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Oxygenases, which catalyze the reductive activation of O2 and incorporation of oxygen atoms into substrates, are widely distributed in aerobes. They function by switching the redox states of essential cofactors that include flavin, heme iron, Rieske non-heme iron, and Fe(II)/α-ketoglutarate. This review summarizes the catalytic features of flavin-dependent monooxygenases, heme iron-dependent cytochrome P450 monooxygenases, Rieske non-heme iron-dependent oxygenases, Fe(II)/α-ketoglutarate-dependent dioxygenases, and ring-cleavage dioxygenases, which are commonly involved in pesticide degradation. Heteroatom release (hydroxylation-coupled hetero group release), aromatic/heterocyclic ring hydroxylation to form ring-cleavage substrates, and ring cleavage are the main chemical fates of pesticides catalyzed by these oxygenases. The diversity of oxygenases, specificities for electron transport components, and potential applications of oxygenases are also discussed. This article summarizes our current understanding of the catalytic mechanisms of oxygenases and a framework for distinguishing the roles of oxygenases in pesticide degradation.
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Dioxigenases , Praguicidas , Compostos Ferrosos , Flavinas , Ferro , Ácidos Cetoglutáricos , Oxigenases de Função Mista , Oxigenases/metabolismoRESUMO
Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma characterized by the COL1A1-PDGFB fusion gene. This study utilized single-cell RNA sequencing to dissect the cellular and molecular landscape of primary DFSP. Distinct DFSP cell clusters, exhibiting fibroblast-like traits, revealed variations in pathways associated with proliferation, inflammation and metabolism. Differential gene expression analysis during the differentiation from tumour stem cells to DFSP cells unveiled SMOC2, DCN and TGFBR3 as potential regulators of tumour invasion and immune infiltration through VEGF/TGF-ß signalling modulation. Cellular communication analysis highlighted interactions within DFSP cell clusters and with endothelial cells, implicating molecules such as NAMPT, ANGPT2 and PTN in pathogenesis and treatment resistance. These findings offer insights into DFSP intratumour heterogeneity, elucidate molecular mechanisms underlying tumour behaviour, and suggest potential therapeutic targets.
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Dermatofibrossarcoma , Análise de Célula Única , Neoplasias Cutâneas , Dermatofibrossarcoma/genética , Dermatofibrossarcoma/patologia , Dermatofibrossarcoma/metabolismo , Humanos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Análise de Sequência de RNA , Comunicação Celular/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Diferenciação Celular , RNA-Seq , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteoglicanas , Receptores de Fatores de Crescimento Transformadores betaRESUMO
Ring-opening polymerization (ROP) offers a striking solution to solve problems encountered in step-growth condensation polymerization, including precise control over molecular weight, molecular weight distribution, and topology. This has inspired our interest in ROP of cycloalkanes with an ultimate goal to rethink polyolefins, which clearly poses a number of challenges. Practicality of ROP of cycloalkanes is actually limited by their low polymerizability and elusive mechanisms which arise from significantly varied ring size and non-polar C-C bonds in monomers. In this work, by using Lewis acid/Brønsted base/C(sp3)-H initiator system previously developed in our laboratory, we focus on cyclobutanes and explore the positional and electronic effects of substituents on the ring, namely electron push-pull effect, in promoting controlled polymerization to afford densely functionalized poly(cyclobutanes), as well as catalytic degradation of obtained polymers for upcycling. More importantly, experiments and DFT calculations unveil considerable population of Lewis-acid-induced thermostabilized 1,4-zwitterions, which distinguish cyclobutanes from cyclopropanes and others. All these findings would shed light on catalytic synthesis and degradation of saturated all-carbon main-chain polymers, as well as small molecule transformations of cyclobutanes.
