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1.
Proc Natl Acad Sci U S A ; 118(42)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34625471

RESUMO

Cellular ionic concentrations are a central factor orchestrating host innate immunity, but no pathogenic mechanism that perturbs host innate immunity by directly targeting metal ions has yet been described. Here, we report a unique virulence strategy of Yersinia pseudotuberculosis (Yptb) involving modulation of the availability of Mn2+, an immunostimulatory metal ion in host cells. We showed that the Yptb type VI secretion system (T6SS) delivered a micropeptide, TssS, into host cells to enhance its virulence. The mutant strain lacking TssS (ΔtssS) showed substantially reduced virulence but induced a significantly stronger host innate immune response, indicating an antagonistic role of this effector in host antimicrobial immunity. Subsequent studies revealed that TssS is a Mn2+-chelating protein and that its Mn2+-chelating ability is essential for the disruption of host innate immunity. Moreover, we showed that Mn2+ enhances the host innate immune response to Yptb infection by activating the stimulator of interferon genes (STING)-mediated immune response. Furthermore, we demonstrated that TssS counteracted the cytoplasmic Mn2+ increase to inhibit the STING-mediated innate immune response by sequestering Mn2+ Finally, TssS-mediated STING inhibition sabotaged bacterial clearance in vivo. These results reveal a previously unrecognized bacterial immune evasion strategy involving modulation of the bioavailability of intracellular metal ions and provide a perspective on the role of the T6SS in pathogenesis.

2.
J Microencapsul ; : 1-11, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34615422

RESUMO

AIM: To prepare several novel microcapsules using chitosan (Cs) and Alginate (Alg) as coating materials, and nano-ZnO, nano-SiO2, nano-TiO2 as UV protective agents for improving UV resistance of Cry1Ac. METHODS: Microcapsules were prepared by the layer-by-layer (LbL) self-assembly technique and electrostatic adsorption. The morphologies were observed by scanning electron microscopy (SEM), and the stability under UV radiation was studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and bioassay. RESULTS: SEM showed that nano-ZnO and nano-TiO2 could be adsorbed on the negatively charged MC with the outermost layer being Alg, while nano-SiO2 could be adsorbed on the positively charged MC with Cs as the outermost layer. SDS-PAGE and bioassay showed that nano-ZnO and nano-SiO2 could provide effective UV protection after 8 h UV irradiation (p > 0.05), and nano-TiO2 could provide effective UV protection after 4 h UV irradiation (p > 0.05). CONCLUSION: The microcapsules loaded with nanoparticles provided excellent UV resistance for Cry1Ac.

3.
Virus Res ; : 198605, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34662681

RESUMO

Japanese encephalitis virus (JEV) causes the most commonly diagnosed viral encephalitis in Asia. JEV is a highly neurotropic flavivirus that can replicate efficiently in the brain. Axl belongs to the TAM (Tyro3, Axl, Mer) family, a group of tyrosine kinase receptors involved in the viral entry, micked as apoptotic bodies and regulation of innate immunity. However, the underlying mechanisms on its regulation in the neurons for JEV are unclear. Here, we found that Axl was upregulated in neurons after JEV infection. Unexpectedly, Axl deficient (Axl-/-) mice were more susceptible to JEV infection with increased viral loads in neurons. The RNA-sequencing analysis between the wild type neurons and Axl-/- neurons infected with JEV showed that many interferon-stimulated genes were downregulated in the Axl-/- neurons which innate immunity was attenuated largely. The rescue experiment in Axl-/- neurons indicated that Axl may be positively involved in the regulation of antiviral immunity. Taken together, our data demonstrated that Axl may play an antiviral role in JEV replication within neurons by modulating neuronal innate immunity.

5.
Mikrochim Acta ; 188(10): 340, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34523015

RESUMO

Using MIL-101(Fe) as the source of carbon and Fe, a magnetic porous carbon (MPC) material with Fe3C nanoparticles encapsulated in porous carbon was prepared through one-pot pyrolysis under N2 atmosphere. With MPC as adsorption material, a stir bar sorptive-dispersive microextraction (SBSDME) method was proposed to extract and preconcentrate sulfonamides (SAs) prior to HPLC-DAD determination. To investigate their extraction ability, different MPC materials were prepared under different carbonization temperatures (600, 700, 800, 900, and 1000 °C). The material prepared under 900 °C (MPC-900) exhibited the highest extraction ability for SAs. The as-prepared MPC materials were also characterized by Raman spectroscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, zeta potential, and other techniques. The main parameters that affect extraction were systematically studied. Under optimal conditions, favorable linearity (R2 ≥ 0.9938) and detection limits (0.02-0.04 ng mL-1) of sulfonamides were obtained. The average recoveries for spiked milk and lake water samples ranged from 76.9 to 109% and from 75.4 to 118% with RSDs of 3.10-9.63% and 1.71-11.3%, respectively. Sulfameter and sulfisoxazole were detected in milk sample. Sulfisoxazole was detected in the lake water sample. The MPC-900 material demonstrated excellent reusability. It can be reused 24 times with peak areas having no obvious decline. The method can be applied to extract ultra-trace compounds in complex sample matrices. Schematic presentation of a stir bar sorptive-dispersive microextraction (SBSDME) by using magnetic porous carbon (MPC) composites as sorbent combined with high-performance liquid chromatography for sensitive analysis of sulfonamides in milk and lake water samples.

