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Selecting adequate ferritic stainless steel (FSS) with a high corrosion resistance and a low cost is critical for solid oxide fuel cells (SOFCs) operating at intermediate temperature. In this study, the corrosion behaviors of four commercial FSSs involving TS430, TY441, YG442, and TY445 with a Cr content ranging from 16.18 wt.% to 21.73 wt.% are investigated at 650 °C. The oxidation mass gains, microstructures of surface oxide scale, and electrical conductivities are measured. The effects of grain size as well as doped elements are estimated together with the Cr volatilization. Flaky Cr2O3 particles are formed on TS430 and TY441 dominated by the outward migration of Cr3+. In comparison, a thin and dense layer of chromia is observed on YG442 and TY445. A high Cr content and a uniformly distributed grain size are conducive to the formation of a thin and dense chromia scale on the FSS surface during the initial oxidation process. On the other hand, the addition of Nb, Ti, and Mo weakens the outward diffusion of Cr3+ and reduces the particle size of chromia. After oxidation at 650 °C for 120 h, scattered (Mn, Cr)3O4 spinel particles occur on TS430, YG442, and TY445. TY445 and YG442 exhibit a higher conductivity although all the results of area specific resistance (ASR) are less than 6 mΩ·cm2. Meanwhile, the effect of Cr volatilization is enlarged on the estimation of mass gain at 650 °C compared with even higher temperatures.
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Small-interfering RNAs (siRNAs) offer promising prospects for treating pyroptosis-related autoimmune diseases. However, poor stability and off-target effects during in vivo transportation hinder their practical clinical applications. Precision delivery and adaptive release of siRNAs into inflamed tissues and immune cells could unleash their full therapeutic potential. This study establishes a pyroptotic-spatiotemporally selective siRNA delivery system (PMRC@siGSDME) that selectively targets inflammatory tissues, responds to pyroptosis, and exhibits remarkable therapeutic efficacy against various autoimmune diseases. Novel hybrid nanovesicles (NVs) are designed as a combination of pyroptotic macrophage membranes (PMs) and R8-cardiolipin-containing nanovesicles (RC-NVs). Evidence provides that PM-derived proteins involved in cell-cell interactions and membrane trafficking may contribute to the specificity of NVs to inflammatory tissue. In addition, cardiolipin anchored in the hybrid NVs increases its affinity for activated gasdermin E (GSDME) and achieves pyroptosis-adaptive release of siGSDME for the spatiotemporally selective suppression of immune responses. More importantly, PMRC@siGSDME displays significant anti-inflammatory and therapeutic effects in multiple mouse autoimmune disease models, including arthritis and inflammatory bowel disease (IBD). Collectively, an innovative siRNA delivery strategy precisely tailored for pyroptotic cells has been developed, paving the way for new treatments for autoimmune inflammatory diseases with minimal side effects and wide clinical applicability.
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Droplet-based single-cell sequencing techniques rely on the fundamental assumption that each droplet encapsulates a single cell, enabling individual cell omics profiling. However, the inevitable issue of multiplets, where two or more cells are encapsulated within a single droplet, can lead to spurious cell type annotations and obscure true biological findings. The issue of multiplets is exacerbated in single-cell multiomics settings, where integrating cross-modality information for clustering can inadvertently promote the aggregation of multiplet clusters and increase the risk of erroneous cell type annotations. Here, we propose a compound Poisson model-based framework for multiplet detection in single-cell multiomics data. Leveraging experimental cell hashing results as the ground truth for multiplet status, we conducted trimodal DOGMA-seq experiments and generated 17 benchmarking datasets from two tissues, involving a total of 280,123 droplets. We demonstrated that the proposed method is an essential tool for integrating cross-modality multiplet signals, effectively eliminating multiplet clusters in single-cell multiomics data-a task at which the benchmarked single-omics methods proved inadequate.
