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1.
Asian J Pharm Sci ; 18(1): 100769, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36698441

RESUMO

The siRNA-loaded lipid nanoparticles have attracted much attention due to its significant gene silencing effect and successful marketization. However, the in vivo distribution and release of siRNA still cannot be effectively monitored. In this study, based on the fluorescence resonance energy transfer (FRET) principle, a fluorescence dye Cy5-modified survivin siRNA was conjugated to nanogolds (Au-DR-siRNA), which were then wrapped with lipid nanoparticles (LNPs) for monitoring the release behaviour of siRNA in vivo. The results showed that once Au-DR-siRNA was released from the LNPs and cleaved by the Dicer enzyme to produce free siRNA in cells, the fluorescence of Cy5 would change from quenched state to activated state, showing the location and time of siRNA release. Besides, the LNPs showed a significant antitumor effect by silencing the survivin gene and a CT imaging function superior to iohexol by nanogolds. Therefore, this work provided not only an effective method for monitoring the pharmacokinetic behaviour of LNP-based siRNA, but also a siRNA delivery system for treating and diagnosing tumors.

2.
Diabetologia ; 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36698021

RESUMO

AIMS/HYPOTHESIS: Accumulating evidence suggests that leucocytes play a critical role in diabetes-induced vascular lesions and other abnormalities that characterise the early stages of diabetic retinopathy. However, the role of monocytes has yet to be fully investigated; therefore, we used Ccr2-/- mice to study the role of CCR2+ inflammatory monocytes in the pathogenesis of diabetes-induced degeneration of retinal capillaries. METHODS: Experimental diabetes was induced in wild-type and Ccr2-/- mice using streptozotocin. After 2 months, superoxide levels, expression of inflammatory genes, leucostasis, leucocyte- and monocyte-mediated cytotoxicity against retinal endothelial cell death, retinal thickness and visual function were evaluated. Retinal capillary degeneration was determined after 8 months of diabetes. Flow cytometry of peripheral blood for differential expression of CCR2 in monocytes was assessed. RESULTS: In nondiabetic mice, CCR2 was highly expressed on monocytes, and Ccr2-/- mice lack CCR2+ monocytes in the peripheral blood. Diabetes-induced retinal superoxide, expression of proinflammatory genes Inos and Icam1, leucostasis and leucocyte-mediated cytotoxicity against retinal endothelial cells were inhibited in diabetic Ccr2-deficient mice and in chimeric mice lacking Ccr2 only from myeloid cells. In order to focus on monocytes, these cells were immuno-isolated after 2 months of diabetes, and they significantly increased monocyte-mediated endothelial cell cytotoxicity ex vivo. Monocytes from Ccr2-deficient mice caused significantly less endothelial cell death. The diabetes-induced retinal capillary degeneration was inhibited in Ccr2-/- mice and in chimeric mice lacking Ccr2 only from myeloid cells. CONCLUSIONS/INTERPRETATION: CCR2+ inflammatory monocytes contribute to the pathogenesis of early lesions of diabetic retinopathy.

3.
Materials (Basel) ; 16(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36676532

RESUMO

The size and distribution of ceramic particles in aluminum matrix composites have been reported to remarkably influence their properties. For a single ceramic particle, the particle size is too small and prone to agglomeration, which makes the mechanical properties of the composites worse. When the ceramic particle size is too large, the particles and alloy at the interface are not firmly bonded, and the effect of dispersion distribution is not achieved, which will also reduce the mechanical properties of the composites. The multi-size ceramic particles are expected to improve this situation, while their effect on hot workability is less studied. In this study, the hot deformation behavior, constitutive model, processing map and SEM microstructure were investigated to evaluate the hot workability of multi-size SiC particle-reinforced 6013 aluminum matrix composites. The results showed that the increased deformation temperature and decreased strain rate could decrease flow stresses. The flow stress behaviors of the composites can be described by the sine-hyperbolic Arrhenius equation with the deformation activation energy of Q = 205.863 kJ/mol. The constitutive equation of the composites is ε Ë™=3.11592×1013sinh0.024909σ4.12413exp-205863RT. Then, the hot processing map of the SiCp/6013 composites was constructed and verified by SEM observations. The rheological instability zone was in the region of a high strain rate. The optimal processing zone for composites was 450~500 °C and 0.03~0.25 s-1. In addition, the strain level was found to increase both the Q value and the area of the instability zone.