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BACKGROUND: Severe asthma is associated with substantial mortality and has unmet therapeutic need. A subset of severe asthma is characterized by neutrophilic airway inflammation. Classically activated (or M1) macrophages which express IL-12 and IL-23 are associated with airway neutrophilia in asthma. Exogenous IL-25 was reported to suppress intestinal inflammation in animal models of inflammatory bowel diseases via suppressing IL-12 and IL-23 production. We hypothesize that IL-25 ameliorates airway neutrophilia via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma. METHODS: In a mouse model of neutrophil-dominant allergic airway inflammation, the effect of mouse recombinant IL-25 on airway inflammation were assessed by H&E staining and bronchoalveolar lavage (BAL) cell counting. The percentage of M1 macrophages in lung tissue and BAL cells were analyzed by flow cytometry. Quantitative PCR and immunostaining were performed to measure the expression of Il12, Il23, and inflammatory cytokines. Mechanistic experiments were performed in primary culture of macrophages from mouse lungs. The expression of IL-12, IL-23 and IL-25 in sputum was analyzed in a cohort of severe asthma and subjects with eosinophilic or non-eosinophilic asthma. RESULTS: Intranasal administration of IL-25 markedly decreased the number of neutrophils in BAL cells in a murine model of neutrophil-dominant allergic airway inflammation. Moreover, exogenous IL-25 decreased the number of M1 macrophages, and reduced the expression of IL-12, IL-23 in the lungs of the mouse model. Exogenous IL-25 also inhibited the expression of inflammatory cytokines IL-1ß, IFN-γ, TNF-α and IL-17 A. In vitro, IL-25 suppressed IL-12 and IL-23 expression in lipopolysaccharide (LPS)-stimulated primary culture of mouse pulmonary macrophages. Mechanistically, IL-25 inhibited LPS-induced c-Rel translocation to nucleus via STAT3-dependent signaling. In a cohort of severe asthma, IL-25 protein levels in sputum were significantly lower than control subjects. The transcript levels of IL-12 and IL-23 were increased whereas IL-25 transcripts were decreased in sputum cells from subjects with non-eosinophilic asthma compared to eosinophilic asthma. CONCLUSIONS: IL-25 expression is downregulated in subjects with severe or non-eosinophilic asthma. Exogenous IL-25 ameliorates airway neutrophilia, at least in part, via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23.
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Asma , Interleucina-12 , Humanos , Animais , Camundongos , Interleucina-12/uso terapêutico , Interleucina-17 , Lipopolissacarídeos , Asma/tratamento farmacológico , Asma/metabolismo , Citocinas/metabolismo , Inflamação , Macrófagos Alveolares/metabolismo , Interleucina-23/uso terapêuticoRESUMO
Chronic obstructive pulmonary disease (COPD) and asthma are chronic inflammatory diseases of the airways. Galectin-13 has recently been forwarded as a biomarker for airway eosinophilic inflammation in asthma. However, the association between galectin-13 and COPD remains unknown. To examine the changes in galectin-13 expression in acute exacerbations of COPD (AECOPD) and the stable phase of COPD and unveil the association between galectin-13 expression and eosinophilic inflammation in COPD, we measured plasma galectin-13 expression in different phases of COPD patients (n = 60, 44 AECOPD patients, and 16 stable COPD patients) and healthy controls (n = 15). Plasma levels of galectin-13 in 60 COPD patients were further analyzed and compared to systemic inflammation, airway eosinophilic inflammation, and lung function. The plasma galectin-13 level was markedly increased in subjects with AECOPD compared to stable COPD patients and healthy controls. Plasma galectin-13 levels in COPD subjects were positively correlated with serum CRP (rs = 0.46, p = 0.0003), peripheral blood eosinophilia count (rs = 0.57, p<0.0001), and FeNO (rs = 0.46, p = 0.0002). In addition, the level of galectin-13 was negatively correlated with FEV1 (rs = -0.43, p = 0.0001), FEV1 pred (%) (rs = -0.544, p<0.0001), as well as FEV1/FVC (rs = -0.46, p<0.0001). Multiple linear regression analysis suggested that plasma galectin-13 levels were affected by FEV1 pred (%), peripheral blood eosinophilia count, and FeNO. We concluded that galectin-13 levels were increased in COPD patients, and elevated galectin-13 expressions related to airway eosinophilic inflammation. Galectin-13 may facilitate the identification of COPD endotypes and may become a potential therapeutic target.