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Análise de Célula Única , Análise de Célula Única/métodos , Humanos , Animais , Análise por Conglomerados , Algoritmos , Camundongos , Distribuição de Poisson , MultiômicaRESUMO
BACKGROUND: Liver ischemia-reperfusion (IR) injury is an inevitable pathophysiological process in various liver surgeries. Previous studies have found that IR injury is exacerbated in fatty liver due to significant hepatocellular damage and macrophage inflammatory activation, though the underlying mechanisms are not fully understood. In this study, we aim to explore the role and mechanism of Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling in regulating hepatocellular damage and macrophage immune response in fatty liver IR injury. METHODS: The study used high-fat diet-induced fatty liver mice to establish an IR model, alongside an in vitro co-culture system of primary hepatocytes and macrophages. This approach was used to examine mitochondrial dysfunction, oxidative stress, mitochondrial DNA (mtDNA) release, and activation of macrophage STING (Stimulator of interferon genes) signaling. We also conducted recovery verification using H-151 (a STING inhibitor) and tBHQ (an Nrf2 activator). RESULTS: Compared to the control group, mice on a high-fat diet demonstrated more severe liver IR injury, as evidenced by increased histological damage, elevated liver enzyme levels, and heightened inflammatory markers. The HFD group showed significant oxidative stress and mitochondrial dysfunction and damage post-IR, as indicated by elevated levels of ROS and lipid peroxidation markers, and decreased antioxidant enzyme activity. Elevated mtDNA release from hepatocytes post-IR activated macrophage STING signaling, worsening inflammation and liver damage. However, STING signaling inhibition with H-151 in vivo or employing STING knockout macrophages significantly reduced these injuries. In-depth mechanism studies have found that the transfer of Nrf2 protein into the nucleus of liver cells after IR in fatty liver is reduced. Pre-treatment with tBHQ ameliorated liver oxidative stress, mitochondrial damage and suppressed the macrophage STING signaling activation. CONCLUSIONS: Our study reveals a novel mechanism where the interaction between hepatocellular damage and macrophage inflammation intensifies liver IR injury in fatty liver. Enhancing Nrf2 activation to protect mitochondrial from oxidative stress damage and inhibiting macrophage STING signaling activation emerge as promising strategies for clinical intervention in fatty liver IR injury.
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Hepatócitos , Hidroquinonas , Macrófagos , Proteínas de Membrana , Fator 2 Relacionado a NF-E2 , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , DNA Mitocondrial , Fígado Gorduroso/patologia , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Hidroquinonas/farmacologia , Fígado/patologia , Fígado/metabolismo , Fígado/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/imunologia , Transdução de SinaisRESUMO
The objective of this investigation was to analyse the correlation between the neutrophil-to-lymphocyte ratio (NLR) status in the immune microenvironment (IME) and the prognostic outcomes of patients who have undergone radical surgery for colorectal cancer (CRC). In light of the continued prevalence of CRC in China, this study utilised Kaplan-Meier and Cox regression analyses to assess the prognostic relevance of NLR status in IME among patients with CRC. Furthermore, cellular experiments, such as cell scratching, were conducted to elucidate the underlying mechanisms of NLR's impact on CRC. The NLR status in IME has been found to have a significant impact on the prognosis of patients with CRC. Patients who exhibit elevated intratumoural and extratumoural NLR are associated with a poor prognosis. Experimental evidence indicates that tumour-associated neutrophil (TAN) augments the migratory, invasive, and proliferative potential of HT-29, HCT-116 and LOVO colorectal cancer cells, while concurrently reducing their sensitivity to oxaliplatin. Conversely, lymphocytes have demonstrated cytotoxic effects on HT-29 cells. The NLR status in IME may serve as a prognostic biomarker for resectable CRC.
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Neoplasias Colorretais , Linfócitos , Neutrófilos , Humanos , Neutrófilos/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/diagnóstico , Linfócitos/patologia , Prognóstico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Microambiente Tumoral/imunologia , Estimativa de Kaplan-Meier , AdultoRESUMO
At present, diabetes mellitus (DM) has been one of the most endangering healthy diseases. Current therapies contain controlling high blood sugar, reducing risk factors like obesity, hypertension, and so on; however, DM patients inevitably and eventually progress into different types of diabetes complications, resulting in poor quality of life. Unfortunately, the clear etiology and pathogenesis of diabetes complications have not been elucidated owing to intricate whole-body systems. The immune system was responsible to regulate homeostasis by triggering or resolving inflammatory response, indicating it may be necessary to diabetes complications. In fact, previous studies have been shown inflammation plays multifunctional roles in the pathogenesis of diabetes complications and is attracting attention to be the meaningful therapeutic strategy. To this end, this review systematically concluded the current studies over the relationships of susceptible diabetes complications (e.g., diabetic cardiomyopathy, diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy) and inflammation, ranging from immune cell response, cytokines interaction to pathomechanism of organ injury. Besides, we also summarized various therapeutic strategies to improve diabetes complications by target inflammation from special remedies to conventional lifestyle changes. This review will offer a panoramic insight into the mechanisms of diabetes complications from an inflammatory perspective and also discuss contemporary clinical interventions.