4.
Nanoscale ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688503

RESUMO

Atomically precise nanoclusters have a critical role in understanding the structure-property relationships at the atomic level. Copper nanoclusters have attracted considerable attention, but the synthesis is limited because of susceptibility to oxidation. Herein, we developed a reduction speed controlling method to synthesize [Cu75(S-Adm)32]2+ (HS-Adm: 1-Adamantanethiol) nanocluster and reveal the key steps in the nucleation process. Cu75 was first observed and characterized with the following features: (i) composed of a face-centered cubic Cu15 kernel and a Cu60 caged shell including 12 distorted octahedra. (ii) The observation of the shortest Cu-Cu bond (2.166(7) Å) in the Cu nanoclusters, which could result from the distortion of the octahedron. (iii) The sole µ3-S mode of S, which plays two roles as a vertex and bridge atom to connect Cu atoms. This work presents a unique nanoball Cu nanocluster with strong cuprophilic interaction and provides a novel method to expand the family of Cu nanoclusters as well.

5.
Viruses ; 15(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36680182

RESUMO

Zika virus (ZIKV) causes microcephaly and congenital eye disease. The cellular and molecular basis of congenital ZIKV infection are not well understood. Here, we utilized a biologically relevant cell-based system of human fetal retinal pigment epithelial cells (FRPEs), hiPSC-derived retinal stem cells (iRSCs), and retinal organoids to investigate ZIKV-mediated ocular cell injury processes. Our data show that FRPEs were highly susceptible to ZIKV infection exhibiting increased apoptosis, whereas iRSCs showed reduced susceptibility. Detailed transcriptomics and proteomics analyses of infected FRPEs were performed. Nucleoside analogue drug treatment inhibited ZIKV replication. Retinal organoids were susceptible to ZIKV infection. The Asian genotype ZIKV exhibited higher infectivity, induced profound inflammatory response, and dysregulated transcription factors involved in retinal organoid differentiation. Collectively, our study shows that ZIKV affects ocular cells at different developmental stages resulting in cellular injury and death, further providing molecular insight into the pathogenesis of congenital eye disease.


Assuntos
Oftalmopatias , Células-Tronco Pluripotentes Induzidas , Infecção por Zika virus , Zika virus , Humanos , Zika virus/fisiologia , Retina/patologia , Replicação Viral , Organoides , Células Epiteliais/patologia , Pigmentos da Retina/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-36674202

RESUMO

Mental fatigue is a common phenomenon in our daily lives. Long-term fatigue can lead to a decline in a person's operational functions and seriously affect work efficiency. In this paper, a method that recognizes the degree of mental fatigue based on relative band power and fuzzy entropy of Electroencephalogram (EEG) is proposed. The N-back experiment was used to induce mental fatigue in subjects, and the corresponding EEG signals were recorded during the experiment. A preprocessing method based on complementary ensemble empirical modal decomposition (CEEMD) and independent component analysis (ICA) was designed to remove noise from the raw EEG signal. The relative band power feature, which has been used extensively in fatigue recognition studies, was extracted from the EEG signals. Meanwhile, fuzzy entropy, a feature commonly used in attention recognition, was also extracted for fatigue recognition, based on previous findings that an increase in fatigue is accompanied by a decrease in attention. The two features were fed into an extreme gradient boosting (XGBoost) classifier to distinguish three different degrees of fatigue, which resulted in an average accuracy of 92.39% based on data from eight subjects. The promising results indicate the effectiveness of the proposed method in mental fatigue degree identification.