7.
Virol Sin ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34558014

RESUMO

Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis in endemic regions of Asia. The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis. Revealing the interplay between virus and host cells in metabolic facet is of great importance both for unraveling the pathogenesis mechanisms and providing novel antiviral targets. This study took advantage of the integration analysis of metabolomics and transcriptomics to depict the metabolic profiles of neurons during the early stage of JEV infection. Increased glycolysis and its branched pentose phosphate pathway (PPP) flux and impaired oxidative phosphorylation (OXPHOS) in glucose utilization, and the catabolic patterns of lipid metabolism were created to facilitate the biosynthesis of precursors needed for JEV replication in neurons. Pharmacological inhibitions of both glycolysis pathway and PPP in neurons suggested its indispensable role in maintaining the optimal propagation of JEV. In addition, analysis of metabolomic-transcriptomic regulatory network showed the pivotal biological function of lipid metabolism during JEV infection. Several pro-inflammatory lipid metabolites were significantly up-regulated and might partially be responsible for the progression of encephalitis. These unique metabolic reprogramming features might give deeper insight into JEV infected neurons and provide promising antiviral approaches targeting metabolism.

8.
Reproduction ; 162(5): 353-365, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34486978

RESUMO

There are around 300 million adolescent pregnancies worldwide, accounting for 11% of all births worldwide. Accumulating evidence demonstrates that many adverse perinatal outcomes are associated with adolescent pregnancies. However, how and why these abnormalities occur remain to be defined. In this study, pregnancy at different stages was compared between 25- and 30- day-old and mature female mice. We found that the litter size of adolescent pregnancy is significantly decreased from F1 to F3 generations compared to mature pregnancy. On days 8 and 12 of pregnancy, multiple abnormalities in decidual and placental development appear in F3 adolescent pregnancy. On days 5 and 8, uterine endoplasmic reticulum stress is dysregulated in F3 adolescent pregnancy. Embryo implantation and decidualization are also compromised in adolescent pregnancy. Many genes are abnormally expressed in adolescent estrous uteri. The abnormal endocrine environment and abnormal implantation from uterine immaturity may result in multiple pregnancy failures in adolescent pregnancy. The aim of this study is to shed light on human adolescent pregnancy.

9.
Comput Struct Biotechnol J ; 19: 4472-4485, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34471493

RESUMO

Because immune checkpoint inhibitors (ICIs) are effective for a subset of melanoma patients, identification of melanoma subtypes responsive to ICIs is crucial. We performed clustering analyses to identify immune subtypes of melanoma based on the enrichment levels of 28 immune cells using transcriptome datasets for six melanoma cohorts, including four cohorts not treated with ICIs and two cohorts treated with ICIs. We identified three immune subtypes (Im-H, Im-M, and Im-L), reproducible in these cohorts. Im-H displayed strong immune signatures, low stemness and proliferation potential, genomic stability, high immunotherapy response rate, and favorable prognosis. Im-L showed weak immune signatures, high stemness and proliferation potential, genomic instability, low immunotherapy response rate, and unfavorable prognosis. The pathways highly enriched in Im-H included immune, MAPK, apoptosis, calcium, VEGF, cell adhesion molecules, focal adhesion, gap junction, and PPAR. The pathways highly enriched in Im-L included Hippo, cell cycle, and ErbB. Copy number alterations correlated inversely with immune signatures in melanoma, while tumor mutation burden showed no significant correlation. The molecular features correlated with favorable immunotherapy response included immune-promoting signatures and pathways of PPAR, MAPK, VEGF, calcium, and glycolysis/gluconeogenesis. Our data recapture the immunological heterogeneity in melanoma and provide clinical implications for the immunotherapy of melanoma.

