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1.
Int J Genomics ; 2021: 3102399, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746298

RESUMO

Auxin/indoleacetic acid (Aux/IAA) family genes respond to the hormone auxin, which have been implicated in the regulation of multiple biological processes. In this study, all 25 Aux/IAA family genes were identified in Tartary buckwheat (Fagopyrum tataricum) by a reiterative database search and manual annotation. Our study provided comprehensive information of Aux/IAA family genes in buckwheat, including gene structures, chromosome locations, phylogenetic relationships, and expression patterns. Aux/IAA family genes were nonuniformly distributed in the buckwheat chromosomes and divided into seven groups by phylogenetic analysis. Aux/IAA family genes maintained a certain correlation and a certain species-specificity through evolutionary analysis with Arabidopsis and other grain crops. In addition, all Aux/IAA genes showed a complex response pattern under treatment of indole-3-acetic acid (IAA). These results provide valuable reference information for dissecting function and molecular mechanism of Aux/IAA family genes in buckwheat.

2.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

4.
Hepatology ; 73(2): 586-605, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32297339

RESUMO

BACKGROUND AND AIMS: Milk fat globule-epidermal growth factor-factor 8 (MFGE8) has been shown to be a critical extracellular molecule that mediates apoptotic signaling in the pathological process of nonalcoholic fatty liver disease (NAFLD). MFGE8 is abundantly expressed in hepatocytes, but its function in the pathogenesis of NAFLD has not been characterized. APPROACH AND RESULTS: In our current study, hepatic MFGE8 showed a protective role in the pathogenesis of NAFLD. Hepatic MFGE8 deletion largely exacerbated lipid accumulation and inflammatory responses in the liver in response to overnutrition. Mechanistically, intercellular MFGE8 was shown to directly bind to apoptosis signal-regulating kinase 1 (ASK1) and to inhibit its dimerization and phosphorylation under a normal diet. However, under metabolic challenges, decreased cytoplasmic MFGE8 facilitated the dimerization and phosphorylation of ASK1 and subsequent mitogen-activated protein kinase signaling in hepatocytes. CONCLUSIONS: Hepatic MFGE8 is an endogenous inhibitor that halts the progression of hepatic steatosis and inflammation. Metabolic challenge-induced loss of intracellular MFGE8 facilitates ASK1 dimerization and phosphorylation. Therefore, maintaining hepatic MFGE8 levels may serve as an alternative strategy for the treatment of NAFLD.


Assuntos
Antígenos de Superfície/metabolismo , Fígado/patologia , Proteínas do Leite/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Animais , Antígenos de Superfície/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Hepatócitos , Humanos , Metabolismo dos Lipídeos/imunologia , Fígado/imunologia , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Masculino , Camundongos , Camundongos Knockout , Proteínas do Leite/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Fosforilação/imunologia , Multimerização Proteica/imunologia
5.
J Orthop Surg Res ; 15(1): 377, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883313

RESUMO

OBJECTIVE: The aim of this study is to assess the prevalence of nonunion in patients with tibia fracture and the association between influencing factors and tibia fracture nonunion. METHOD: A database searches of PubMed, the Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Weipu database, and Wanfang database from inception until June 2019 was conducted. The pooled prevalence, odds ratio (OR), and 95% confidence intervals (CI) were calculated with Stata software. RESULTS: In this study, 111 studies involving 41,429 subjects were included. In the study of the relationship between influencing factors and tibia fracture nonunion, 15 factors significantly influenced the fracture union, including > 60 years old, male, tobacco smoker, body mass index > 40, diabetes, nonsteroidal anti-inflammatory drugs (NSAIDs) user, opioids user, fracture of middle and distal tibia, high-energy fracture, open fracture, Gustilo-Anderson grade IIIB or IIIC, Müller AO Classification of Fractures C, open reduction, fixation model, and infection. CONCLUSION: The prevalence of nonunion in patients with tibia fracture was 0.068 and 15 potential factors were associated with the prevalence. Closed reduction and minimally invasive percutaneous plate osteosynthesis (MIPPO) have the low risks of nonunion for the treatment of tibial fractures.


