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1.
Free Radic Biol Med ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34656698

RESUMO

Increasing evidence suggests the significant contribution of high levels of thioredoxin reductase (TrxR) in various stages of tumorigenesis and resistance to tumor chemotherapy. Thus, inhibition of TrxR with small molecules is an attractive strategy for cancer therapy. Eriocalyxin B (EriB), a naturally occurring diterpenoid extracted from Isodon eriocalyx, has reflected potential anticancer activities through numerous pathways. Here, we describe that EriB covalently modifies GSH and selectively inhibits TrxR activity by targeting the Sec residue of the enzyme. Pharmacological inhibition of TrxR by EriB results in elevated ROS levels, reduced total GSH and thiols content, which ultimately induced potent RKO cell apoptosis mediated by oxidative stress. Importantly, EriB indicates potent synthetic lethality with GSH inhibitors, BSO, in RKO cells. In summary, our results highlight that targeting TrxR by EriB explores a novel mechanism for the biological action of EriB. This opened up a new therapeutic indication for using EriB to combat cancers.

2.
Biotechnol Adv ; 53: 107841, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34610353

RESUMO

Metabolic energy (ME) homeostasis is essential for the survival and proper functioning of microbial cell factories. However, it is often disrupted during bioproduction because of inefficient ME supply and excessive ME consumption. In this review, we propose strategies, including reinforcement of the capacity of ME-harvesting systems in autotrophic microorganisms; enhancement of the efficiency of ME-supplying pathways in heterotrophic microorganisms; and reduction of unessential ME consumption by microbial cells, to address these issues. This review highlights the potential of biotechnology in the engineering of microbial ME homeostasis and provides guidance for the higher efficient bioproduction of microbial cell factories.

3.
Front Pediatr ; 9: 726769, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660487

RESUMO

Objective: To evaluate the efficacy, safety, and fungal sensitivity of prophylactic fluconazole use in very premature infants. Methods: We performed a retrospective historical comparative analysis of 196 very premature infants (113 in the prophylaxis group and 83 in the rescue group). The incidence of nosocomial fungal infection (NCFI) and pathogenic fungi, their drug sensitivity, and the minimum inhibitory concentration (MIC) of fluconazole were compared between the two groups. We also analyzed differences in short-term adverse outcomes, such as drug-induced liver or renal function disruption, fungal-attributable death, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC), between the groups. The effects of the prophylactic fluconazole strategy on NCFI and short-term adverse outcomes were assessed by multivariate logistic regression. Results: Candida albicans (46.7%) and Candida glabrata (43.3%) were the main culprit pathogens causing NCFI. The incidence of NCFI was significantly lower in the prophylaxis group than in the rescue group (15.9 vs. 45.8%, P < 0.001). However, fewer fungi were completely sensitive to fluconazole (40 vs. 85%, P < 0.05) and the MIC of fluconazole was higher [16.0 (3.5 ~ 16.0) vs. 3.0 (1.0 ~ 8.0) µg/ml, P < 0.001] in the prophylaxis group than in the rescue group. Compared with the rescue group, the prophylaxis group had a lower risk of NCFI (adjusted OR 0.25; 95% CI 0.11, 0.55). Additionally, the prophylaxis group had significantly lower risks of combined outcomes (one or more complications, such as BPD, ROP needing interventions, PVL/IVH (grade > 2), NEC stage ≥2, and fungal-attributable death) (adjusted OR 0.44; 95% CI 0.21, 0.92). There was no significant difference in serum alanine transferase (ALT), aspartate transaminase (AST), creatinine (Cr), or direct bilirubin (DBIL) levels between the two groups. Conclusions: Fluconazole prophylaxis reduced NCFI and improved combined clinical outcomes in very premature infants, with no increased risks of serious short-term adverse side effects; however, the MIC of fluconazole showed significant increases. Therefore, further optimization of preventive strategies is necessary to maintain the sensitivity of fluconazole against fungal isolates.

