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1.
Nature ; 621(7980): 857-867, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37730992

RESUMO

Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.


Assuntos
Fibrose Cística , Modelos Animais de Doenças , Furões , Pulmão , Transgenes , Animais , Humanos , Animais Geneticamente Modificados , Linhagem da Célula , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Furões/genética , Furões/fisiologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Pulmão/patologia , Traqueia/citologia , Transgenes/genética
2.
Nature ; 604(7904): 120-126, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35355013

RESUMO

The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.


Assuntos
Bronquíolos , Furões , Células-Tronco Multipotentes , Alvéolos Pulmonares , Animais , Bronquíolos/citologia , Linhagem da Célula , Humanos , Pulmão/patologia , Camundongos , Células-Tronco Multipotentes/citologia , Alvéolos Pulmonares/citologia , Doença Pulmonar Obstrutiva Crônica
3.
Nature ; 590(7845): 290-299, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568819

RESUMO

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Genômica , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisão , Citocromo P-450 CYP2D6/genética , Haplótipos/genética , Heterozigoto , Humanos , Mutação INDEL , Mutação com Perda de Função , Mutagênese , Fenótipo , Polimorfismo de Nucleotídeo Único , Densidade Demográfica , Medicina de Precisão/normas , Controle de Qualidade , Tamanho da Amostra , Estados Unidos , Sequenciamento Completo do Genoma/normas
4.
Blood ; 143(4): 320-335, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-37801708

RESUMO

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with resistant clonal propagation in recurrence. We performed high-throughput droplet-based 5' single-cell RNA with paired T-cell receptor (TCR) sequencing of paired diagnosis-relapse (Dx_Rel) T-ALL samples to dissect the clonal diversities. Two leukemic evolutionary patterns, "clonal shift" and "clonal drift" were unveiled. Targeted single-cell DNA sequencing of paired Dx_Rel T-ALL samples further corroborated the existence of the 2 contrasting clonal evolution patterns, revealing that dynamic transcriptional variation might cause the mutationally static clones to evolve chemotherapy resistance. Analysis of commonly enriched drifted gene signatures showed expression of the RNA-binding protein MSI2 was significantly upregulated in the persistent TCR clonotypes at relapse. Integrated in vitro and in vivo functional studies suggested that MSI2 contributed to the proliferation of T-ALL and promoted chemotherapy resistance through the posttranscriptional regulation of MYC, pinpointing MSI2 as an informative biomarker and novel therapeutic target in T-ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteínas de Ligação a RNA , Humanos , Evolução Clonal/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Recidiva , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Linfócitos T/metabolismo
6.
Opt Express ; 32(4): 5206-5213, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38439252

RESUMO

Artificially designed metamaterial structures can manipulate electromagnetic waves, endowing them with exotic physical properties that are not found in natural materials, such as negative refractive index, superlens, and inverse Doppler effect. These characteristics are widely applied in various engineering and military applications. Due to increasingly complex application environments and innovation in radar detection technology, the combination of broadband absorption performance under thin thickness and efficient preparation methods at low cost is often the focus of research on new generation stealth materials. Here, we propose Al@SiO2 composite conductive film metamaterial (Al@SiO2 CCFM) to achieve wideband absorption of electromagnetic waves. This metamaterial structure combines two resonant units, resulting in three absorption bands in the absorption curve. The results show that the absorption rate of the metamaterial is above 90% in the frequency range of 10.6 GHz to 26.0 GHz. The resonance mechanism between multiple structures is a prerequisite for achieving wideband absorption. The materials Al and SiO2 used in Al@SiO2 CCFM are inexpensive and abundant, and the fabrication method is simple. Therefore, they hold great potential for large-scale applications in the multispectral stealth and electromagnetic shielding field.

