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BACKGROUND AIMS: Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary ducts. Current CCA diagnostic and prognostic assessments cannot satisfy the clinical requirement. Bile detection is rarely performed, and herein, we aim to estimate the clinical significance of bile liquid biopsy by assessing bile exosomal concentrations and components. APPROACH RESULTS: Exosomes in bile and sera from CCA, pancreatic cancer, and common bile duct stone were identified and quantified by transmission electronmicroscopy, nanoparticle tracking analysis, and nanoFCM. Exosomal components were assessed by liquid chromatography with tandem mass spectrometry and microRNA sequencing (miRNA-seq). Bile exosomal concentration in different diseases had no significant difference, but miR-182-5p and miR-183-5p were ectopically upregulated in CCA bile exosomes. High miR-182/183-5p in both CCA tissues and bile indicates a poor prognosis. Bile exosomal miR-182/183-5p is secreted by CCA cells and can be absorbed by biliary epithelium or CCA cells. With xenografts in humanized mice, we showed that bile exosomal miR-182/183-5p promotes CCA proliferation, invasion, and epithelial-mesenchymal transition (EMT) by targeting hydroxyprostaglandin dehydrogenase in CCA cells and mast cells (MCs), and increasing prostaglandin E2 generation, which stimulates PTGER1 and increases CCA stemness. In single-cell mRNA-seq, hydroxyprostaglandin dehydrogenase is predominantly expressed in MCs. miR-182/183-5p prompts MC to release VEGF-A release from MC by increasing VEGF-A expression, which facilitates angiogenesis. CONCLUSIONS: CCA cells secret exosomal miR-182/183-5p into bile, which targets hydroxyprostaglandin dehydrogenase in CCA cells and MCs and increases prostaglandin E2 and VEGF-A release. Prostaglandin E2 promotes stemness by activating PTGER1. Our results reveal a type of CCA self-driven progression dependent on bile exosomal miR-182/183-5p and MCs, which is a new interplay pattern of CCA and bile.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , MicroARNs , Humanos , Animales , Ratones , Dinoprostona , MicroARNs/genética , Bilis/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Colangiocarcinoma/patología , Conductos Biliares Intrahepáticos/patología , Hidroxiprostaglandina Deshidrogenasas/genética , Proliferación Celular , Regulación Neoplásica de la Expresión GénicaRESUMEN
ABSTRACT AND AIM: Cholangiocarcinoma (CCA) is a highly aggressive and lethal cancer that originates from the biliary epithelium. Systemic treatment options for CCA are currently limited, and the first targeted drug of CCA, pemigatinib, emerged in 2020 for CCA treatment by inhibiting FGFR2 phosphorylation. However, the regulatory mechanism of FGFR2 phosphorylation is not fully elucidated. APPROACH AND RESULTS: Here we screened the FGFR2-interacting proteins and showed that protein tyrosine phosphatase (PTP) N9 interacts with FGFR2 and negatively regulates FGFR2 pY656/657 . Using phosphatase activity assays and modeling the FGFR2-PTPN9 complex structure, we identified FGFR2 pY656/657 as a substrate of PTPN9, and found that sec. 14p domain of PTPN9 interacts with FGFR2 through ACAP1 mediation. Coexpression of PTPN9 and ACAP1 indicates a favorable prognosis for CCA. In addition, we identified key amino acids and motifs involved in the sec. 14p-APCP1-FGFR2 interaction, including the "YRETRRKE" motif of sec. 14p, Y471 of PTPN9, as well as the PH and Arf-GAP domain of ACAP1. Moreover, we discovered that the FGFR2 I654V substitution can decrease PTPN9-FGFR2 interaction and thereby reduce the effectiveness of pemigatinib treatment. Using a series of in vitro and in vivo experiments including patient-derived xenografts (PDX), we showed that PTPN9 synergistically enhances pemigatinib effectiveness and suppresses CCA proliferation, migration, and invasion by inhibiting FGFR2 pY656/657 . CONCLUSIONS: Our study identifies PTPN9 as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib treatment. The molecular mechanism, oncogenic function, and clinical significance of the PTPN9-ACAP1-FGFR2 complex are revealed, providing more evidence for CCA precision treatment.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Morfolinas , Pirimidinas , Pirroles , Humanos , Colangiocarcinoma/tratamiento farmacológico , Epitelio , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Proteínas Activadoras de GTPasaRESUMEN