4.
Crit Rev Biotechnol ; : 1-20, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34634988

RESUMO

Abnormal vasoconstriction, inflammation, and vascular remodeling can be promoted by angiotensin II (Ang II) in the renin-angiotensin system (RAS), leading to vascular dysfunction diseases such as hypertension and atherosclerosis. Researchers have recently focused on angiotensin I-converting enzyme inhibitory peptides (ACEIPs), that have desirable efficacy in vascular dysfunction therapy due to Ang II reduction by inhibiting ACE activity. Promising methods for the large-scale preparation of ACEIPs include selective enzymatic hydrolysis and microbial fermentation. Thus far, ACEIPs have been widely reported to be hydrolyzed from protein-rich sources, including animals, plants, and marine organisms, while many emerging microorganism-derived ACEIPs are theoretically biosynthesized through the nonribosomal peptide synthase (NRPS) pathway. Notably, vasodilatation, anti-inflammation, and vascular reconstruction reversal of ACEIPs are strongly correlated. However, the related molecular mechanisms underlying signal transduction regulation in vivo remain unclear. We provide a comprehensive update of the ACE-Ang II-G protein-coupled type 1 angiotensin receptor (AT1R) axis signaling and its functional significance for potential translation into therapeutic strategies, particularly targeting AT1R by ACEIPs, as well as specific related signaling pathways. Future studies are expected to verify the biosynthetic regulatory mechanism of ACEIPs via the NRPS pathway, the effect of gut microbiota metabolism on vascular dysfunction and rigorous studies of ACE-Ang II-AT1R signaling pathways mediated by ACEIPs in large animals and humans.

5.
Blood Adv ; 5(19): 3799-3806, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34605871

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and risk of hemorrhage. Treatment with eltrombopag increases and maintains hemostatic platelet counts; however, to date, long-term data are lacking on the outcome of children with ITP who are treated with eltrombopag. This prospective, observational, longitudinal cohort study evaluated the efficacy and safety of eltrombopag in pediatric patients with persistent or chronic ITP. For the 116 pediatric patients enrolled, duration of eltrombopag treatment was at least 3 months. Median effective dose was 25 mg/day, 50 mg/day, and 50 mg/day, respectively, for children age 5 years or younger, 6 to 11 years, or 12 years or older. In all, 89 patients (76.7%) achieved overall response, 53 (45.7%) achieved complete response, and 36 (31.0%) achieved response. Median platelet counts increased by week 1 and were sustained throughout the treatment period. During treatment with eltrombopag, the proportion of patients with grade 1 to 4 bleeding symptoms decreased from 83.61% at baseline to 9.88% at 6 months when only grade 1 was reported. Forty-three patients (37.1%) reported using concomitant medications at study entry, which was reduced to 1 patient (2.5%) who needed concomitant medications at 12 months. All adverse events were grade 1 or 2 according to Common Terminology Criteria for Adverse Events. No serious adverse events, cataracts, malignancies, or thromboses were reported during the study. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts and reducing bleeding in most pediatric patients with persistent or chronic ITP. Combined with future studies, these findings will help establish how eltrombopag should best be used in the management of pediatric patients with East Asian ancestry.