7.
Analyst ; 149(11): 3064-3072, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38712864

RESUMO

Ratiometric near-infrared fluorescent pH probes with various pKa values were innovatively designed and synthesized based on cyanine with a diamine moiety. The photochemical properties of these probes were thoroughly evaluated. Among the series, IR-PHA exhibited an optimal pKa value of approximately 6.40, closely matching the pH of cancerous tissues. This feature is particularly valuable for real-time pH monitoring in both living cells and living mice. Moreover, when administered intravenously to tumor-bearing mice, IR-PHA demonstrated rapid and significant enhancement of near-infrared fluorescence and photoacoustic signals within the tumor region. This outcome underscores the probe's exceptional capability for dual-modal cancer imaging utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) modalities. Concurrently, the application of a continuous-wave near-infrared laser efficiently ablated cancer cells in vivo, attributed to the photothermal effect induced by IR-PHA. The results strongly indicate that IR-PHA is well-suited for NIRF/PA dual-modality imaging and photothermal therapy of tumors. This makes it a promising candidate for theranostic applications involving small molecules.


Assuntos
Corantes Fluorescentes , Raios Infravermelhos , Técnicas Fotoacústicas , Terapia Fototérmica , Animais , Técnicas Fotoacústicas/métodos , Humanos , Camundongos , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Terapia Fototérmica/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Camundongos Nus , Imagem Óptica/métodos , Feminino
8.
Macromol Rapid Commun ; 45(12): e2400083, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38537692

RESUMO

Photoactive conjugated microporous polymers (CMPs) as heterogeneous photocatalysts provide a sustainable alternative to classical metal-based semiconductor photosensitizers. However, previously reported CMPs are typically synthesized through metal catalyzed coupling reactions, which bears product separation, but also increases the price of materials. Herein, a new type of sp2 carbon linked DCM-CMPs are successfully designed and synthesized by organic base catalyzed Knoevenagel reaction using 2,6-Dimethyl-4H-pyran-4-ylidene-malononitrile and aromatic polyaldehydes as monomers. The new polymers feature inherent porosity, excellent stability, and fully π-conjugated skeleton with broad visible-light absorption. They effectively induce the synthesis of benzimidazole compounds under light irradiation, and exhibit wide substrate adaptability with outstanding recyclability.


Assuntos
Nitrilas , Processos Fotoquímicos , Polímeros , Catálise , Nitrilas/química , Porosidade , Polímeros/química , Polímeros/síntese química , Estrutura Molecular , Luz , Piranos/química , Piranos/síntese química , Propriedades de Superfície , Benzimidazóis/química , Tamanho da Partícula
9.
Nature ; 560(7718): 382-386, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089911

RESUMO

Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2-4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.


Assuntos
Antígeno B7-H1/imunologia , Exossomos/metabolismo , Tolerância Imunológica/imunologia , Melanoma/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral/imunologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/sangue , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Tolerância Imunológica/efeitos dos fármacos , Interferon gama/sangue , Interferon gama/imunologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos Nus , Metástase Neoplásica , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Environ Res ; 248: 118283, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38253190

RESUMO

Atmospheric fine particulate matter (PM2.5) enters the human body through respiration and poses a threat to human health. This is not only dependent on its mass concentration in the atmosphere, but also related to seasonal variations in its chemical components, which makes it important to study the cytotoxicity of PM2.5 in different seasons. Traditional immersion exposure cannot simulate the living environment of human epithelial cells in the human body, making this method unsuitable for evaluating the inhalation toxicity of PM2.5. In this study, a novel air-liquid interface (ALI) particulate matter exposure device (VITROCELL Cloud 12 system) was used to evaluate the toxic effects and potential mechanisms of human lung epithelial cells (A549) after exposure to seasonal PM2.5. PM2.5 samples from four seasons were collected and analyzed for chemical components. After 6 h of exposure to seasonal PM2.5, winter PM2.5 exhibited the highest cytotoxicity among most toxicity indicators, especially apoptosis rate, reactive oxygen species (ROS), inflammatory responses and DNA damage (γ-H2AX). The effect of autumn PM2.5 on apoptosis rate was significantly higher than that in spring, and there was no significant difference in other toxicity indicators between spring and autumn. The cytotoxicity of summer PM2.5 was the lowest among the four seasons. It should be noted that even exposure to low doses of summer PM2.5 leads to significant DNA damage in A459 cells. Correlation analysis results showed that water-soluble ions, metallic elements, and polycyclic aromatic hydrocarbons (PAHs) were associated with most toxicological endpoints. Inhibitors of oxidative stress and endoplasmic reticulum (ER) stress significantly inhibited cellular damage, indicating that PM2.5-induced cytotoxicity may be related to the generation of ROS and ER stress. In addition, PM2.5 can induce ER stress through oxidative stress, which ultimately leads to apoptosis.