10.
Oncol Rep ; 46(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34476504

RESUMO

Extracellular acidosis is associated with various immunopathological states. The microenvironment of numerous solid tumours and inflammatory responses during acute or chronic infection are all related to a pH range of 5.5­7.0. The relationship between inflammation and immune escape, cancer metabolism, and immunologic suppression drives researchers to focus on the effects of low pH on diverse components of disease immune monitoring. The potential effect of low extracellular pH on the immune function reveals the importance of pH in inflammatory and immunoreactive processes. In this review, the mechanism of how pH receptors, including monocarboxylate transporters (MCTs), Na+/H+ exchanger 1, carbonic anhydrases (CAs), vacuolar­ATPase, and proton­sensing G­protein coupled receptors (GPCRs), modulate the immune system in disease, especially in cancer, were studied. Their role in immunocyte growth and signal transduction as part of the immune response, as well as cytokine production, have been documented in great detail. Currently, immunotherapy strategies have positive therapeutic effects for patients. However, the acidic microenvironment may block the effect of immunotherapy through compensatory feedback mechanisms, leading to drug resistance. Therefore, we highlight promising therapeutic developments regarding pH manipulation and provide a framework for future research.

11.
Talanta ; 235: 122818, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517674

RESUMO

As a type of environmental endocrine disrupting chemicals, bisphenols (BPs) have a certain embryonic toxicity and teratogenicity, which can significantly increase the risks of breast cancer, prostate cancer, leukemia and other cancers. In this work, stable multivariate metal-organic frameworks (UiO-66-NH2/TCPPx) were synthesized via in situ one-pot method and used as miniaturized dispersive solid-phase extraction (dµSPE) sorbents for extraction of trace BPs from environmental samples. The phase purity, crystal morphology and physical properties of UiO-66-NH2/TCPPx samples were varied by adjusting the mass ratio of TCPP. The extraction performance of UiO-66-NH2/TCPPx samples were investigated and UiO-66-NH2/TCPP1.0 exhibited the highest adsorption efficiency. Besides, UiO-66-NH2/TCPP1.0 possessed excellent recycling stability for the adsorption and desorption of BPs more than 20 cycles. The experimental parameters including amount of adsorbent, adsorption time, sample solution pH, temperature, desorption time and desorption solvents which affecting the efficiency of dµSPE were studied, respectively. Good linearity (R2 > 0.9992) in range of 0.1-200 ng mL-1 was obtained. The detection limits (S/N = 3) and quantification limits (S/N = 10) were achieved at 0.03-0.08 ng mL-1 and 0.1-0.5 ng mL-1, respectively. The relative standard deviations (RSDs) of intra-day and inter-day ranged from 2.5 to 5.5% and 1.1-6.8%. Enrichment factors were calculated in the range of 303-338. The obtained recoveries of bisphenol F (BPF), bisphenol A (BPA), bisphenol B (BPB) and bisphenol AF (BPAF) were 81.26-91.03% (RSDs = 0.96-6.47%), 82.2-97.27% (RSDs = 0.45-6.15%), 87.56-97.26% (RSDs = 1.1-6.22%) and 82.2-100.8% (RSDs = 0.46-4.07%). The UiO-66-NH2/TCPP1.0 can be employed as potential dµSPE sorbents for the enrichment of trace BPs in the environmental samples.


Assuntos
Estruturas Metalorgânicas , Adsorção , Compostos Benzidrílicos , Humanos , Masculino , Fenóis , Extração em Fase Sólida , Solventes
12.
Chem Commun (Camb) ; 57(70): 8810-8813, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34382969

RESUMO

Herein, a new gas-cycle-assisted (GCA) headspace solid-phase microextraction (HS-SPME) device was designed to rapidly extract organic pollutants with high Kow and boiling points, which have difficulty in volatilization from matrix to headspace. Organic pollutants, including three polycyclic aromatic hydrocarbons (PAHs), four polychlorinated biphenyls (PCBs), and five phthalate esters (PAEs), were selected to evaluate the performance of GCA HS-SPME. Compared with conventional HS-SPME, the equilibrium times of GCA HS-SPME for extraction of PAHs, PCBs, and PAEs were greatly shortened from 70-90 to 5-11 min. Moreover, the limits of detection for analysis of PAHs were achieved at pg mL-1 level by GCA HS-SPME coupled with gas chromatography-flame ionization detection.