Assuntos
Redução Fechada/métodos , Fixação Interna de Fraturas/métodos , Fraturas não Consolidadas/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Fraturas da Tíbia/cirurgia , Adolescente , Adulto , Fatores Etários , Idoso , Anti-Inflamatórios não Esteroides , Índice de Massa Corporal , Feminino , Fraturas não Consolidadas/epidemiologia , Fraturas não Consolidadas/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides , Prevalência , Fatores de Risco , Fatores Sexuais , Fraturas da Tíbia/epidemiologia , Fraturas da Tíbia/etiologia , Fumar Tabaco , Adulto Jovem
6.
Free Radic Biol Med ; 152: 116-141, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32156524

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide and is strongly associated with the presence of oxidative stress. Disturbances in lipid metabolism lead to hepatic lipid accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. Mitochondrial function adapts to NAFLD mainly through the downregulation of the electron transport chain (ETC) and the preserved or enhanced capacity of mitochondrial fatty acid oxidation, which stimulates ROS overproduction within different ETC components upstream of cytochrome c oxidase. However, non-ETC sources of ROS, in particular, fatty acid ß-oxidation, appear to produce more ROS in hepatic metabolic diseases. Endoplasmic reticulum stress and NADPH oxidase alterations are also associated with NAFLD, but the degree of their contribution to oxidative stress in NAFLD remains unclear. Increased ROS generation induces changes in insulin sensitivity and in the expression and activity of key enzymes involved in lipid metabolism. Moreover, the interaction between redox signaling and innate immune signaling forms a complex network that regulates inflammatory responses. Based on the mechanistic view described above, this review summarizes the mechanisms that may account for the excessive production of ROS, the potential mechanistic roles of ROS that drive NAFLD progression, and therapeutic interventions that are related to oxidative stress.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
7.
J Cell Biochem ; 120(10): 17337-17344, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31209945

RESUMO

Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, promotes tumor progression by serving as a transcriptional coactivator with TEAD. Here, we introduced a new construct which can express the TEAD-binding domain of TAZ protein (TAZBD), and determined its antitumor effect in malignant glioma both in vitro and in vivo. We first observed that TAZ was upregulated in glioma tissues and related to malignant clinicopathologic characteristic, indicating the crucial role of TAZ during glioma progression. In U87 and U251 cells, TAZBD expression increased the proportion of apoptotic cells, and suppressed the colony formation and tumorigenicity. Further, TAZBD also decreased cell metastasis through the repression of epithelial-mesenchymal transition. The mechanistic study showed that TAZBD suppression of glioma cells was predominantly through blocking the TAZ-TEAD complex formation by competing with endogenous TAZ. Thus, the gene therapy of malignant glioma through blocking TAZ-TEAD complex by TAZBD may provide a new way for the targeted therapy of glioma.


Assuntos
Apoptose , Neoplasias Encefálicas/secundário , Proteínas de Ligação a DNA/metabolismo , Transição Epitelial-Mesenquimal , Glioma/patologia , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica , Proteínas Nucleares/genética , Prognóstico , Transativadores/genética , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Hepatology ; 70(5): 1750-1769, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31077413

RESUMO

Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Fígado/irrigação sanguínea , Proteômica , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
9.
Nat Med ; 24(1): 73-83, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29227475

RESUMO

Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.


Assuntos
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Araquidonato 12-Lipoxigenase/metabolismo , Fígado/irrigação sanguínea , Receptores Acoplados a Proteínas G/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/antagonistas & inibidores , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biossíntese , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Metabolismo dos Lipídeos , Camundongos , Traumatismo por Reperfusão/parasitologia , Suínos
10.
Eur J Pharmacol ; 771: 84-92, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26688570