Assuntos
Poluentes Atmosféricos , Hidrocarbonetos Policíclicos Aromáticos , Humanos , Poluentes Atmosféricos/toxicidade , Estações do Ano , Células A549 , Espécies Reativas de Oxigênio/análise , Material Particulado/análise , Estresse Oxidativo , Estresse do Retículo Endoplasmático , Monitoramento Ambiental/métodos , Hidrocarbonetos Policíclicos Aromáticos/análise , China
11.
BMC Nephrol ; 25(1): 107, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504194

RESUMO

BACKGROUND: This study intends to explore the role and molecular mechanism of hsa_circ_0005519 in acute kidney injury (AKI). METHODS: We conducted reverse transcription-qPCR for human serum to determine levels of hsa_circ_0005519 in AKI patients and healthy controls. Hsa_circ_0005519 was inhibited for expression in HK-2 cells using specific siRNAs. A number of techniques, MTT and ELISA assays, were used to analyze the potential role of hsa_circ_0005519 in cell viability, oxidative stress, and inflammation of LPS-induced HK-2 cells. RESULTS: The serum of patients with AKI exhibited a significant increase in hsa_circ_0005519 expression, compared with healthy controls. Hsa_circ_0005519 was knockdown by siRNA, and its knockdown led to cell viability increase in LPS-induced HK-2 cells. Inhibition of hsa_circ_0005519 can reverse the TNF-α, IL-6 and IL-1ß increase in LPS-induced HK-2 cells. Inhibiting hsa_circ_0005519 led to downregulation of MPO and MDA levels. MiR-98-5p was a downstream miRNA for hsa_circ_0005519. MiR-98-5p can offset the effects of hsa_circ_0005519 on LPS-induced HK-2 cells. IFG1R was a target gene for miR-98-5p. CONCLUSIONS: These findings indicate that the highly expressed hsa_circ_0005519 plays a promoting role in AKI.


Assuntos
Injúria Renal Aguda , MicroRNAs , Humanos , RNA Circular/genética , Lipopolissacarídeos , MicroRNAs/genética , Injúria Renal Aguda/genética , Sobrevivência Celular , RNA Interferente Pequeno , Apoptose , Proliferação de Células
12.
Postgrad Med J ; 100(1181): 179-186, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38079630

RESUMO

OBJECTIVES: We determined the common clinical characteristics of patients infected with Helicobacter pylori (H. pylori) and investigated the relationship between H. pylori infection, and clinical symptoms, and gastroscopic manifestations. Our focus was specifically on the clinical manifestations in asymptomatic patients. METHODS: We obtained the physical examination data of patients who underwent the 14C urea breath test between January 2018 and December 2020 at our Hospital. Basic demographic data, questionnaire data on clinical symptoms, and clinical examination data of the patients were also collected, and the correlation analysis was performed. RESULTS: A total of 2863 participants were included in the study. The overall H. pylori infection rate was 26.30%. The clinical symptoms between H. pylori-positive patients and H. pylori-negative patients did not differ significantly (P > .05). However, H. pylori-positive patients exhibited more severe gastroscopic manifestations (P < .001). The 14C urea breath test disintegrations per minute (DPM) values in H. pylori-positive patients correlated with their serum pepsinogen and gastrin-17 levels. With an increase in the DPM value, more combinations of clinical symptoms appeared in the patients. Among H. pylori-positive patients, DPM levels in asymptomatic patients were lower than those in symptomatic patients (P < .001). However, gastroscopic manifestations did not vary significantly between asymptomatic and symptomatic patients (P > .05). CONCLUSION: Patients infected with H. pylori showed no specific gastrointestinal symptoms. Patients with asymptomatic infection showed lower DPM levels, but their gastroscopic manifestations were similar to those of patients with symptomatic infection, and their lesions were more severe than H. pylori-negative people.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Infecções Assintomáticas/epidemiologia , Ureia/análise , Gastroscopia , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/epidemiologia , Radioisótopos de Carbono
13.
Sensors (Basel) ; 24(11)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38894263