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BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.
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Background: Evidence from observational studies and clinical trials suggests that the gut microbiota is associated with gynecological diseases. However, the causal relationship between gut microbiota and menstrual disorders remains to be determined. Methods: We obtained summary data of gut microbiota from the global consortium MiBio-Gen's genome-wide association study (GWAS) dataset and data on menstrual disorders from the IEU Open GWAS project. MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode were used to examine the causal association between gut microbiota and menstrual disorders. Thorough sensitivity studies were performed to confirm the data's horizontal pleiotropy, heterogeneity, and robustness. Results: Through MR analysis of 119 kinds of gut microbiota and 4 kinds of clinical phenotypes, it was discovered that 23 different kinds of gut microbiota were loosely connected to menstrual disorders. After FDR correction, the results showed that only Escherichia/Shigella (p = 0.00032, PFDR = 0.0382, OR = 1.004, 95%CI = 1.002-1.006) is related to menstrual disorders. Conclusion: According to our MR Analysis, there are indications of a causal relationship between menstrual disorders and gut microbiota. This finding could lead to new discoveries into the mechanisms behind menstrual disorders and clinical research involving the microbiota.
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We introduce the Discrete-Temporal Sobolev Network (DTSN), a neural network loss function that assists dynamical system forecasting by minimizing variational differences between the network output and the training data via a temporal Sobolev norm. This approach is entirely data-driven, architecture agnostic, and does not require derivative information from the estimated system. The DTSN is particularly well suited to chaotic dynamical systems as it minimizes noise in the network output which is crucial for such sensitive systems. For our test cases we consider discrete approximations of the Lorenz-63 system and the Chua circuit. For the network architectures we use the Long Short-Term Memory (LSTM) and the Transformer. The performance of the DTSN is compared with the standard MSE loss for both architectures, as well as with the Physics Informed Neural Network (PINN) loss for the LSTM. The DTSN loss is shown to substantially improve accuracy for both architectures, while requiring less information than the PINN and without noticeably increasing computational time, thereby demonstrating its potential to improve neural network forecasting of dynamical systems.
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Algoritmos , Redes Neurais de Computação , Aprendizagem , Memória de Longo Prazo , PrevisõesRESUMO
Radioactive iodine in the nuclear field is considered very dangerous nuclear waste because of its chemical toxicity, high mobility and long radioactive half-life. Herein, a conjugated two-dimensional covalent organic framework, TPB-TMPD-COF, has been designed and synthesized for iodine capture. TPB-TMPD-COF has been well characterized by several techniques and showed long order structure and a large surface area (1090 m2 g-1). Moreover, TPB-TMPD-COF shows a high iodine capture value at 4.75 g g-1 under 350 K and normal pressure conditions, benefitting from the increased density of adsorption sites. By using multiple techniques, the iodine vapor adsorbed into the pores may readily generate the electron transfer species (I3- and I5-) due to the strong interactions between imine groups and iodine molecules, which contributes to the high iodine uptake for TPB-TMPD-COF. Our study will stimulate the design and synthesis of COFs as a solid-phase adsorbent for iodine uptake.