OBJECTIVE: The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites. DESIGN: Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9. RESULTS: Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation. CONCLUSION: Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Mastocitos , Microambiente Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Colangiocarcinoma/genética , Mastocitos/metabolismo , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/genética , Animales , Humanos , Ratones , Bilis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Histamínicos/metabolismo , Histamina/metabolismo , Proliferación Celular , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Degranulación de la CélulaRESUMEN
MAIN CONCLUSION: OsNAC103 negatively regulates rice plant height by influencing the cell cycle and crosstalk of phytohormones. Plant height is an important characteristic of rice farming and is directly related to agricultural yield. Although there has been great progress in research on plant growth regulation, numerous genes remain to be elucidated. NAC transcription factors are widespread in plants and have a vital function in plant growth. Here, we observed that the overexpression of OsNAC103 resulted in a dwarf phenotype, whereas RNA interference (RNAi) plants and osnac103 mutants showed no significant difference. Further investigation revealed that the cell length did not change, indicating that the dwarfing of plants was caused by a decrease in cell number due to cell cycle arrest. The content of the bioactive cytokinin N6-Δ2-isopentenyladenine (iP) decreased as a result of the cytokinin synthesis gene being downregulated and the enhanced degradation of cytokinin oxidase. OsNAC103 overexpression also inhibited cell cycle progression and regulated the activity of the cell cyclin OsCYCP2;1 to arrest the cell cycle. We propose that OsNAC103 may further influence rice development and gibberellin-cytokinin crosstalk by regulating the Oryza sativa homeobox 71 (OSH71). Collectively, these results offer novel perspectives on the role of OsNAC103 in controlling plant architecture.
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Oryza , Factores de Transcripción , Factores de Transcripción/genética , Oryza/genética , Ciclo Celular/genética , División Celular , CitocininasRESUMEN
Photonic skyrmions have been a hot topic in recent years. However, modulating the spin distributions of the skyrmions is still a challenging topic. In this paper, we investigate the detailed spin distributions of photonic skyrmions in thin metal film sandwiched by different dielectrics. We find that the ratios of different spin components can be adjusted by the thickness of the metal film, while the absolute value of total spin can be controlled by the frequency of the light source. Therefore, by choosing proper metal thickness in the preparation process and certain beam frequency in actual experiment, we can get the exact type of spin distribution we prefer. In addition, when the dielectric layers are arranged asymmetrically, the spin distributions can also be modulated significantly by adjustig the ratio of the dielectric constants of the upper and lower dielectric layers. Our results provide a new pathway for the modulation of photonic skyrmions.
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The uncontrolled bacterial infection-induced cytokine storm and sequential immunosuppression are commonly observed in septic patients, which indicates that the activation of phagocytic cells and the efficient and timely elimination of bacteria are crucial for combating bacterial infections. However, the role of dysregulated immune cells and their disrupted function in sepsis remains unclear. Here, we found that macrophages exhibited the impaired endocytosis capabilities in sepsis by Single-cell RNA sequencing and bulk RNA sequencing. Caveolae protein Caveolin-1 (Cav-1) of macrophages was inactivated by SHP2 rapidly during Escherichia coli (E.coli) infection. Allosteric inhibitor of SHP2 effectively maintains Cav-1 phosphorylation to enhance macrophage to endocytose and eliminate bacteria. Additionally, TLR4 endocytosis of macrophage was also enhanced upon E.coli infection by SHP099, inducing an increased and rapidly resolved inflammatory response. In vivo, pretreatment or posttreatment with inhibitor of SHP2 significantly reduced the bacterial burden in organs and mortality of mice subjected E.coli infection or CLP-induced sepsis. The cotreatment of inhibitor of SHP2 with an antibiotic conferred complete protection against mortality in mice. Our findings suggest that Cav-1-mediated endocytosis and bacterial elimination may play a critical role in the pathogenesis of sepsis, highlighting inhibitor of SHP2 as a potential therapeutic agent for sepsis.