RESUMO

In order to improve the efficiency and accuracy of multitarget detection of soldering defects on surface-mounted components in Printed Circuit Board (PCB) fabrication, we propose a sample generation method using Stable Diffusion Model and ControlNet, as well as a defect detection method based on the Swin Transformer. The method consists of two stages: First, high-definition original images collected in industrial production and the corresponding prompts are input to Stable Diffusion Model and ControlNet for automatic generation of nonindependent samples. Subsequently, we integrate Swin Transformer as the backbone into the Cascade Mask R-CNN to improve the quality of defect features extracted from the samples for accurate detection box localization and segmentation. Instead of segmenting individual components on the PCB, the method inspects all components in the field of view simultaneously over a larger area. The experimental results demonstrate the effectiveness of our method in scaling up nonindependent sample datasets, thereby enabling the generation of high-quality datasets. The method accurately recognizes targets and detects defect types when performing multitarget inspection on printed circuit boards. The analysis against other models shows that our improved defect detection and segmentation method improves the Average Recall (AR) by 2.8% and the mean Average Precision (mAP) by 1.9%.

14.
J Environ Manage ; 361: 121255, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38815426

RESUMO

The energy consumption and carbon emissions in the construction field, coupled with the accumulation of various industrial solid wastes, particularly bauxite residue (red mud), represent formidable barriers to sustainable development. The synergistic utilization of bauxite residue (red mud) in cementitious materials and special concrete is widely considered one of the most practical approaches for these issues. In this comprehensive review, characteristics and composition of red mud worldwide were investigated. By comparing and reviewing the latest research, the current achievements in applying red mud with various solid wastes in cementitious materials and special concrete were discussed. In addition, critical mechanisms and environmental suitability issues are emphasized. In conclusion, the present work culminates in identifying the challenges faced and opportunities for progressing in synergizing red mud and multi-solid wastes, which will contribute to the international research community for sustainable development in the industry.


Assuntos
Óxido de Alumínio , Materiais de Construção , Resíduos Sólidos , Óxido de Alumínio/química
15.
J Headache Pain ; 25(1): 74, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38724948

RESUMO

BACKGROUND: Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM. METHODS: A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated. RESULTS: Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE. CONCLUSION: EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.


Assuntos
Sensibilização do Sistema Nervoso Central , Modelos Animais de Doenças , Hiperalgesia , Transtornos de Enxaqueca , Nitroglicerina , Animais , Nitroglicerina/toxicidade , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/metabolismo , Hiperalgesia/induzido quimicamente , Feminino , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Sensibilização do Sistema Nervoso Central/fisiologia , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Meio Ambiente , Camundongos Endogâmicos C57BL
16.
Angew Chem Int Ed Engl ; : e202411546, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38949611

