in 16HBE cells. Therefore, these results indicate that MIF may be an important contributor in airway inflammation and airway epithelial barrier disruption of HDM-induced asthma. Moreover, HDM specifically induces airway inflammation and airway epithelial barrier disruption of 16HBE cells through MIF-mediated enhancement of aerobic glycolysis.