Assuntos
Reconhecimento Psicológico , Processamento de Sinais Assistido por Computador , Humanos , Entropia , Eletroencefalografia/métodos , Fadiga Mental
7.
Artigo em Inglês | MEDLINE | ID: mdl-36602643

RESUMO

PURPOSE: Scalpels are typical tools used for cutting in surgery, and the surgical tray is one of the locations where the scalpel is present during surgery. However, there is no known method for the classification and segmentation of multiple types of scalpels. This paper presents a dataset of multiple types of scalpels and a classification and segmentation method that can be applied as a first step for validating segmentation of scalpels and further applications can include identifying scalpels from other tools in different clinical scenarios. METHODS: The proposed scalpel dataset contains 6400 images with labeled information of 10 types of scalpels, and a classification and segmentation model for multiple types of scalpels is obtained by training the dataset based on Mask R-CNN. The article concludes with an analysis and evaluation of the network performance, verifying the feasibility of the work. RESULTS: A multi-type scalpel dataset was established, and the classification and segmentation models of multi-type scalpel were obtained by training the Mask R-CNN. The average accuracy and average recall reached 94.19% and 96.61%, respectively, in the classification task and 93.30% and 95.14%, respectively, in the segmentation task. CONCLUSION: The first scalpel dataset is created covering multiple types of scalpels. And the classification and segmentation of multiple types of scalpels are realized for the first time. This study achieves the classification and segmentation of scalpels in a surgical tray scene, providing a potential solution for scalpel recognition, localization and tracking.

8.
Anal Chem ; 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36655772

RESUMO

Sensitive and reliable clustered regularly interspaced short palindromic repeats (CRISPR) quantification without preamplification of the sample remains a challenge. Herein, we report a CRISPR Cas12a-powered silicon surface-enhanced Raman spectroscopy (SERS) ratiometric chip for sensitive and reliable quantification. As a proof-of-concept application, we select the platelet-derived growth factor-BB (PDGF-BB) as the target. We first develop a microfluidic synthetic strategy to prepare homogeneous silicon SERS substrates, in which uniform silver nanoparticles (AgNPs) are in situ grown on a silicon wafer (AgNPs@Si) by microfluidic galvanic deposition reactions. Next, one 5'-SH-3'-ROX-labeled single-stranded DNA (ssDNA) is modified on AgNPs via Ag-S bonds. In our design, such ssDNA has two fragments: one fragment hybridizes to its complementary DNA (5'-Cy3-labeled ssDNA) to form double-stranded DNA (dsDNA) and the other fragment labeled with 6'-carboxy-X-rhodmine (ROX) extends out as a substrate for Cas12a. The cleavage of the ROX-tagged fragment by Cas12a is controlled by the presence or not of PDGF-BB. Meanwhile, Cy3 molecules serving as internal standard molecules still stay at the end of the rigid dsDNA, and their signals remain constant. Thereby, the ratio of ROX signal intensity to Cy3 intensity can be employed for the reliable quantification of PDGF-BB concentration. The developed chip features an ultrahigh sensitivity (e.g., the limit of detection is as low as 3.2 pM, approximately 50 times more sensitive than the fluorescence counterpart) and good reproducibility (e.g., the relative standard deviation is less than 5%) in the detection of PDGF-BB.

9.
Chem Commun (Camb) ; 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36628466

RESUMO

We present organic-halide treatment in advance to maximize electron extraction of Cs2AgBiBr6 double perovskite solar cells. Through optimizing the organic halide and concentration systematically, the best carbon-based Cs2AgBiBr6 perovskite solar cell fabricated in an airing chamber achieves a power conversion efficiency of 2.03% and shows excellent long-term stability in air over 30 days.