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Caveolas , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Sepsis , Animales , Humanos , Ratones , Bacterias , Caveolas/metabolismo , Endocitosis , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/metabolismo , Macrófagos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/metabolismoRESUMEN
BACKGROUND: Peripheral vascular disease remains a leading cause of vascular morbidity and mortality worldwide despite advances in medical and surgical therapy. Besides traditional approaches, which can only restore blood flow to native arteries, an alternative approach is to enhance the growth of new vessels, thereby facilitating the physiological response to ischemia. METHODS: The ActinCreER/R26VT2/GK3 Rainbow reporter mouse was used for unbiased in vivo survey of injury-responsive vasculogenic clonal formation. Prospective isolation and transplantation were used to determine vessel-forming capacity of different populations. Single-cell RNA-sequencing was used to characterize distinct vessel-forming populations and their interactions. RESULTS: Two populations of distinct vascular stem/progenitor cells (VSPCs) were identified from adipose-derived mesenchymal stromal cells: VSPC1 is CD45-Ter119-Tie2+PDGFRa-CD31+CD105highSca1low, which gives rise to stunted vessels (incomplete tubular structures) in a transplant setting, and VSPC2 which is CD45-Ter119-Tie2+PDGFRa+CD31-CD105lowSca1high and forms stunted vessels and fat. Interestingly, cotransplantation of VSPC1 and VSPC2 is required to form functional vessels that improve perfusion in the mouse hindlimb ischemia model. Similarly, VSPC1 and VSPC2 populations isolated from human adipose tissue could rescue the ischemic condition in mice. CONCLUSIONS: These findings suggest that autologous cotransplantation of synergistic VSPCs from nonessential adipose tissue can promote neovascularization and represents a promising treatment for ischemic disease.
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Células Madre Mesenquimatosas , Neovascularización Fisiológica , Ratones , Humanos , Animales , Neovascularización Fisiológica/fisiología , Tejido Adiposo , Neovascularización Patológica , Isquemia/terapia , Modelos Animales de Enfermedad , Miembro Posterior/irrigación sanguíneaRESUMEN
Carbon dioxide (CO2) emissions and haze pollution are often thought to have the same origin, the burning of fossil fuels. However, their relationship is not always synergistic and may even exhibit mutual constraints. Carbon-biased technological progress has emerged as a promising approach for simultaneously achieving three goals - to reduce CO2 emissions, alleviate the haze pressure, and keep economic growth. This study empirically investigates the impact and mechanisms of carbon-biased technological progress on carbon haze collaborative governance using data from 286 Chinese cities during 2006-2021. The results indicate that: (1) Carbon biased technological progress positively influences carbon haze collaborative governance. (2) This progress achieves coordination by enhancing element allocation efficiency, carbon efficiency, and responding to public environmental demands. (3) The facilitating role of carbon biased technological progress to carbon haze collaborative governance will work better if external conditions are met. Moreover, the effectiveness of carbon-biased technological progress in promoting coordination is contingent upon high levels of marketization, government intervention, environmental regulation, and technical advancements. Local and regional governments should foster conducive conditions for carbon dioxide and haze pollution coordination, optimize the allocation and flow of carbon resources, ensure harmonization between environmental regulation policies and other sectors, and bolster international cooperation and technical knowledge exchange to collectively address global environmental challenges.
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Contaminación del Aire , Dióxido de Carbono , Ciudades , China , Contaminación del Aire/prevención & control , Dióxido de Carbono/análisis , Contaminantes Atmosféricos/análisis , Política Ambiental , CarbonoRESUMEN
BACKGROUND: Hypertension and frailty often coexist in older people. The present study aimed to evaluate the association of frailty status with overall survival in elderly hypertensive patients, using data from the Chinese Longitudinal Healthy Longevity Survey. METHODS: A total of 10,493 elderly hypertensive patients were included in the present study (median age 87.0 years, 58.3% male). Frailty status was assessed according to a 36-item frailty index (FI), which divides elderly individuals into four groups: robustness (FI ≤ 0.10), pre-frailty (0.10 < FI ≤ 0.20), mild-frailty (0.20 < FI ≤ 0.30), and moderate-severe frailty (FI > 0.30). The study outcome was overall survival time. Accelerated failure time model was used to evaluate the association of frailty status with overall survival. RESULTS: During a period of 44,616.6 person-years of follow-up, 7327 (69.8%) participants died. The overall survival time was decreased with the deterioration of frailty status. With the robust group as reference, adjusted time ratios (TRs) were 0.84 (95% confidence interval [CI]: 0.80-0.87) for the pre-frailty group, 0.68 (95% CI: 0.64-0.72) for the mild frailty group, and 0.52 (95% CI: 0.48-0.56) for the moderate-severe frailty group, respectively. In addition, restricted cubic spline analysis revealed a nearly linear relationship between FI and overall survival (p for non-linearity = 0.041), which indicated the overall survival time decreased by 17% with per standard deviation increase in FI (TR = 0.83, 95% CI: 0.82-0.85). Stratified and sensitivity analyses suggested the robustness of the results. CONCLUSIONS: The overall survival time of elderly hypertensive patients decreased with the deterioration of frailty status. Given that frailty is a dynamic and even reversible process, early identification of frailty and active intervention may improve the prognosis of elderly hypertensive patients.