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Asma , Eosinofilia , Doença Pulmonar Obstrutiva Crônica , Humanos , Asma/complicações , Inflamação , GalectinasRESUMO
Activation of IL-4R (IL-4 receptor) signaling in airway epithelial cells leads to airway hyperresponsiveness and mucus overproduction in asthma. CDH26 (cadherin-26), a cadherin implicated in the polarization of airway epithelial cells, is upregulated in asthma. However, the role of CDH26 in asthma remains unknown. In this study, we demonstrated that Cdh26 deficiency significantly reduced airway mucus overproduction, airway hyperresponsiveness, and airway eosinophilia in a murine model of allergic airway disease. Interestingly, allergen-induced Il-4Rα upregulation in airway epithelium was markedly reduced in Cdh26-/- mice. In cultured human bronchial epithelial cells, CDH26 knockdown inhibited IL-13, a ligand for IL-4R; induced IL-4Rα and IL-13Rα1 (IL-13 receptor α1) upregulation; and suppressed downstream Jak1 (Janus kinase 1) and Stat6 (signal transducer and activator of transcription 6) phosphorylation. Moreover, CDH26 knockdown inhibited IL-13-induced MUC5AC and eosinophilic chemokine expression. These results suggest that CDH26 plays a key role in epithelial IL-4R signaling activation and downstream effectors. In contrast, CDH26 overexpression amplified IL-13-activated IL-4R signaling in BEAS-2B cells. In the airway epithelium of patients with asthma, IL-4Rα expression was elevated, and CDH26 was the only cadherin that was upregulated among 11 cadherin family members. CDH26 expression was strongly correlated with epithelial IL-4Rα and MUC5AC expression, sputum eosinophilia, and fractional exhaled nitric oxide in patients with asthma. Taken together, we identified CDH26 as a key regulator of epithelial IL-4R signaling in asthma and a potential therapeutic target for IL-4R-mediated allergic diseases.
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Asma , Eosinofilia , Hipersensibilidade , Humanos , Camundongos , Animais , Interleucina-13 , Receptores de Interleucina-4 , Asma/metabolismo , Hipersensibilidade/metabolismo , CaderinasRESUMO
Since its advent two decades ago, asymmetric organo/transition-metal combined catalysis (AOMC), including cooperative catalysis and relay catalysis, has leveraged redistribution of chemical bonds to build up molecular complexity and enantio-differentiation to form individual enantiomers with activations from versatile organocatalysts and transition-metal complexes. The goal of this perspective is to provide readers with the fundamental attributes of AOMCâorthogonality, kinetics, mechanism, and selectivityâto understand how an organocatalyst and a transition-metal complex would collaborate to enable fruitful new reaction development and what are the intrinsic pathways of unproductive events, such as catalyst self-quenching. In closing, future opportunities of AOMC have been directed toward the prediction of effective catalyst combination, introducing enzyme catalysis, and a focus on transient radical intermediate, to animate this area in the years to come.
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Labeling RNA molecules at specific positions is critical for RNA research and applications. Such methods are in high demand but still a challenge, especially those that enable native co-synthesis rather than post-synthesis labeling of long RNAs. The method we developed in this work meets these requirements, in which a leader RNA is extended on the hybrid solid-liquid phase by an engineered transcriptional complex following the pause-restart mode. A custom-designed short oligonucleotide is used to functionalize the engineered complex. This remarkable co-transcriptional labeling method incorporates labels into RNAs in high yields with great flexibility. We demonstrate the method by successfully introducing natural modifications, a fluorescent nucleotide analogue and a donor-acceptor fluorophore pair to specific sites located at an internal loop, a pseudoknot, a junction, a helix, and the middle of consecutive identical nucleotides of various RNAs. This newly developed method overcomes efficiency and position-choosing constraints that have hampered routine strategies to label RNAs beyond 200 nucleotides (nt).