6.
Medicine (Baltimore) ; 100(39): e27402, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596166

RESUMO

BACKGROUND: Problem-based learning (PBL) was widely adopted in medical cell biology education for Chinese student; however, there was no systematic analysis to prove PBL was much more effective than lecture-based learning (LBL). Our aim is to evaluate the effectiveness of PBL on cell biology curriculum compared with LBL. METHOD: We systematically searched the publications related to PBL teaching approach in cell biology curriculum for medical education from databases until to February 2021. Pooled standard mean differences (SMDs) and risk ratios with their 95% confidence intervals were used to assess the effectiveness of PBL and the satisfaction of students to PBL compared to LBL in meta-analysis. The heterogeneity of the included studies was assessed by statistical I2 of heterogeneity. Meta-regression and subgroup analysis were performed to analyze the source of heterogeneity. Funnel plots and Egger tests were performed to assess publication bias. RESULT: After initial searching and selection, 9 studies were included for meta-analysis. All of these 9 studies were in high quality. The SMDs (95% confidence intervals) of total examination scores and comprehensive examination scores between PBL and LBL curriculum in cell biology teaching was calculated to be 0.89 (0.52, 1.26) and 0.53 (0.29, 0.78). Meanwhile, the risk ratios of the satisfaction of PBL vs LBL were calculated to be 1.18 (0.96, 1.46). However, there was a heterogeneity among the pooled SMDs of 10 studies with I2 = 89.7%, P < .001. The factors including the different teachers, the similar or same examination paper and over 100 student numbers among PBL and LBL groups raised the heterogeneity in the pooled SMDs. There is no publication bias in these 10 publications after Egger and Begg test. CONCLUSION: The result indicated PBL was better than LBL in improvement of examination scores and comprehensive examination scores in cell biology curriculum to some extent. However, the satisfaction of students to PBL and LBL had no difference. The factors, including the different teachers, the similar or same examination papers and over 100 student numbers, affected the effectiveness of PBL and raised the heterogeneity of the pooled SMDs.


Assuntos
Biologia Celular/educação , Aprendizagem Baseada em Problemas/normas , Currículo , Educação Médica/métodos , Humanos
7.
Arch Biochem Biophys ; 711: 109028, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34509463

RESUMO

Elevated expression of thioredoxin reductase (TrxR) is associated with the tumorigenesis and resistance to cancer chemoradiotherapy, highlighting the potential of TrxR inhibitors as anticancer drugs. Deoxyelephantopin (DET) is the major active ingredient of Elephantopus scaber and reveals potent anticancer activity. However, the potential mechanism of action and the cellular target of DET are still unknown. Here, we found that DET primarily targets the Sec residue of TrxR and irreversibly prohibits enzyme activity. Suppression of TrxR by DET leads to accumulation of reactive oxygen species and dysregulation in intracellular redox balance, eventually inducing cancer cell apoptosis mediated by oxidative stress. Noticeably, down-regulation of TrxR1 by shRNA increases cell sensitivity to DET. Collectively, targeting of TrxR1 by DET uncovers a novel mechanism of action in DET and deepens the understanding of developing DET as a potential chemotherapeutic agent for treating cancers.

8.
J Diabetes Res ; 2021: 2611250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34541004

RESUMO

Purpose: The objective of this study was to establish diagnostic technology to automatically grade the severity of diabetic retinopathy (DR) according to the ischemic index and leakage index with ultra-widefield fluorescein angiography (UWFA) and the Early Treatment Diabetic Retinopathy Study (ETDRS) 7-standard field (7-SF). Methods: This is a cross-sectional study. UWFA samples from 280 diabetic patients and 119 normal patients were used to train and test an artificial intelligence model to differentiate PDR and NPDR based on the ischemic index and leakage index with UWFA. A panel of retinal specialists determined the ground truth for our data set before experimentation. A confusion matrix as a metric was used to measure the precision of our algorithm, and a simple linear regression function was implemented to explore the discrimination of indexes on the DR grades. In addition, the model was tested with simulated 7-SF. Results: The model classification of DR in the original UWFA images achieved 88.50% accuracy and 73.68% accuracy in the simulated 7-SF images. A simple linear regression function demonstrated that there is a significant relationship between the ischemic index and leakage index and the severity of DR. These two thresholds were set to classify the grade of DR, which achieved 76.8% accuracy. Conclusions: The optimization of the cycle generative adversarial network (CycleGAN) and convolutional neural network (CNN) model classifier achieved DR grading based on the ischemic index and leakage index with UWFA and simulated 7-SF and provided accurate inference results. The classification accuracy with UWFA is slightly higher than that of simulated 7-SF.