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Anciano Frágil , Fragilidad , Hipertensión , Humanos , Masculino , Femenino , Estudios Longitudinales , Hipertensión/mortalidad , Anciano de 80 o más Años , China/epidemiología , Fragilidad/mortalidad , Anciano , Anciano Frágil/estadística & datos numéricos , Longevidad , Evaluación Geriátrica , Análisis de Supervivencia , Encuestas Epidemiológicas , Pueblos del Este de AsiaRESUMEN
As a crucial economic trait, fat deposition is directly related to carcass quality and feed efficiency in sheep. The purpose of this study was to investigate the polymorphisms of the FGB gene related to fat deposition and detect the expression features of the FGB gene in different adipose tissues of sheep by using Sanger sequencing, MassARRAY® SNP technique, and quantitative real-time PCR (qRT-PCR). Results showed that in the intron region of the FGB gene, a SNP g. 3378953 A > T has been identified, and significant association was found between perirenal fat weight, perirenal fat relative weight, mesenteric fat weight, and mesenteric fat relative weight (P < 0.05). Moreover, qRT-PCR analysis showed that FGB was expressed in all three adipose tissues, and FGB gene expression level in the AA genotype was significantly lower than that in the AT or TT genotypes (P < 0.05). Therefore, the FGB gene can be used as a candidate gene to reduce fat deposition in Hu sheep breeding, and the selection of the AA genotype in Hu sheep in production practice is more conducive to improving production efficiency.
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Tejido Adiposo , Polimorfismo de Nucleótido Simple , Animales , Polimorfismo de Nucleótido Simple/genética , Tejido Adiposo/metabolismo , Ovinos/genética , Ovinos/fisiología , Genotipo , Oveja Doméstica/genética , Oveja Doméstica/fisiología , Masculino , Femenino , CruzamientoRESUMEN
Scrotal circumference is an important reproductive index of breeding rams, which has a high genetic correlation with ejaculation volume and semen quality. In this study, the scrotal circumference of 1353 male Hu sheep at different stages of development was measured and descriptive statistical analysis was performed. The results showed that the coefficient of variation of scrotal circumference at each stage was greater than 10%, and its heritability were moderately to high, ranging from 0.318 to 0.719. We used PCR amplification and Sanger sequencing to scan the polymorphisms of the IGFALS gene, and performed association analysis with the circumference of the scrotum at different stages. We identified a synonymous mutation g.918 G > C in exon 1 of the IGFALS gene, and this mutation was significantly associated with scrotal circumference at 100, 120, 140, 160 and 180 days (p < 0.05). Therefore, IGFALS gene polymorphism can be used as a molecular marker affecting scrotal circumference of Hu sheep, which can provide a reference for future molecular marker-assisted selection of scrotal circumference in sheep.
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Escroto , Análisis de Semen , Ovinos/genética , Masculino , Animales , Análisis de Semen/veterinaria , Oveja Doméstica , Reproducción , Polimorfismo Genético/genéticaRESUMEN
BACKGROUND: the feasibility of the capacitance method for detecting the water content in standing tree trunks was investigated using capacitance-based equipment that was designed for measuring the water content of standing tree trunks. METHODS: In laboratory experiments, the best insertion depth of the probe for standing wood was determined by measurement experiments conducted at various depths. The bark was to be peeled when specimens and standing wood were being measured. The actual water content of the test object was obtained by specimens being weighed and the standing wood being weighed after the wood core was extracted. RESULTS: A forecast of the moisture content of standing wood within a range of 0 to 180% was achieved by the measuring instrument. The feasibility of the device for basswood and fir trees is preliminarily studied. When compared to the drying method, the average error of the test results was found to be less than 8%, with basswood at 7.75%, and fir at 7.35%. CONCLUSIONS: It was concluded that the measuring instrument has a wide measuring range and is suitable for measuring wood with low moisture content, as well as standing timber with high moisture content. The measuring instrument, being small in size, easy to carry, and capable of switching modes, is considered to have a good application prospect in the field of forest precision monitoring and quality improvement.