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Oligonucleotídeos , RNA , Corantes Fluorescentes/química , Nucleotídeos , RNA/químicaRESUMO
Dialectical thinking is an overarching and sophisticated thinking style that involves accepting and resolving contradictions. The current study examined whether the dispositional tendency of dialectical thinking is mediated by organizational patterns of intrinsic brain networks. Based on previous theoretical and empirical works, we hypothesized that the dorsal anterior cingulate cortex (dACC), the hub for conflict processing, shows increased couplings with nodes in the default mode network (DMN). A sample of 380 young and healthy participants completed a self-reported measure of dialectical thinking and underwent resting-state functional magnetic resonance imaging scanning. Results of seed-based correlational ROI and whole-brain analyses supported our hypothesis that trait dialectical thinking was positively correlated with the strength of the dACC-DMN couplings. These findings demonstrate the possibility of identifying network-level neural representations of sociocultural orientations.
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Rede de Modo Padrão , Giro do Cíngulo , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Type 2-high asthma is a prominent endotype of asthma which is characterized by airway eosinophilic inflammation. Airway epithelial cells play a critical role in the pathogenesis of asthma. Our previous miRNA profiling data showed that miR-30a-3p was downregulated in bronchial epithelial cells from asthma patients. We hypothesize that epithelial miR-30a-3p plays a role in asthma airway inflammation. METHODS: We measured miR-30a-3p expression in bronchial brushings of asthma patients (n = 51) and healthy controls (n = 16), and analyzed the correlations between miR-30a-3p expression and airway eosinophilia. We examined whether Runt-related transcription factor 2 (RUNX2) was a target of miR-30a-3p and whether RUNX2 bound to the promoter of high mobility group box 1 (HMGB1) by using luciferase reporter assay and chromatin immunoprecipitation (ChIP)-PCR. The role of miR-30a-3p was also investigated in a murine model of allergic airway inflammation. RESULTS: We found that miR-30a-3p expression were significantly decreased in bronchial brushings of asthma patients compared to control subjects. Epithelial miR-30a-3p expression was negatively correlated with parameters reflecting airway eosinophilia including eosinophils in induced sputum and bronchial biopsies, and fraction of exhaled nitric oxide in asthma patients. We verified that RUNX2 is a target of miR-30a-3p. Furthermore, RUNX2 bound to the promoter of HMGB1 and upregulated HMGB1 expression. RUNX2 and HMGB1 expression was both enhanced in airway epithelium and was correlated with each other in asthma patients. Inhibition of miR-30a-3p enhanced RUNX2 and HMGB1 expression, and RUNX2 overexpression upregulated HMGB1 in BEAS-2B cells. Intriguingly, airway overexpression of mmu-miR-30a-3p suppressed Runx2 and Hmgb1 expression, and alleviated airway eosinophilia in a mouse model of allergic airway inflammation. CONCLUSIONS: Epithelial miR-30a-3p could possibly target RUNX2/HMGB1 axis to suppress airway eosinophilia in asthma.
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Asma/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Eosinofilia/genética , Regulação da Expressão Gênica , Proteína HMGB1/genética , Inflamação/genética , MicroRNAs/genética , Animais , Asma/complicações , Asma/patologia , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Modelos Animais de Doenças , Eosinofilia/complicações , Eosinofilia/patologia , Feminino , Proteína HMGB1/biossíntese , Humanos , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , Escarro/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Mutations in proline-rich transmembrane protein 2 (PRRT2) are the major cause of paroxysmal kinesigenic dyskinesia (PKD). We recently reported transmembrane protein 151A (TMEM151A) mutations caused PKD. Herein, we aimed to conduct phenotypic comparisons of patients with PKD carrying PRRT2 variants, carrying TMEM151A variants, and carrying neither the PRRT2 nor TMEM151A variant. METHODS: Sanger sequencing of PRRT2 and TMEM151A was performed, and phenotypic characteristics were analyzed. RESULTS: In a cohort of 131 PKD probands (108 without PRRT2 variants and 23 newly recruited), five novel TMEM151A variants were identified and one (c.647C > A) occurred de novo. Together with our previous studies, PRRT2 and TMEM151A variants accounted for 34.7% (85/245) and 6.9% (17/245) of PKD probands, respectively. Compared with patients carrying PRRT2 variants, those with TMEM151A variants tended to exbibit dystonia with shorter durations, have no history of benign infantile epilepsy, and have residual attacks/aura when treated with carbamazepine/oxcarbazepine. CONCLUSIONS: Patients with TMEM151A variants have different features from patients with PRRT2 variants. © 2022 International Parkinson and Movement Disorder Society.