9.
Microb Pathog ; : 105195, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34571150

RESUMO

BACKGROUND: Porcine epidemic diarrhea virus (PEDV) is an enveloped positive-sense ssRNA virus which is highly lethal to piglets, causing enormous economic losses to swine industry worldwide. Nsp15 protein is an endoribonuclease of PEDV and plays an indispensable role in the viral proliferation. We reported the transcription files of nsp15 transfected IPEC-J2 cells for the first time to broaden our understanding of PEDV pathogenesis. METHODS: RNA-seq was performed to compare gene expression profiles between pCAGGS-HA-nsp15 transfected IPEC-J2 cells and pCAGGS-HA (empty vector) transfected IPEC-J2 cells. Immune-related genes and pathways were identified and analyzed to deepen our understanding of nsp15 for PEDV pathogenicity. IPEC-J2 cells transfected with pCAGGS-HA-CCL5/CXCL8/CXCL10 were infected with CV777 and the virus load of PEDV was detected by qRT-PCR. RESULTS: A total of 21,654 genes were obtained by RNA-Seq and 415 differential expressed genes (DEGs) were identified, including 136 up-regulated and 279 down-regulated genes. A number of effect genes involved in immune responses and inflammation were differentially expressed. GO and KEGG enrichment analysis showed that 32 GO terms were significantly enriched and the DEGs were mainly enriched in immune-related pathways such as TNF signaling pathway, RIG-I-like receptor signaling pathway and Cytosolic DNA-sensing pathway. qRT-PCR results indicated the overexpression of selected chemokines, CCL5/CXCL8/CXCL10, can inhibit PEDV proliferation in IPEC-J2 cells. CONCLUSIONS: Our transcriptome profile illustrated a number of genes involving in immune responses and inflammation were inhibited by nsp15, such as CCL5, CXCL8, CXCL10, OAS, MXs, STAT1 and IRF9. The results suggested that nsp15 can antagonize IFNs and block chemokine system to provide an adequate intracellular environment for viral proliferation.

10.
Arch Microbiol ; 203(9): 5635-5645, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34467433

RESUMO

Self-healing is an intrinsic ability that exists widely in every multicellular biological organism. Our recent experiments have shown that bacterial biofilms also have the ability to self-heal after man-make cuts, but the mechanism of biofilm self-healing have not been studied. We find that the healing process of cuts on the biofilm depends on cut geometries like its location or direction, the biofilm itself like the biofilm age, the growing substrate properties like its hardness, and also the environments such as the competitive growth of multiple biofilms. What is more, the healing rate along the cut is heterogeneous, and the maximum healing rate can reach 260 µm/h, which is three times the undestroyed biofilm expansion rate. The cut does not change the rounded shape growth of biofilms. Further study of phenotypic evolution shows that the cut delays bacterial differentiation; motile cells perceive the cut and move to the cut area, while the cut only heals when there are enough matrix-producing cells in the cut area. Our work suggests new ideas for developing self-healing materials.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34570706

RESUMO

Traditional Chinese Medicine (TCM) has the longest clinical history in Asia and contributes a lot to health maintenance worldwide. An essential step during the TCM diagnostic process is syndrome induction, which comprehensively analyzes the symptoms and generates an overall summary of the symptoms. Given a set of symptoms, the existing herb recommenders aim to generate the corresponding herbs as a treatment by inducing the implicit syndrome representations based on TCM prescriptions. As different symptoms have various importance during the comprehensive consideration, we argue that treating the co-occurred symptoms equally to do syndrome induction in the previous studies will lead to the coarse-grained syndrome representation. In this paper, we bring the attention mechanism to model the syndrome induction process. Given a set of symptoms, we leverage an attention network to discriminate the symptom importance and adaptively fuse the symptom embeddings. Besides, we introduce a TCM knowledge graph to enrich the input corpus and improve the quality of representation learning. Further, we build a KG-enhanced Multi-Graph Neural Network architecture, which performs the attentive propagation to combine node feature and graph structural information. Extensive experimental results on two TCM data sets show that our proposed model has the outstanding performance over the state-of-the-arts.