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Functionalization is a major challenge for the application of photoswitches. With the aim to develop novel bis-functional azo photoswitches with stationary photophysical properties, a series of phenolylazoindole derivatives were designed, synthesized, and characterized via NMR spectroscopy studies and high-resolution mass spectrometry (HRMS). Herein, UV/Vis and 1H NMR spectra revealed that the photostationary state (PSS) proportions for PSScis and PSStrans were 76-80% and 68-81%, respectively. Furthermore, the thermal half-lives (t1/2) of compounds A2-A4 and B2 ranged from 0.9 to 5.3 h, affected by the diverse substituents at the R1 and R2 positions. The results indicated that azo photoswitches based on the phenolylazoindole scaffold had stationary photophysical properties and wouldn't be excessively affected by modifying the functional groups. Compounds A4 and B2, which were modified with an aryl group, also exhibited fluorescence emission properties (the quantum yields of A4 and B2 were 2.32% and 13.34%) through the modification of the flexible conjugated structure (benzene) at the R2 position. Significantly, compound C1 was obtained via modification with a pharmacophore in order to acquire antifungal activities against three plant fungi, Rhizoctonia solani (R. solani), Botrytis cinerea (B. cinerea), and Fusarium graminearum (F. graminearum). Strikingly, the inhibitory activity of the cis-isomer of compound C1towards R. solani (53.3%) was significantly better than that of the trans-isomer (34.2%) at 50 µg mL-1. In order to further reveal the antifungal mechanism, molecular docking simulations demonstrated that compound C1 effectively integrates into the cavity of succinate dehydrogenase (SDH); the optically controlled cis-isomer showed a lower binding energy with SDH than that of the trans-isomer. This research confirmed that phenolylazoindole photoswitches can be appropriately applied as molecular regulatory devices and functional photoswitch molecules via bis-functionalization.
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Antifúngicos , Fungicidas Industriais , Antifúngicos/química , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Rhizoctonia , Fungicidas Industriais/químicaRESUMO
PURPOSE: The albumin to alkaline phosphatase ratio (AAPR) is a newly developed blood biomarker that has been reported to have prognostic value in several types of cancers. The aim of this study was to investigate the predictive value of AAPR in overall survival after radical colon cancer surgery in patients with stage I-III colorectal cancer (CRC). METHODS: The clinical data of 221 eligible patients with stage I â¼ III CRC were retrospectively analyzed. A series of survival analyses were performed to assess the prognostic value of AAPR. Univariate and multifactorial Cox analyses were performed to identify independent risk factors. Columnar graph prediction models were further constructed based on independent risk factors such as AAPR, and their predictive properties were validated. RESULTS: The optimal cutoff value of preoperative AAPR for postoperative overall survival (OS) in patients undergoing laparoscopic radical CRC was .495 as shown by univariate and multifactorial Cox regression analysis. The factors of age ≤65 years, Tumor-Node-Metastasis (TNM) stage I-II, tumor grading (high/medium differentiation), CEA ≤5, and AAPR ≥.495 were associated with better OS (P < .05). CONCLUSIONS: Preoperative AAPR level was a good predictor of postoperative survival in patients undergoing laparoscopic radical CRC surgery, and AAPR <.495 was an independent risk factor for decreased postoperative OS.
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Albuminas , Fosfatase Alcalina , Neoplasias Colorretais , Idoso , Humanos , Albuminas/análise , Fosfatase Alcalina/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Nomogramas , Prognóstico , Estudos Retrospectivos , Período Pré-OperatórioRESUMO
Acute myeloid leukemia (AML) cell survival and chemoresistance are influenced by the existence of bone marrow mesenchymal stem cells (BMMSCs); however, the pathways by which BMMSCs contribute to these processes remain unclear. We earlier revealed that methyltransferase-like 3 (METTL3) expression is significantly reduced in AML BMMSCs and that METTL3 mediates BMMSC adipogenesis to promote chemoresistance in human AML cell lines in vitro. In this investigation, we evaluated the METTL3 function in vivo. Mice exhibiting a conditional removal of Mettl3 in BMMSCs were developed by mating Prrx1-CreERT2;Mettl3fl/+ mice with Mettl3fl/fl mice using the CRISPR-Cas9 system. The Mettl3 deletion increased bone marrow adiposity, enhanced disease progression in the transplantation-induced MLL-AF9 AML mouse model, and chemoresistance to cytarabine. The removal of Mettl3 in BMMSCs resulted in a significant increase in BMMSC adipogenesis. This effect was attributed to the downregulation of AKT1 expression, an AKT serine/threonine kinase 1, in an m6A-dependent manner. The development of chemoresistance in AML is linked to the promoted adipogenesis of BMMSCs. We conclude that METTL3 expression in BMMSCs has a critical function in limiting AML progression and chemoresistance, providing a basis for the progression of therapeutic approaches for AML.