13.
Mol Ther ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34450250

RESUMO

Cold tumor microenvironment (TME) marked with low effector T cell infiltration leads to weak response to immune checkpoint inhibitor (ICI) treatment. Thus, switching cold to hot TME is critical to improve potent ICI therapy. Previously, we reported extracellular vesicle (EV)-like ginseng-derived nanoparticles (GDNPs) that were isolated from Panax ginseng C.A. Mey and can alter M2 polarization to delay the hot tumor B16F10 progression. However, the cold tumor is more common and challenging in the real world. Here, we explored a combinatorial strategy with both GDNPs and PD-1 (programmed cell death protein-1) monoclonal antibody (mAb), which exhibited the ability to alter cold TME and subsequently induce a durable systemic anti-tumor immunity in multiple murine tumor models. GDNPs enhanced PD-1 mAb anti-tumor efficacy in activating tumor-infiltrated T lymphocytes. Our results demonstrated that GDNPs could reprogram tumor-associated macrophages (TAMs) to increase CCL5 and CXCL9 secretion for recruiting CD8+ T cells into the tumor bed, which have the synergism to PD-1 mAb therapy with no detected systemic toxicity. In situ activation of TAMs by GDNPs may broadly serve as a facile platform to modulate the suppressive cold TME and optimize the PD-1 mAb immunotherapy in future clinical application.

14.
BMJ Open ; 11(8): e055874, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433612

RESUMO

INTRODUCTION: Studies have shown that acupuncture has significant therapeutic effects on painful diabetic peripheral neuropathy (PDPN) yet the precise mechanism of action underpinning these effects remains controversial. Resting-state functional MRI (rs-fMRI) is an advanced imaging technique that can be used to monitor changes in the activity of the brain, particularly in PDPN. However, the data from several studies remain inconclusive and there is currently no systematic review and meta-analysis for the use of rs-fMRI in PDPN. METHODS AND ANALYSIS: In this study, we will select all eligible studies published on or before 30 June 2021. Four English and four Chinese databases will be searched, specifically, PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, WanFang database, China Science Technology Journal Database (VIP) and China Doctor/Master Dissertations Full-text Database. Only clinical trials and the first cycle of a cross-over trial linked to acupuncture for PDPN will be included in the analysis. The main outcomes include the amplitude of low-frequency fluctuation, regional homogeneity, functional connectivity of the brain, bilateral superficial peroneal nerve sensory nerve conduction velocity, bilateral dorsal current perception threshold values and the degree of subjective pain. The secondary outcomes include biochemical indicators, the degree of depression and anxiety and changes in efficiency. The study selection, data extraction and risk of bias assessment will be performed by two investigators. For statistical analyses, Review Manager V.5.4 software will be used. If necessary, heterogeneity testing, data synthesis, and subgroup analysis will be performed. ETHICS AND DISSEMINATION: Our systematic review and meta-analysis will be based on published literature for data extraction and will not include the use of individual patient data and so no ethical approval required. PROSPERO REGISTRATION NUMBER: CRD42021211644.


Assuntos
Terapia por Acupuntura , Diabetes Mellitus , Neuropatias Diabéticas , Neuropatias Diabéticas/terapia , Humanos , Imageamento por Ressonância Magnética , Metanálise como Assunto , Dor , Projetos de Pesquisa , Revisões Sistemáticas como Assunto
16.
J Arthroplasty ; 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34419317

RESUMO

BACKGROUND: Alcohol withdrawal (AW) syndrome is an independent risk factor for postoperative complications. This study aims to evaluate the influence of AW on perioperative outcomes in patients who underwent primary total knee (TKA) or total hip arthroplasty (THA). METHODS: We used the National Inpatient Sample database to identify patients undergoing TKA/THA from 2003 to 2014. The primary exposure of interest was AW. Multivariable adjusted models were used to evaluate the association of AW with in-hospital medical complications, surgical complications, mortality, cost, and length of stay (LOS) in patients undergoing TKA/THA. RESULTS: There were 2,971,539 adult hospitalizations for THAs and 6,367,713 hospitalizations for TKAs included in the present study, among which 0.14% of AW for THA patients and 0.10% of AW for TKA patients. Multivariable adjustment analysis suggested that AW was associated with an increased risk of medical complications (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.79-2.42, P < .0001), surgical complications (OR 1.75, 95% CI 1.51-2.03, P < .0001), and had 4.79 times increase of in-hospital mortality, 26% increase of total cost, and 53% increase of LOS in THA procedures. For TKA procedures, AW was also associated with increased risk of medical complications (OR 3.14, 95% CI 2.78-3.56, P < .0001), surgical complications (OR 2.07, 95% CI 1.82-2.34, P < .0001) and 4.24 times increase of in-hospital mortality, 29% increase of total cost, and 58% increase of LOS after multivariable adjustment. CONCLUSION: AW is associated with increased risk of in-hospital mortality, medical and surgical complications. Proactive surveillance and management of AW may be important in improving outcomes in patients who underwent THA and TKA procedure.