12.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575938

RESUMO

By employing an innovative biohybrid membrane, the present study aimed at elucidating the mechanistic role of the focal adhesion kinase (FAK) in epithelial morphogenesis in vitro over 4, 7, and 10 days. The consequences of siRNA-mediated FAK knockdown on epithelial morphogenesis were monitored by quantifying cell layers and detecting the expression of biomarkers of epithelial differentiation and homeostasis. Histologic examination of FAK-depleted samples showed a significant increase in cell layers resembling epithelial hyperplasia. Semiquantitative fluorescence imaging (SQFI) revealed tissue homeostatic disturbances by significantly increased involucrin expression over time, persistence of yes-associated protein (YAP) and an increase of keratin (K) 1 at day 4. The dysbalanced involucrin pattern was underscored by ROCK-IISer1366 activity at day 7 and 10. SQFI data were confirmed by quantitative PCR and Western blot analysis, thereby corroborating the FAK shutdown-related expression changes. The artificial FAK shutdown was also associated with a significantly higher expression of filaggrin at day 10, sustained keratinocyte proliferation, and the dysregulated expression of K19 and vimentin. These siRNA-induced consequences indicate the mechanistic role of FAK in epithelial morphogenesis by simultaneously considering prospective biomaterial-based epithelial regenerative approaches.

13.
Theor Appl Genet ; 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34420062

RESUMO

KEY MESSAGE: A quantitative trait locus GW10 is located on Chromosome 10 by map-based cloning, which encodes a P450 Subfamily protein. The GW10 regulates grain size and grain number in rice involved in the BR pathway. Grain size and grain number play extremely important roles in rice grain yield. Here, we identify GW10, which encodes a P450 subfamily protein and controls grain size and grain number by using Lemont (tropical japonica) as donor parent and HJX74 (indica) as recipient parent. The GW10 locus was mapped into a 14.6 kb region in HJX74 genomic on the long arm of chromosome 10. Lower expression of the gw10 in panicle is contributed to the shorter and narrower rice grain, and the increased number of grains per panicle. In contrast, overexpression of GW10 is contributed to longer and wider rice grain. Furthermore, the higher expression levels of some of the brassinosteroid (BR) biosynthesis and response genes are associated with the NIL-GW10. The sensitivity of the leaf angle to exogenous BR in NIL-GW10 is lower than that in NIL-gw10 and in the KO-GW10, which implied that the GW10 should involve in the brassinosteroid-mediated regulation of rice grain size and grain number.

14.
J Phys Chem Lett ; : 8237-8245, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34423984

RESUMO

Photoluminescence (PL) intensity in organic or metal-organic emitters usually suffers from thermal quenching (TQ), which severely hinders their industrial applications. The development of negative thermal quenching (NTQ) and/or zero thermal quenching (ZTQ) materials depends on a better understanding of the mechanisms underpinning TQ in luminescent solids. In this work, we investigated the temperature dependence of thermally activated delayed fluorescence (TADF) in copper(I)-organic coordination polymers (CP) ligated with an imidazole or triazole derivative over a broad temperature range. The efficient PL emission of CP1 is heavily quenched as the crystalline samples are cooled to 77 K; the PL intensity shows the NTQ effect in the region of 77-238 K followed by a ZTQ effect in the temperature range of 238-318 K. No NTQ or ZTQ effect is observed for reference coordination polymer CP2, where the 1,2,4-triazole group was used instead of the imidazole one. Our work highlights the important role of the ligand's electronic structure in optimizing photophysical properties of coordination polymer emitters and may stimulate new efforts to design luminescent materials exhibiting NTQ and ZTQ effect at higher temperature.