11.
Sci China Life Sci ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36680676

RESUMO

The maintenance of proteostasis is essential for cellular and organism healthspan. How proteostasis collapse influences reproductive span remains largely unclear. In Caenorhabditis elegans, excess accumulation of vitellogenins, the major components in yolk proteins, is crucial for the development of the embryo and occurs throughout the whole body during the aging process. Here, we show that vitellogenin accumulation leads to reproduction cessation. Excess vitellogenin is accumulated in the intestine and transported into the germline, impairing lysosomal activity in these tissues. The lysosomal function in the germline is required for reproductive span by maintaining oocyte quality. In contrast, autophagy and sperm depletion are not involved in vitellogenin accumulation-induced reproductive aging. Our findings provide insights into how proteome imbalance has an impact on reproductive aging and imply that improvement of lysosomal function is an effective approach for mid-life intervention for maintaining reproductive health in mammals.

12.
Med Biol Eng Comput ; 61(2): 567-578, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36542320

RESUMO

To develop a deep-learning system for the automatic identification of triple-negative breast cancer (TNBC) solely from ultrasound images. A total of 145 patients and 831 images were retrospectively enrolled at Peking Union College Hospital from April 2018 to March 2019. Ultrasound images and clinical information were collected accordingly. Molecular subtypes were determined from immunohistochemical (IHC) results. A CNN with VGG-based architecture was then used to predict TNBC. The model's performance was evaluated using randomized k-fold stratified cross-validation. A t-SNE analysis and saliency maps were used for model visualization. TNBC was identified in 16 of 145 (11.03%) patients. One hundred fifteen (80%) patients, 15 (10%) patients, and 15 (10%) patients formed the train, validation, and test set respectively. The deep learning system exhibits good efficacy, with an AUC of 0.86 (95% CI: 0.64, 0.95), an accuracy of 85%, a sensitivity of 86%, a specificity of 86%, and an F1-score of 0.74. In addition, the internal representation features learned by the model showed clear differentiation across molecular subtype groups. Such a deep learning system can automatically predict triple-negative breast cancer preoperatively and accurately. It may help to get to more precise and comprehensive management.


Assuntos
Neoplasias da Mama , Aprendizado Profundo , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Estudos Retrospectivos , Neoplasias da Mama/diagnóstico por imagem , Ultrassonografia/métodos
13.
Adv Drug Deliv Rev ; 192: 114641, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36509173

RESUMO

Direct delivery to the lung via inhalation is arguably one of the most logical approaches to treat lung cancer using drugs. However, despite significant efforts and investment in this area, this strategy has not progressed in clinical trials. Imaging drug delivery is a powerful tool to understand and develop novel drug delivery strategies. In this review we focus on imaging studies of drug delivery by the inhalation route, to provide a broad overview of the field to date and attempt to better understand the complexities of this route of administration and the significant barriers that it faces, as well as its advantages. We start with a discussion of the specific challenges for drug delivery to the lung via inhalation. We focus on the barriers that have prevented progress of this approach in oncology, as well as the most recent developments in this area. This is followed by a comprehensive overview of the different imaging modalities that are relevant to lung drug delivery, including nuclear imaging, X-ray imaging, magnetic resonance imaging, optical imaging and mass spectrometry imaging. For each of these modalities, examples from the literature where these techniques have been explored are provided. Finally the different applications of these technologies in oncology are discussed, focusing separately on small molecules and nanomedicines. We hope that this comprehensive review will be informative to the field and will guide the future preclinical and clinical development of this promising drug delivery strategy to maximise its therapeutic potential.


Assuntos
Sistemas de Liberação de Medicamentos , Pulmão , Humanos , Sistemas de Liberação de Medicamentos/métodos , Pulmão/diagnóstico por imagem , Preparações Farmacêuticas , Administração por Inalação , Imageamento por Ressonância Magnética
14.
Front Pharmacol ; 13: 1040999, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457708