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Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Camundongos , Humanos , Animais , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Medula Óssea , Metiltransferases/genética , Metiltransferases/metabolismo , Células-Tronco Mesenquimais/metabolismoRESUMO
BACKGROUND: Due to antibiotic abuse, the problem of bacterial resistance is becoming increasingly serious, and rapid detection of bacterial resistance has become an urgent issue. Because under the action of antibiotics, different active bacteria have different metabolism of heavy water, antibiotic resistance of bacteria can be identified according to the existence of a C-D peak in the 2030-2400 cm-1 range in the Raman spectrum. METHODS: To ensure data veracity, a large number of bacteria need to be detected, however, due to the limitation of the field of view of the high magnification objective, the number of single cells in a single field of view is very small. By combining an image stitching algorithm, image recognition algorithm, and processing of Raman spectrum and peak-seeking algorithm, can identify and locate single cells in multiple fields of view at one time and can discriminate whether they are Antimicrobial-resistant bacteria. RESULTS: In experiments 1 and 2, 2706 bacteria in 9 × 11 fields of view and 2048 bacteria in 11 × 11 fields of view were detected. Results showed that in experiment 1, there are 1137 antibiotic-resistant bacteria, accounting for 42%, and 1569 sensitive bacteria, accounting for 58%. In experiment 2, there are 1087 antibiotic-resistant bacteria, accounting for 53%, and 961 sensitive bacteria, accounting for 47%. It showed excellent performance in terms of speed and recognition accuracy as compared to traditional manual detection approaches. And solves the problems of low accuracy of data, a large number of manual experiments, and low efficiency due to the small number of single cells in the high magnification field of view and different peak-seeking parameters of different Raman spectra. CONCLUSIONS: The detection and analysis method of bacterial Raman spectra based on image stitching can be used for unattended, automatic, rapid and accurate detection of single cells at high magnification with multiple fields of view. With the characteristics of automatic, high-throughput, rapid, and accurate identification, it can be used as an unattended, universal and non-invasive means to measure antibiotic-resistant bacteria to screen for effective antibiotics, which is of great importance for studying the persistence and spread of antibiotics in bacterial pathogens.
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Infecções Bacterianas , Análise Espectral Raman , Humanos , Análise Espectral Raman/métodos , Bactérias/metabolismo , Infecções Bacterianas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/metabolismoRESUMO
Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including ß-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.
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In order to exploit novel multi-stimuli responsive fluorescent materials, a series of novel fluorescent molecules of salicylic acid derivatives were designed and synthesized via introducing pyrazole or cyclopentane to the salicylic acid scaffold through a special Schiff base-acylhydrazone, and the molecular structures of representative compounds A2 and A4 were verified via single crystal X-ray diffraction. All title molecules could exhibit obvious solvatofluorochromism from cyan to indigo in several solutions with different polarity. The fluorescence titration data exhibited compound A2 and complex A2-Cu2+ with prime detection limits to Cu2+ (0.24 µM) and S2- ions (2.83 µM). The sensitive recognition of A2 to trifluoroacetic (TFA) and A2-TFA to triethylamine (TEA) were also confirmed via fluorescent titration experiments in various solutions, respectively. What's more, the 1H NMR and UV/Vis absorption spectra further explained the mechanism between molecules and ions or molecules and TFA/TEA. Besides, the photoswitching properties of the compounds A2 and A3 could be demonstrated via the irradiation of special wavelength light or heating accompanied with changes in quantum yields. In addition, these phenomena of multiple responses were explained via Density Functional Theory (DFT) based on the Gaussian calculations. Thus, this work provided a preliminary basis for the research of multi-stimuli responsive fluorescent molecules with photoswitching properties.