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Coreia , Distonia , Epilepsia , Humanos , Coreia/genética , Estudos de Coortes , Distonia/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
Sensory neuronopathies are a rare and distinct subgroup of peripheral neuropathies, characterized by degeneration of the dorsal root ganglia neurons. About 50% of sensory neuronopathies are idiopathic and genetic causes remain to be clarified. Through a combination of homozygosity mapping and whole exome sequencing, we linked an autosomal recessive sensory neuronopathy to pathogenic variants in the COX20 gene. We identified eight unrelated families from the eastern Chinese population carrying a founder variant c.41A>G (p.Lys14Arg) within COX20 in either a homozygous or compound heterozygous state. All patients displayed sensory ataxia with a decrease in non-length-dependent sensory potentials. COX20 encodes a key transmembrane protein implicated in the assembly of mitochondrial complex IV. We showed that COX20 variants lead to reduction of COX20 protein in patient's fibroblasts and transfected cell lines, consistent with a loss-of-function mechanism. Knockdown of COX20 expression in ND7/23 sensory neuron cells resulted in complex IV deficiency and perturbed assembly of complex IV, which subsequently compromised cell spare respiratory capacity and reduced cell proliferation under metabolic stress. Consistent with mitochondrial dysfunction in knockdown cells, reduced complex IV assembly, enzyme activity and oxygen consumption rate were also found in patients' fibroblasts. We speculated that the mechanism of COX20 was similar to other causative genes (e.g. SURF1, COX6A1, COA3 and SCO2) for peripheral neuropathies, all of which are functionally important in the structure and assembly of complex IV. Our study identifies a novel causative gene for the autosomal recessive sensory neuronopathy, whose vital function in complex IV and high expression in the proprioceptive sensory neuron further underlines loss of COX20 contributing to mitochondrial bioenergetic dysfunction as a mechanism in peripheral sensory neuron disease.
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Deficiência de Citocromo-c Oxidase/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Perda de Heterozigosidade , Mitocôndrias/genética , Adolescente , Adulto , Proliferação de Células/genética , Criança , Pré-Escolar , Deficiência de Citocromo-c Oxidase/fisiopatologia , Feminino , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Masculino , Nervo Mediano/fisiopatologia , Mutação , Condução Nervosa/fisiologia , Linhagem , Nervo Radial/fisiopatologia , Nervo Ulnar/fisiopatologiaRESUMO
BACKGROUND: CYP2C19 gene polymorphisms have been described to have an important influence on the drug metabolism observed in human populations. A series of PCR-based molecule detection methods are applied to identify CYP2C19 genotype. The aim of the study is to validate the novel CYP2C19 genotyping approach with other methods and reveal the allele frequency distribution of CYP2C19 in Chinese Han population. METHODS: We applied a novel genotyping approach for CYP2C19 gene which was combining direct PCR and capillary electrophoresis (CE) technique. A series of fluorescent labeled primers were designed to amplify the particular DNA fragments which indicated the wild type of CYP2C19 genotype. The variants consist of CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles. Both the novel PCR-based CE method and real-time quantitative PCR (RT-qPCR) method were used to identify the CYP2C19 genotypes in 324 whole blood samples originated from Chinese Han population. According to the different criterions for judgement of two methods, we can obtain the CYP2C19 alleles and genotypes of the same participants. Kappa statistics was used to evaluate the consistency of the two results and the frequencies of CYP2C19 alleles. The genotypes in Chinese Han population were calculated using EXCEL. Furthermore, to ensure the accuracy and reliability of the CYP2C19 genotypes obtained by using the novel approach, Sanger sequencing was conducted to validate the CYP2C19 genotypes *1/*17 and *2/*3. RESULTS: Among the 324 specimens, 111 were *1/*1, 141 were *1/*2, 10 were *1/*3, 4 were *1/*17, 46 were *2/*2, 10 were *2*/3, 1 was *2/*17, and 1 was *3/*17. Allele distributions for CYP2C19 were *1, *2, *3, and *17 at 58.18%, 37.65%, 3.24%, and 0.93%, respectively. Both PCR-based CE method and RT-qPCR methods had good consistency in the genotypes of CYP2C19 polymorphism (Kappa value = 1.000, p < 0.05). The DNA sequences of CYP2C19 genotype *1/*17 were composed of c.681 G/G, c.636 G/G, and c.-806 C>T. In the same way, the DNA sequences of CYP2C19 genotype *2/*3 were composed of c.681 G>A, c.636 G>A, and c.-806 C/C. CONCLUSIONS: The variants including the CYP2C19*2 allele were the most common mutations in Chinese Han unrelated individuals. Both PCR-based CE method and RT-qPCR method had good consistency in the genotypes of CYP2C19 polymorphism. Nevertheless, because of more convenience and higher throughput, the novel PCR-based capillary electrophoresis approach showed to be more suitable for clinical gene screening.