RESUMO

Two-dimensional covalent organic frameworks (2D-COFs) have recently emerged as fascinating scaffolds for solar-to-chemical energy conversion because of their customizable structures and functionalities. Herein, two tris(triazolo)triazine-based COF materials (namely COF-JLU51 and COF-JLU52) featuring large surface area, high crystallinity, excellent stability and photoelectric properties were designed and constructed for the first time. Remarkably, COF-JLU51 gave an outstanding H2O2 production rate of over 4200 µmol g-1 h-1 with excellent reusability in pure water and O2 under one standard sun light, that higher than its isomorphic COF-JLU52 and most of the reported metal-free materials, owing to its superior generation, separation and transport of photogenerated carriers. Experimental and theoretical researches prove that the photocatalytic process undergoes a combination of indirect 2e- O2 reduction reaction (ORR) and 4e- H2O oxidation reaction (WOR). Specifically, an ultrahigh yield of 7624.7 µmol g-1 h-1 with apparent quantum yield of 18.2% for COF-JLU52 was achieved in a 1:1 ratio of benzyl alcohol and water system. This finding contributes novel, nitrogen-rich and high-quality tris(triazolo)triazine-based COF materials, and also designate their bright future in photocatalytic solar transformations.

17.
Am J Respir Cell Mol Biol ; 69(3): 295-309, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37141531

RESUMO

Pulmonary ionocytes express high levels of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that is critical for hydration of the airways and mucociliary clearance. However, the cellular mechanisms that govern ionocyte specification and function remain unclear. We observed that increased abundance of ionocytes in cystic fibrosis (CF) airway epithelium was associated with enhanced expression of Sonic Hedgehog (SHH) effectors. In this study, we evaluated whether the SHH pathway directly impacts ionocyte differentiation and CFTR function in airway epithelia. Pharmacological HPI1-mediated inhibition of SHH signaling component GLI1 significantly impaired human basal cell specification of ionocytes and ciliated cells but significantly enhanced specification of secretory cells. By contrast, activation of the SHH pathway effector smoothened (SMO) with the chemical agonist SAG significantly enhanced ionocyte specification. The abundance of CFTR+ BSND+ ionocytes under these conditions had a direct relationship with CFTR-mediated currents in differentiated air-liquid interface (ALI) airway cultures. These findings were corroborated in ferret ALI airway cultures generated from basal cells in which the genes encoding the SHH receptor PTCH1 or its intracellular effector SMO were genetically ablated using CRISPR-Cas9, causing aberrant activation or suppression of SHH signaling, respectively. These findings demonstrate that SHH signaling is directly involved in airway basal cell specification of CFTR-expressing pulmonary ionocytes and is likely responsible for enhanced ionocyte abundance in the CF proximal airways. Pharmacologic approaches to enhance ionocyte and reduce secretory cell specification after CFTR gene editing of basal cells may have utility in the treatment of CF.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Proteínas Hedgehog , Animais , Humanos , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Epitélio/metabolismo , Furões , Proteínas Hedgehog/metabolismo
18.
BMC Genomics ; 24(1): 539, 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37700248

RESUMO

BACKGROUND: 5-methylcytosine (m5C) modification is widely associated with many biological and pathological processes. However, knowledge of m5C modification in osteoarthritis (OA) remains lacking. Thus, our study aimed to identify common m5C features in OA. RESULTS: In the present study, we identified 1395 differentially methylated genes (DMGs) and 1673 differentially expressed genes (DEGs) using methylated RNA immunoprecipitation next-generation sequencing (MeRIP-seq) and RNA-sequencing. A co-expression analysis of DMGs and DEGs showed that the expression of 133 genes was significantly affected by m5C methylation. A protein-protein interaction network of the 133 genes was constructed using the STRING database, and the cytoHubba plug-in of Cytoscape was used to hub genes were screen out 11 hub genes, including MMP14, VTN, COL15A1, COL6A2, SPARC, COL5A1, COL6A3, COL6A1, COL8A2, ADAMTS2 and COL7A1. The Pathway enrichment analysis by the ClueGO and CluePedia plugins in Cytoscape showed that the hub genes were significantly enriched in collagen degradation and extracellular matrix degradation. CONCLUSIONS: Our study indicated that m5C modification might play an important role in OA pathogenesis, and the present study provides worthwhile insight into identifying m5C-related therapeutic targets in OA.