17.
Front Chem ; 9: 723186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395386

RESUMO

Rapid glucose testing is very important in the care of diabetes. Monitoring of blood glucose is the most critical indicator of disease control in diabetic patients. The invention and popularity of electrochemical sensors have made glucose detection fast and inexpensive. The first generation of glucose sensors had limitations in terms of sensitivity and selectivity. In order to overcome these problems, scientists have used a range of new materials to produce new glucose electrochemical sensors with higher sensitivity, selectivity and lower cost. A variety of different electrochemical sensors including enzymatic electrochemical sensors and enzyme-free electrochemical sensors have been extensively investigated. We discussed the development process of electrochemical glucose sensors in this review. We focused on describing the benefits of carbon materials in nanomaterials, specially graphene for sensors. In addition, we discussed the limitations of the sensors and challenges in future research.

18.
Cancer Sci ; 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34431598

RESUMO

The Wnt/ß-catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid-enhancing factor (LEF) luciferase reporter system, the high-throughput screening of 18 840 small-molecule compounds was performed. A novel scaffold compound, C644-0303, was identified as a Wnt/ß-catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644-0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644-0303 could suppress various tumor-promoting transcription factor activities in addition to Wnt/ß-catenin. Finally, C644-0303 suppressed tumor spheroidization in a 3-dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/ß-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.

19.
Front Microbiol ; 12: 699913, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335534

RESUMO

Aerobactin is a citrate-hydroxamate siderophore that is critical for the virulence of pathogenic enteric bacteria. However, although the aerobactin-producing iucABCD-iutA operon is distributed widely in the genomes of Yersinia species, none of the pathogenic Yersinia spp. was found to produce aerobactin. Here, we showed that the iucABCD-iutA operon in the food-borne enteric pathogen Yersinia pseudotuberculosis YPIII is a functional siderophore system involved in iron acquisition. The expression of the operon was found to be directly repressed by the ferric uptake regulator (Fur) in an iron concentration-dependent manner. In addition, we demonstrated that the aerobactin-mediated iron acquisition contributes to bacterial growth under iron-limited conditions. Moreover, we provided evidence that aerobactin plays important roles in biofilm formation, resistance to oxidative stress, ROS removal, and virulence of Y. pseudotuberculosis. Overall, our study not only uncovered a novel strategy of iron acquisition in Y. pseudotuberculosis but also highlighted the importance of aerobactin in the pathogenesis of Y. pseudotuberculosis.

20.
J Orthop Surg Res ; 16(1): 455, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34271974

RESUMO

BACKGROUND: Femoral neck fractures in elderly patients typically warrant operative treatment and are related to high risks of mortality and morbidity. As early hip arthroplasties for elderly femoral neck fractures are widely accepted, rapid predicting models that allowed quantitative and individualized prognosis assessments are strongly needed as references for orthopedic surgeons during preoperative conversations. METHODS: Data of patients aged ≥ 65 years old who underwent primary unilateral hemiarthroplasty or total hip arthroplasty due to femoral neck fracture between January 1st, 2012 and June 30th, 2019 in our center were collected. Candidate variables included demographic data, comorbidities, and routine preoperative screening tests. The main outcomes included 1-year mortality and free walking rate after hip arthroplasty. Patients were randomly divided into derivation and validation groups in the ratio of three to one. Nomograms were developed based on multivariable logistic regressions of derivation group via R language. One thousand bootstraps were used for internal validation. Those models were further tested in the validation group for external validation. RESULTS: The final analysis was performed on 702 patients after exclusion and follow-up. All-cause 1-year mortality of the entire data set was 23.4%, while the free walking rate was 57.3%. Preoperative walking ability showed the biggest impact on predicting 1-year mortality and walking ability. Static nomograms were created from the final multivariable models, which allowed simplified graphical computations for the risks of 1-year mortality and walking ability in a certain patient. The bias-corrected C index of those nomograms for predicting 1-year mortality in the derivation group and the validation group were 0.789 and 0.768, while they were 0.807 and 0.759 for predicting postoperative walking ability. The AUC of the mortality and walking ability predicting models were 0.791 and 0.818, respectively. CONCLUSIONS: Our models enabled rapid preoperative 1-year mortality and walking ability predictions in Asian elderly femoral neck fracture patients who planned for hip arthroplasty, with adequate predictive discrimination and calibration. Those rapid assessment models could help surgeons in making more reasonable clinical decisions and subsequently reducing the risk of potential medical dispute via quantitative and individualized prognosis assessments.

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