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Capacidad Eléctrica , Árboles , Agua , Madera , Agua/química , Madera/químicaRESUMEN
SMAD4 is a tumour suppressor and an important regulator of tumour immune scape which is downregulated in cholangiocarcinoma (CCA). STING1 is a vital sensing factor of abnormal DNA; however, the correlation between SMAD4 and STING1 and the role of the SMAD4-STING1 interaction in the progression of CCA have not yet been evaluated. Public database was analysed to reveal the expression of SMAD4 and STING1. A cohort comprising 50 iCCA, 113 pCCA and 119 dCCA patients was assembled for the study. Immunohistochemistry was employed to evaluate the expression levels of STING1 and SMAD4. In vitro transwell and CCK8 assays, along with luciferase reporter assay, were conducted to analyse the potential regulatory mechanisms of SMAD4 on the expression of STING1. Expression of SMAD4 and STING1 were downregulated in CCA tumours and STING1 expression correlated with SMAD4 expression. The overexpression of SMAD4 was found to suppress the migration, invasion and proliferation capabilities of CCA cells; whereas, the knockdown of SMAD4 enhanced these abilities. Furthermore, it was observed that SMAD4 translocated into the nucleus following TGF-ß1 stimulation. Knockdown of SMAD4 resulted in the inhibition of STING1 transcriptional activity, whereas the overexpression of SMAD4 promoted the transcriptional activity of STING1. Clinically, low STING1 and SMAD4 expression indicated poor prognosis in CCA, and simultaneously low expression of STING1 and SMAD4 predicts poorer patient survival. SMAD4 regulates the expression of STING1 through its transcription regulating function. Dual low expression of STING1 and SMAD4 had more power in predicting patient survival. These results indicate that SMAD4-silenced CCA may downregulate its STING1 expression to adapt to the immune system.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Proteína Smad4 , Humanos , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Colangiocarcinoma/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteína Smad4/genética , Proteína Smad4/metabolismoRESUMEN
BACKGROUND: Plant immunity relies on the perception of immunogenic signals by cell-surface and intracellular receptors and subsequent activation of defense responses like programmed cell death. Under certain circumstances, the fine-tuned innate immune system of plants results in the activation of autoimmune responses that cause constitutive defense responses and spontaneous cell death in the absence of pathogens. RESULTS: Here, we characterized the onset of leaf death 12 (old12) mutant that was identified in the Arabidopsis accession Landsberg erecta. The old12 mutant is characterized by a growth defect, spontaneous cell death, plant-defense gene activation, and early senescence. In addition, the old12 phenotype is temperature reversible, thereby exhibiting all characteristics of an autoimmune mutant. Mapping the mutated locus revealed that the old12 phenotype is caused by a mutation in the Lectin Receptor Kinase P2-TYPE PURINERGIC RECEPTOR 2 (P2K2) gene. Interestingly, the P2K2 allele from Landsberg erecta is conserved among Brassicaceae. P2K2 has been implicated in pathogen tolerance and sensing extracellular ATP. The constitutive activation of defense responses in old12 results in improved resistance against Pseudomonas syringae pv. tomato DC3000. CONCLUSION: We demonstrate that old12 is an auto-immune mutant and that allelic variation of P2K2 contributes to diversity in Arabidopsis immune responses.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Lectinas/genética , Lectinas/metabolismo , Resistencia a la Enfermedad/fisiología , Hojas de la Planta/metabolismo , Mutación , Proteínas Portadoras/genética , Fenotipo , Receptores Mitogénicos/genética , Receptores Mitogénicos/metabolismo , Pseudomonas syringae/metabolismo , Enfermedades de las Plantas/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
The incidence of lung cancer (LC) in chronic obstructive pulmonary disease (COPD) patients is dozens of times higher than that in patients without COPD. Elevated activity of nuclear factor-k-gene binding (NF-κB) was found in lung tissue of patients with COPD, and the continuous activation of NF-κB is observed in both malignant transformation and tumor progression of LC, suggesting that NF-κB and its regulators may play a key role in the progression of LC in COPD patients. Here, we report for the first time that a key long non-coding RNA (lncRNA)-ICL involved in the regulation of NF-κB activity in LC tissues of COPD patients. The analyses showed that the expression of ICL significantly decreased in LC tissues of LC patients with COPD than that in LC tissues of LC patients without COPD. Functional experiments in vitro showed that exogenous ICL only