RESUMO

Obesity-induced metabolic syndrome is a rapidly growing conundrum, reaching epidemic proportions globally. Chronic inflammation in obese adipose tissue plays a key role in metabolic syndrome with a series of local and systemic effects such as inflammatory cell infiltration and inflammatory cytokine secretion. Adipose tissue macrophages (ATM), as one of the main regulators in this process, are particularly crucial for pharmacological studies on obesity-related metabolic syndrome. Ponatinib, a multi-targeted tyrosine kinase inhibitor originally used to treat leukemia, has recently been found to improve dyslipidemia and atherosclerosis, suggesting that it may have profound effect on metabolic syndrome, although the mechanisms underlying have not yet been revealed. Here we discovered that ponatinib significantly improved insulin sensitivity in leptin deficient obese mice. In addition to that, ponatinib treatment remarkably ameliorated high fat diet-induced hyperlipidemia and inhibited ectopic lipid deposition in the liver. Interestingly, although ponatinib did not reduce but increase the weight of white adipose tissue (WAT), it remarkably suppressed the inflammatory response in WAT and preserved its function. Mechanistically, we showed that ponatinib had no direct effect on hepatocyte or adipocyte but attenuated free fatty acid (FFA) induced macrophage transformation from pro-inflammatory to anti-inflammatory phenotype. Moreover, adipocytes co-cultured with FFA-treated macrophages exhibited insulin resistance, while pre-treat these macrophages with ponatinib can ameliorate this process. These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.

15.
Food Res Int ; 162(Pt B): 112135, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36461359

RESUMO

The physiological status of Salmonella after its ultrasonication was investigated to reveal the potential mechanism through which ultrasound enhances the lethality of chlorine dioxide against Salmonella. Applying either the probe ultrasound (US) or water bath ultrasound (WUS) disrupted the cellular structure of Salmonella bacteria, increased the permeability of their bacterial outer membrane (US: 9.00 %, WUS: 11.96 %), and caused intracellular reactive oxygen species to accumulate (US: 13.95 %, WUS: 4.34 %,), which resulted in a reduction of ATP (US: 15.22 %, WUS: 14.15 %) and ATPase activity (US: 3.13 %, WUS: 26.06 %). This series of adverse effects eventually led to the disruption of the metabolic process in Salmonella cells, by mainly altering the metabolism of lipids, small molecules, and energy. Therefore, ultrasound enhances the lethality of chlorine dioxide primarily by disrupting the cellular structure, intracellular material, and energy homeostasis of Salmonella. This finding will promote the development and application of ultrasonic-assisted sterilization technology in food industries.


Assuntos
Compostos Clorados , Salmonella typhimurium , Compostos Clorados/farmacologia , Metaboloma , Metabolismo Energético
16.
Sci Total Environ ; : 160608, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36462658

RESUMO

The use of electron microscopy to analyze the morphology, composition, and sources of atmospheric particles has been studied extensively worldwide. However, in China, there are few studies on single-particle source analysis based on computer-controlled scanning electron microscopy (CCSEM) technology for a large number of particles, and the related technical methods need to be established and improved. In this study, ambient particulate matter (PM) was collected simultaneously from urban, suburban, and background areas of Beijing in spring 2018 and subsequently characterized using the IntelliSEM-EPAS™ technology (an advanced CCSEM software). The deposition velocity model was used to deduce the size distribution and calculate the concentration of ambient PM. Based on the k-means algorithm and empirical rules, all particles investigated were quantitatively apportioned to nine major sources, including soil/road dust, carbonates-silicates, carbonates, irregular carbonaceous particles, irregular iron oxides, combustion/industry, calcium sulfate, secondary particles, and salt-related particles. The size-resolved contributions (mass and number) of different sources were calculated. For example, soil/road dust (65.1 %), carbonate-silicate (16.1 %), and carbonate (7.1 %) were the top three sources contributing to PM10 mass. This study was the first localized application of IntelliSEM-EPAS technology in China, demonstrating its great promise in PM source apportionment. For further accurate and refined source apportionment, it is essential to build localized individual particle source profiles.