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Eletroforese Capilar , Polimorfismo de Nucleotídeo Único , Humanos , Citocromo P-450 CYP2C19/genética , Genótipo , Reprodutibilidade dos Testes , Frequência do Gene , Alelos , ChinaRESUMO
BACKGROUND: Several predictors of COVID-19 severity have been reported. However, chronic airway inflammation characterised by accumulated lymphocytes or eosinophils may affect the pathogenesis of COVID-19. METHODS: In this retrospective cohort study, we reviewed the medical records of all patients with laboratory-confirmed COVID-19 with chronic bronchitis, chronic obstructive pulmonary disease (COPD) and asthma admitted to the Sino-French New City Branch of Tongji Hospital, a large regional hospital in Wuhan, China, from 26 January to 3 April. The Tongji Hospital Ethics Committee approved this study. RESULTS: There were 59 patients with chronic bronchitis, COPD and asthma. When compared with non-severe patients, severe patients were more likely to have decreased lymphocyte counts (0.6×109/L vs 1.1×109/L, p<0.001), eosinopaenia (<0.02×109/L; 73% vs 24%, p<0.001), increased lactate dehydrogenase (LDH) (471.0 U/L vs 230.0 U/L, p<0.001) and elevated interleukin 6 level (47.4 pg/mL vs 5.7 pg/mL, p=0.002) on admission. Eosinopaenia and elevated LDH were significantly associated with disease severity in both univariate and multivariate regression models including the above variables. Moreover, eosinophil count and LDH level tended to return to normal range over time in both groups after treatment and severe patients recovered slower than non-severe patients, especially in eosinophil count. CONCLUSIONS: Eosinopaenia and elevated LDH are potential predictors of disease severity in patients with COVID-19 with underlying chronic airway diseases. In addition, they could indicate disease progression and treatment effectiveness.
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Asma , Bronquite Crônica , COVID-19 , Doença Pulmonar Obstrutiva Crônica , Humanos , Asma/complicações , Bronquite Crônica/patologia , COVID-19/complicações , Eosinófilos , Inflamação/patologia , Lactato Desidrogenases , Estudos RetrospectivosRESUMO
Insects have evolved effectors to conquer plant defense. Most known insect effectors are isolated from sucking insects, and examples from chewing insects are limited. Moreover, the targets of insect effectors in host plants remain unknown. Here, we address a chewing insect effector and its working mechanism. Cotton bollworm (Helicoverpa armigera) is a lepidopteran insect widely existing in nature and severely affecting crop productivity. We isolated an effector named HARP1 from H. armigera oral secretion (OS). HARP1 was released from larvae to plant leaves during feeding and entered into the plant cells through wounding sites. Expression of HARP1 in Arabidopsis mitigated the global expression of wounding and jasmonate (JA) responsive genes and rendered the plants more susceptible to insect feeding. HARP1 directly interacted with JASMONATE-ZIM-domain (JAZ) repressors to prevent the COI1-mediated JAZ degradation, thus blocking JA signaling transduction. HARP1-like proteins have conserved function as effectors in noctuidae, and these types of effectors might contribute to insect adaptation to host plants during coevolution.