significantly inhibited the proliferation, invasion and migration in primary tumor cells of LC patients with COPD compared to LC patients without COPD. Mechanism studies have shown that ICL could suppress the activation of NF-κB by blocking the hsa-miR19-3p/NKRF/NF-κB pathway as a microRNA sponge. Furthermore, In vivo experiments showed that exogenous ICL effectively inhibited the growth of patient-derived subcutaneous tumor xenografts (PDX) of LC patients with COPD and significantly prolonged the survival time of tumor-bearing mice. In a word, our study shows that the decrease of ICL is associated with an increased risk of LC in patients with COPD, ICL is not only expected to be a new therapeutic target for LC in COPD patients, but also has great potential to be used as a new marker for evaluating the occurrence, severity stratification and prognosis of LC in patients with COPD.
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The quantum battery capacity is introduced in this Letter as a figure of merit that expresses the potential of a quantum system to store and supply energy. It is defined as the difference between the highest and the lowest energy that can be reached by means of the unitary evolution of the system. This function is closely connected to the ergotropy, but it does not depend on the temporary level of energy of the system. The capacity of a quantum battery can be directly linked with the entropy of the battery state, as well as with measures of coherence and entanglement.
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Azecine fragments are frequently presented in natural products and bioactive compounds. However, minor efforts have been devoted to these 10-membered N-heterocycles, and their synthesis is still challenging. Reported herein is the first catalytic formal [6+4] cycloaddition for the synthesis of 10-membered azecines. Under palladium catalysis, the reaction of δ-vinylvalerolactones and benzofuran-derived azadienes proceeds smoothly to afford benzofuran-fused azecines with high diastereoselectivity in moderate to good yields. A unique transannular reaction of these 10-membered azecines for the construction of polycyclic compounds is also demonstrated.
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A divergent reaction of indoline-derived azadienes with α-bromohydroxamates for the selective synthesis of spiro-indolinepyrrolidinones and indoline-fused diazepinones was disclosed. This reaction sequence involved an initial formation of five-membered spirocyclic products followed by an intramolecular ring-opening and ring expansion to produce seven-membered diazepinones. We demonstrated that controlling the reaction time could modulate the reaction pathway for formation of different molecular frameworks for the same set of substrates. Based on the experimental results, the reaction mechanism was also discussed and proposed to explain the phenomena observed in the process.
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Antimicrobial agents are safe preservatives having the ability to protect foods from microbial spoilage and extend their shelf life. Many factors, including antimicrobials' chemical features, storage environments, delivery methods, and diffusion in foods, can affect their antimicrobial activities. The physical-chemical characteristics of the food itself play an important role in determining the efficacy of antimicrobial agents in foods; however the mechanisms behind it have not been fully explored. This review provides new insights and comprehensive knowledge regarding the impacts of the food matrix, including the food components and food (micro)structures, on the activities of antimicrobial agents. Studies of the last 10 years regarding the influences of the food structure on the effects of antimicrobial agents against the microorganisms' growth were summarized. The mechanisms underpinning the loss of the antimicrobial agents' activity in foods are proposed. Finally, some strategies/technologies to improve the protection of antimicrobial agents in specific food categories are discussed.
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A metal-free Meerwein arylation reaction from aryl(alkyl)idenemalononitriles and diazonium salts for the synthesis of 2-(aryl(alkyl)/arylmethylene)malononitrile derivatives under mild conditions was well developed. Different from the general addition reactions between alkenes and diazonium salts, this study performed the traditional coupling reaction for the formation of C(sp2)-C(sp2) bond arylation products. The radical reaction mechanism was well verified in the control experiments. The other advantages of the approach are broad-scope substrates and good group tolerance. Moreover, the obtained products can be readily converted into high-value asymmetric ketones and hydrogenation reactions.