18.
Nanomedicine ; 48: 102646, 2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36549559

RESUMO

Synthetic high-density lipoproteins nanomedicine (sHDL) composed of apolipoprotein A-I (ApoA-I) mimetic peptides and lipids have shown very promising results for the treatment of various cardiovascular diseases. Numerous efforts have also been made to design different ApoA-I mimetic peptides to improve the potency of sHDL, especially the efficiency of reverse cholesterol transport. However, the way in which ApoA-I mimetic peptides affect the properties of sHDL, including stability, cholesterol efflux, cholesterol esterification, elimination in vivo, and the relationship of these properties, is still poorly understood. Revealing the effect of these factors on the potency of sHDL is important for the design of better ApoA-I mimetic peptides. In this study, three widely used ApoA-I mimetic peptides with different sequences, lengths, LCAT activation and lipid binding affinities were used for the preparation of sHDL and were evaluated in terms of physical/chemical properties, cholesterol efflux, cholesterol esterification, remodeling, and pharmacokinetics/pharmacodynamics. Our results showed that ApoA-I mimetic peptides with the highest cholesterol efflux and cholesterol esterification in vitro did not exhibit the highest cholesterol mobilization in vivo. Further analysis indicated that other factors, such as pharmacokinetics and remodeling of sHDL, need to be considered in order to predict the efficiency of cholesterol mobilization in vivo. Thus, our study highlights the importance of using the overall performance, rather than in vitro results alone, as the blueprint for the design and optimization of ApoA-I mimetic peptides.

19.
Genes (Basel) ; 13(12)2022 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-36553485

RESUMO

Neurological phenotypes such as intellectual disability occur in almost half of patients with neurofibromatosis 1 (NF1). Current genotype-phenotype studies have failed to reveal the mechanism underlying this clinical variability. Despite the presence of pathogenic variants of NF1, modifier genes likely determine the occurrence and severity of neurological phenotypes. Exome sequencing data were used to identify genetic variants in 13 NF1 patients and 457 healthy controls, and this information was used to identify candidate modifier genes underlying neurological phenotypes based on an optimal sequence kernel association test. Thirty-six genes were identified as significant modifying factors in patients with neurological phenotypes and all are highly expressed in the nervous system. A review of the literature confirmed that 19 genes including CUL7, DPH1, and BCO1 are clearly associated with the alteration of neurological functioning and development. Our study revealed the enrichment of rare variants of 19 genes closely related to neurological development and functioning in NF1 patients with neurological phenotypes, indicating possible modifier genes and variants affecting neurodevelopment. Further studies on rare genetic variants of candidate modifier genes may help explain the clinical heterogeneity of NF1.


Assuntos
Neurofibromatose 1 , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Genes Modificadores , Fenótipo , Exoma
20.
Am J Transl Res ; 14(11): 8049-8063, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505306

RESUMO

OBJECTIVE: The purpose of this investigation was to study the expression profile and potential function of circular RNA (circRNA) and long noncoding RNA (lncRNA) in triple-negative breast cancer (TNBC). METHODS: RNA sequencing technology was used to detect differentially expressed circRNAs and lncRNAs between TNBC tissues and the adjacent tissue. The potential functions of these different RNAs were analyzed by GO and KEGG enrichment analysis by bioinformatics tools. We also selected and analyzed these key circRNAs and lncRNAs to verify their important functions in TNBC. RESULTS: A total of 139 differentially expressed circRNAs and 1001 lncRNAs were obtained. The co-expression analysis showed that the hub lncRNAs (OIP5-AS1, DRAIC) were associated with several tumors and mainly enriched in tumor metastasis. We also screened 5 circRNA-hosting genes (NTRK2, FNTA, BAPGEF2, MGST2, ADH1B) that were associated with the brain-derived neurotrophic factor (BDNF) receptor signaling pathway and cerebral cortex development, as well as AMPK and TGF-ß signaling pathway. CONCLUSION: We identified a large number of differentially expressed circRNAs and lncRNAs, which provide useful insight in understanding TNBC carcinogenesis.

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