Assuntos
Osteoartrite , RNA , Humanos , 5-Metilcitosina , Bases de Dados Factuais , Sequenciamento de Nucleotídeos em Larga Escala , Osteoartrite/genética , Colágeno Tipo VII
19.
BMC Genomics ; 24(1): 584, 2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37789264

RESUMO

BACKGROUND: B-box (BBX) proteins play important roles in regulating plant growth, development, and abiotic stress responses. BBX family genes have been identified and functionally characterized in many plant species, but little is known about the BBX family in blueberry (Vaccinium corymbosum). RESULT: In this study, we identified 23 VcBBX genes from the Genome Database for Vaccinium (GDV). These VcBBXs can be divided into five clades based on gene structures and conserved domains in their encoded proteins. The prediction of cis-acting elements in the upstream sequences of VcBBX genes and protein-protein interactions indicated that VcBBX proteins are likely involved in phytohormone signaling pathways and abiotic stress responses. Analysis of transcriptome deep sequencing (RNA-seq) data showed that VcBBX genes exhibited organ-specific expression pattern and 11 VcBBX genes respond to ultraviolet B (UV-B) radiation. The co-expression analysis revealed that the encoded 11 VcBBX proteins act as bridges integrating UV-B and phytohormone signaling pathways in blueberry under UV-B radiation. Reverse-transcription quantitative PCR (RT-qPCR) analysis showed that most VcBBX genes respond to drought, salt, and cold stress. Among VcBBX proteins, VcBBX24 is highly expressed in all the organs, not only responds to abiotic stress, but it also interacts with proteins in UV-B and phytohormone signaling pathways, as revealed by computational analysis and co-expression analysis, and might be an important regulator integrating abiotic stress and phytohormone signaling networks. CONCLUSIONS: Twenty-three VcBBX genes were identified in blueberry, in which, 11 VcBBX genes respond to UV-B radiation, and act as bridges integrating UV-B and phytohormone signaling pathways according to RNA-seq data. The expression patterns under abiotic stress suggested that the functional roles of most VcBBX genes respose to drought, salt, and cold stress. Our study provides a useful reference for functional analysis of VcBBX genes and for improving abiotic stress tolerance in blueberry.


Assuntos
Mirtilos Azuis (Planta) , Mirtilos Azuis (Planta)/genética , Reguladores de Crescimento de Plantas/metabolismo , Estresse Fisiológico/genética , Genoma de Planta , Transcriptoma , Resposta ao Choque Frio , Proteínas de Plantas/metabolismo , Filogenia , Regulação da Expressão Gênica de Plantas
20.
J Am Chem Soc ; 2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36917067

RESUMO

Two-dimensional covalent-organic frameworks (2D COFs) have recently emerged as great prospects for their applications as new photocatalytic platforms in solar-to-hydrogen conversion; nevertheless, their inefficient solar energy capture and fast charge recombination hinder the improvement of photocatalytic hydrogen production performance. Herein, two photoactive three-component donor-π-acceptor (TCDA) materials were constructed using a multicomponent synthesis strategy by introducing electron-deficient triazine and electron-rich benzotrithiophene moieties into frameworks through sp2 carbon and imine linkages, respectively. Compared with two-component COFs, the novel TCDA-COFs are more convenient in regulating the inherent photophysical properties, thereby realizing outstanding photocatalytic activity for hydrogen evolution from water. Remarkably, the first sp2 carbon-linked TCDA-COF displays an impressive hydrogen evolution rate of 70.8 ± 1.9 mmol g-1 h-1 with excellent reusability in the presence of 1 wt % Pt under visible-light illumination (420-780 nm). Utilizing the combination of diversified spectroscopy and theoretical prediction, we show that the full π-conjugated linkage not only effectively broadens the visible-light harvesting of COFs but also enhances charge transfer and separation efficiency.

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