15.
Chem Pharm Bull (Tokyo) ; 69(10): 989-994, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34421065

RESUMO

Bitter tastes are innately aversive and are thought to help protect animals from consuming poisons. Children are extremely sensitive to drug tastes, and their compliance is especially poor with bitter medicine. Therefore, judging whether a drug is bitter and adopting flavor correction and taste-masking strategies are key to solving the problem of drug compliance in children. Although various machine learning models for bitterness and sweetness prediction have been reported in the literature, no learning model or bitterness database for children's medication has yet been reported. In this study, we trained four different machine learning models to predict bitterness. The goal of this study was to develop and validate a machine learning model called the "Children's Bitter Drug Prediction System" (CBDPS) based on Tkinter, which predicts the bitterness of a medicine based on its chemical structure. Users can enter the Simplified Molecular-Input Line-Entry System (SMILES) formula for a single compound or multiple compounds, and CBDPS will predict the bitterness of children's medicines made from those XGBoost-Molecular ACCess System (XgBoost-MACCS) model yielded an accuracy of 88% under cross-validation.

16.
Biomed Res Int ; 2021: 8828677, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235223

RESUMO

Analysis and diagnosis according to the collected physical data are an important part in the physical examination. Through the data analysis of the physical examination results and expert diagnoses, the physical condition of a specific physical examination unit can be achieved which may guide individual health development. However, in general, the application of physical examination data is insufficient in most of the current physical examination organizations. Therefore, in the present study, statistical analysis and intelligent diagnosis were applied to maximize the utilization of physical examination data. The physical examination data collected from different departments of Dalian University of Technology were statistically analyzed and then synthesized for stimulating the thinking mode and knowledge framework of medical experts by a learning model on machine, resulting in the construction of an intelligent physical examination diagnosis method with 93.4% accuracy confirmed by experts. In conclusion, a potential artificial intelligence model of psychical examination data on health analysis and intelligent diagnosis was established, which may become more and more accurate with data accumulation in the near future.

17.
Nat Commun ; 12(1): 4543, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315889

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill. Using integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles, we report a trans-omics landscape for COVID-19. Our analyses find neutrophils heterogeneity between asymptomatic and critically ill patients. Meanwhile, neutrophils over-activation, arginine depletion and tryptophan metabolites accumulation correlate with T cell dysfunction in critical patients. Our multi-omics data and characterization of peripheral blood from COVID-19 patients may thus help provide clues regarding pathophysiology of and potential therapeutic strategies for COVID-19.


Assuntos
COVID-19/genética , COVID-19/metabolismo , Estado Terminal , Genômica/métodos , Humanos , Lipidômica/métodos , Metabolômica/métodos , Neutrófilos/metabolismo , Transcriptoma/genética
18.
Eur Biophys J ; 50(7): 1013-1023, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34308485

RESUMO

In either a living system or a non-living system, the interaction among its constituent cells or particles is a fundamental aspect at all scales. For example, during the Bacillus subtilis biofilm formation, cells differentiate into multiple phenotypes to adapt to the environments; few hours after the initial inoculation, we find the phenotype of matrix-producing cells form "chain" structure surrounding the phenotype of the "running" motile cells. We use "chain" to characterize the structure of matrix-producing cells, and "running" to characterize the proliferation and growth of motile cells. Due to a large number of cells in the biofilm, it is impossible to construct a traditional kinetic model to describe the causal link between the single-cell movement and the colony behavior. Here, we obtain cell state information and cell group shape information through experiments; after the image analysis, we get the key interaction rules between cells, and then, we simulate the comparable movement of two cell types and the resulting colony geometry using the multi-agent model. Our work makes a better understanding of the relationship between the macroscopic shape of colonies and microscopic mechanical interactions among cells in the early stage of biofilm growth.

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