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Regulating of pore environment is an efficient way to improve the performance of covalent organic frameworks (COFs) for specific application requirements. Herein, the design and synthesis of two pyrene-based 2D COFs with -H or -Me substituents, TFFPy-PPD-COF and TFFPy-TMPD-COF are reported. Both of them show long order structure and high porosity, in which TFFPy-PPD-COF displays a larger pore volume and bigger BET surface area (2587 m2 g-1 , 1.17 cm3 g-1 ). Interestingly, TFPPy-TMPD-COF exhibits a much higher vapor iodine capacity (4.8 g g-1 ) than TFPPy-PPD-COF (2.9 g g-1 ), in contrast to their pore volume size. By using multiple techniques, the better performance of TFPPy-TMPD-COF in iodine capture is ascribed to the altered pore environment by introducing methyl groups, which contributes to the formation of polyiodide anions and enhances the interactions between the frameworks and iodine. These results will be helpful for understanding the effect of pore environment in COFs for iodine uptake and constructing novel structure with high iodine capture performance.
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Iodo , Estruturas Metalorgânicas , Adsorção , PirenosRESUMO
Aged livers have shown aggravated liver ischemia and reperfusion (IR) injury. Timely efferocytosis of apoptotic cells is a key mechanism for avoiding excessive inflammation and tissue injury. Here, we investigated the alteration of efferocytosis by aged macrophages and its role in regulating macrophage STING (stimulator of interferon genes) signaling and liver IR injury. Aged and young mice were subjected to liver partial IR model. Liver injury and inflammation were measured. Efferocytosis by aged macrophages and the underlying regulatory mechanism were analyzed as well. Aged macrophages exhibited impaired efferocytosis with decreased MerTK (c-mer proto-oncogene tyrosine kinase) activation, which was reversed by treatment of the MerTK CRISPR activation plasmid. Increased MerTK cleavage by ADAM17 (a disintegrin and metalloproteinase 17) due to enhanced ROS (reactive oxygen species) levels contributed to defective efferocytosis by aged macrophages. MerTK activation by suppressing ADAM17 or ROS improved aged macrophage efferocytosis, leading to reduced inflammatory liver injury. Moreover, increased apoptotic hepatocytes, DNA accumulation, and macrophage STING activation were observed in aged ischemic livers. Improvement in efferocytosis by aged macrophages via MerTK activation suppressed STING activation and inflammatory liver injury. Our study demonstrates that aging suppresses MerTK- mediated macrophage efferocytosis to promote macrophage STING activation and inflammatory liver IR injury, suggesting a new mechanism and potential therapy to promote inflammation resolution and efferocytosis in aged livers.
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The aim of this study is to explore the mechanism of ligustilide, the main active constituent of essential oils of traditional Chinese medicine Angelicae Sinensis Radix, on alleviating oxygen-glucose deprivation/reperfusion(OGD/R) injury in PC12 cells from the perspective of ferroptosis. OGD/R was induced in vitro, and 12 h after ligustilide addition during reperfusion, cell viability was detected by cell counting kit-8(CCK-8) assay. DCFH-DA staining was used to detect the level of intracellular reactive oxygen species(ROS). Western blot was employed to detect the expression of ferroptosis-related proteins, glutathione peroxidase 4(GPX4), transferrin receptor 1(TFR1), and solute carrier family 7 member 11(SLC7A11), and ferritinophagy-related proteins, nuclear receptor coactivator 4(NCOA4), ferritin heavy chain 1(FTH1), and microtubule-associated protein 1 light chain 3(LC3). The fluorescence intensity of LC3 protein was analyzed by immunofluorescence staining. The content of glutathione(GSH), malondialdehyde(MDA), and Fe was detected by chemiluminescent immunoassay. The effect of ligustilide on ferroptosis was observed by overexpression of NCOA4 gene. The results showed that ligustilide increased the viability of PC12 cells damaged by OGD/R, inhibited the release of ROS, reduced the content of Fe and MDA and the expression of TFR1, NCOA4, and LC3, and improved the content of GSH and the expression of GPX4, SLC7A11, and FTH1 compared with OGD/R group. After overexpression of the key protein NCOA4 in ferritinophagy, the inhibitory effect of ligustilide on ferroptosis was partially reversed, indicating that ligustilide may alleviate OGD/R injury of PC12 cells by blocking ferritinophagy and then inhibiting ferroptosis. The mechanism by which ligustilide reduced OGD/R injury in PC12 cells is that it suppressed the ferroptosis involved in ferritinophagy.