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Gossypium/genética , Interações Hospedeiro-Parasita/genética , Mariposas/patogenicidade , Doenças das Plantas/genética , Animais , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Ciclopentanos/metabolismo , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas/genética , Gossypium/crescimento & desenvolvimento , Gossypium/parasitologia , Mariposas/metabolismo , Oxilipinas/metabolismo , Doenças das Plantas/parasitologia , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Airway eosinophilic inflammation is a central feature in asthma which is mainly driven by type 2 response. The expression of galectin-13 was up-regulated in a parasitic infection model which is also characterized by type 2 immune response. We hypothesized that galectin-13 may be involved in airway eosinophilic inflammation in asthma. OBJECTIVE: To unveil the role of galectin-13 in asthma airway inflammation. METHODS: We measured galectin-13 expressions in bronchial brushings, sputum, and plasma of asthma patients (n = 54) and healthy controls (n = 15), and analysed the correlations between galectin-13 expression and airway eosinophilia. We used human bronchial epithelial cell line 16HBE to investigate the possible mechanism by which galectin-13 participates in eosinophilic inflammation. RESULTS: The expression of galectin-13 was markedly increased in subjects with asthma compared to controls. Epithelial galectin-13 mRNA levels in asthmatic subjects were strongly correlated with eosinophilic airway inflammation (the percentage of sputum eosinophils, the number of eosinophils in bronchial submucosa and FeNO) and the expression of Th2 signature genes (CLCA1, POSTN and SERPINB2). Inhaled corticosteroid (ICS) treatment reduced plasma galectin-13 levels, and baseline plasma galectin-13 levels reflect the response to ICS treatment. In cultured 16HBE cells, knockdown of galectin-13 suppressed IL-13-stimulated MCP-1 and eotaxin-1 expression by inhibiting the activation of EGFR and ERK. CONCLUSIONS & CLINICAL RELEVANCE: Galectin-13 is a novel marker for airway eosinophilia in asthma, and may contribute to allergic airway eosinophilic inflammation by up-regulating the expression of MCP-1 and eotaxin-1. Plasma galectin-13 levels may be useful for predicting responses to ICS treatment.
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Asma , Eosinofilia , Galectinas/metabolismo , Proteínas da Gravidez/metabolismo , Asma/tratamento farmacológico , Eosinofilia/genética , Eosinófilos/metabolismo , Humanos , Inflamação/metabolismo , Escarro/metabolismoRESUMO
1-Naphthol, a widely used raw material for organic synthesis, is also a well-known organic pollutant. Due to its high toxicity, 1-naphthol is rarely used by microorganisms as the sole carbon source for growth. In this study, catabolism of 1-naphthol by Sphingobium sp. strain B2 was found to be greatly enhanced by additional supplementation with primary carbon sources (e.g., glucose, maltose, and sucrose), and 1-naphthol was even used as the carbon source for growth when strain B2 cells had been preinduced by both 1-naphthol and glucose. A distinct two-component flavin-dependent monooxygenase, NdcA1A2, was found to be responsible for the initial hydroxylation of 1-naphthol to 1,2-dihydroxynaphthalene, a more toxic compound. Transcriptional levels of ndcA1A2 genes were significantly upregulated when strain B2 cells were cultured with both 1-naphthol and glucose compared to cells cultured with only 1-naphthol or glucose. Two transcriptional regulators, the activator NdcS and the inhibitor NdcR, were found to play key roles in the synergistic regulation of the transcription of the 1-naphthol initial catabolism genes ndcA1A2IMPORTANCE Cometabolism is a widely observed phenomenon, especially in the field of microbial catabolism of highly toxic xenobiotics. However, the mechanisms of cometabolism are ambiguous, and the roles of the obligately coexisting growth substrates remain largely unknown. In this study, we revealed that the roles of the coexisting primary carbon sources (e.g., glucose) in the enhanced catabolism of the toxic compound 1-naphthol in Sphingobium sp. strain B2 were not solely because they were used as growth substrates to support cell growth but, more importantly, because they acted as coinducers to interact with two transcriptional regulators, the activator NdcS and the inhibitor NdcR, to synergistically regulate the transcription of the 1-naphthol initial catabolism genes ndcA1A2 Our findings provide new insights into the cometabolic mechanism of highly toxic compounds in microorganisms.
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Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Oxigenases de Função Mista/genética , Naftóis/metabolismo , Sphingomonadaceae/genética , Proteínas de Bactérias/metabolismo , Oxigenases de Função Mista/metabolismo , Sphingomonadaceae/enzimologiaRESUMO
BACKGROUND: Distinguishing parotid pleomorphic adenoma (PPA) from parotid adenolymphoma (PA) is important for precision treatment, but there is a lack of readily available diagnostic methods. In this study, we aimed to explore the diagnostic value of radiomic signatures based on magnetic resonance imaging (MRI) for PPA and PA. METHODS: The clinical characteristic and imaging data were retrospectively collected from 252 cases (126 cases in the training cohort and 76 patients in the validation cohort) in this study. Radiomic features were extracted from MRI scans, including T1-weighted imaging (T1WI) sequences and T2-weighted imaging (T2WI) sequences. The radiomic features from three sequences (T1WI, T2WI and T1WI combined with T2WI) were selected using univariate analysis, LASSO correlation and Spearman correlation. Then, we built six quantitative radiomic models using the selected features through two machine learning methods (multivariable logistic regression, MLR, and support vector machine, SVM). The performances of the six radiomic models were assessed and the diagnostic efficacies of the ideal T1-2WI radiomic model and the clinical model were compared. RESULTS: The T1-2WI radiomic model using MLR showed optimal discriminatory ability (accuracy = 0.87 and 0.86, F-1 score = 0.88 and 0.86, sensitivity = 0.90 and 0.88, specificity = 0.82 and 0.80, positive predictive value = 0.86 and 0.84, negative predictive value = 0.86 and 0.84 in the training and validation cohorts, respectively) and its calibration was observed to be good (p > 0.05). The area under the curve (AUC) of the T1-2WI radiomic model was significantly better than that of the clinical model for both the training (0.95 vs. 0.67, p < 0.001) and validation (0.90 vs. 0.68, p = 0.001) cohorts. CONCLUSIONS: The T1-2WI radiomic model in our study is complementary to the current knowledge of differential diagnosis for PPA and PA.
Assuntos
Adenolinfoma/diagnóstico por imagem , Adenoma Pleomorfo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neoplasias Parotídeas/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Área Sob a Curva , Diagnóstico Diferencial , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Variações Dependentes do Observador , Estudos Retrospectivos , Sensibilidade e Especificidade , Máquina de Vetores de Suporte , Adulto JovemRESUMO
Chiral indoline-2-carboxylic acid has been identified to enable a highly enantioselective Catellani-type annulation of (hetero)aryl, alkenyl triflate and conjugated vinyl iodides with 4-(bromomethyl)cyclohexanone, directly assembling a diverse range of chiral all-carbon bridged ring systems. Control experiments and DFT calculations suggest that the coordinating orientation of the chiral amino acid to the arylpalladium(II) center allows for high levels of stereochemical control.
RESUMO
The Birch reduction is a powerful synthetic methodology that uses solvated electrons to convert inert arenes to 1,4-cyclohexadienes-valuable intermediates for building molecular complexity. Birch reductions traditionally employ alkali metals dissolved in ammonia to produce a solvated electron for the reduction of unactivated arenes such as benzene (Ered < -3.42 V vs SCE). Photoredox catalysts have been gaining popularity in highly reducing applications, but none have been reported to demonstrate reduction potentials powerful enough to reduce benzene. Here, we introduce benzo[ghi]perylene imides as new organic photoredox catalysts for Birch reductions performed at ambient temperature and driven by visible light from commercially available LEDs. Using low catalyst loadings (<1 mol percent), benzene and other functionalized arenes were selectively transformed to 1,4-cyclohexadienes in moderate to good yields in a completely metal-free reaction. Mechanistic studies support that this unprecedented visible-light-induced reactivity is enabled by the ability of the organic photoredox catalyst to harness the energy from two visible-light photons to affect a single, high-energy chemical transformation.