RESUMO

Rutin exhibits antidiabetic, antioxidant and anti-inflammatory properties, which makes rutin an attractive candidate for diabetic complications. The present study was designed to investigate the potential effect of rutin on diabetic neuropathy. After induction of diabetic neuropathy, rutin (5mg/kg, 25mg/kg and 50mg/kg) were daily given to the diabetic rats for 2 weeks. At the end of rutin administration, rutin produced a significant inhibition of mechanical hyperalgesia, thermal hyperalgesia and cold allodynia, as well as partial restoration of nerve conduction velocities in diabetic rats. Furthermore, rutin significantly increased Na(+), K(+)-ATPase activities in sciatic nerves and decreased caspase-3 expression in dorsal root ganglions (DRG). In addition, rutin significantly decreased plasma glucose, attenuated oxidative stress and neuroinflammation. Further studies showed that rutin significantly increased hydrogen sulfide (H2S) level, up-regulated the expression of nuclear factor-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in DRG. The evidences suggest the beneficial effect of rutin on diabetic neuropathy. Additionally, insulin (2 IU) and BG-12 (15mg/kg) were used to investigate the mechanisms underlying the beneficial effect of rutin on diabetic neuropathy. Insulin achieved lower plasma glucose and BG-12 achieved comparable Nrf2 expression than/to rutin (50mg/kg), respectively. In contrast, the beneficial effect of insulin and BG-12 was inferior to that of rutin (50mg/kg), suggesting that both lowered plasma glucose and Nrf2 signaling contribute to the beneficial effect of rutin on diabetic neuropathy. In conclusion, rutin produces significant protection in diabetic neuropathy, which makes it an attractive candidate for the treatment of diabetic neuropathy.


Assuntos
Glicemia/metabolismo , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Rutina/uso terapêutico , Animais , Caspase 3/biossíntese , Caspase 3/genética , Heme Oxigenase-1/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Insulina/uso terapêutico , Masculino , Condução Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo
11.
Pathol Res Pract ; 208(8): 437-43, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22682760

RESUMO

Hepatoma-derived growth factor (HDGF) plays an important role in tumor progression. Highly expressed HDGF has been found to indicate poor prognosis in many cancers. However, no information is available regarding the prognostic value of nuclear or cytoplasmic HDGF staining level in breast cancer. In the present study, the nuclear or cytoplasmic HDGF staining level was investigated in 86 patients with primary breast cancer by immunohistochemistry; the relationship between nuclear or cytoplasmic HDGF staining level and clinicopathological parameters was examined by Two-tailed Mann-Whitney U-test or Krustal-Wallis. The prognostic value of nuclear or cytoplasmic HDGF staining level in disease-free survival and overall survival was analyzed by Kaplan-Meier methods and log-rank test. We found that the percentage of cases with strong nuclear HDGF staining level was significantly higher in the cases with high tumor grade, high stage, high proliferation index (Ki-67 index>20%), as well as in those with lymph node invasion and recurrence (p<0.05) compared to those without. No significant correlation was found between cytoplasmic HDGF expression and any clinicopathological variables. In addition, disease-free survival and overall survival were significantly lower in patients with high nuclear HDGF expression (level 2) than in those with low nuclear HDGF expression (level 0 and level 1). Further Cox multivariate analysis showed that high nuclear HDGF expression is an independent factor for indicating poor prognosis in breast cancer patients. No significant difference in disease-free survival rate and overall survival was found between different cytoplasmic HDGF staining levels. All these findings suggest that increased nuclear HDGF expression is involved in tumor progression and might be used as a new prognosticator for breast cancer.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias da Mama/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Núcleo Celular/metabolismo , Núcleo Celular/patologia , China/epidemiologia , Citoplasma/metabolismo , Citoplasma/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico
12.
Neurosci Lett ; 478(2): 66-71, 2010 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-20438804

RESUMO

Searching for effective drugs which are capable of promoting nerve regeneration after nerve injuries has gained extensive attention. Ginsenoside Rg1 (GRg1) is one of the bioactive compounds extracted from ginseng. GRg1 has been shown to be neuroprotective in many in vitro studies, which raises the possibility of using GRg1 as a neuroprotective agent after nerve injuries. However, such a possibility has never been tested in in vivo studies. The present study was designed to investigate the efficacy of GRg1 in promoting nerve regeneration after nerve crush injury in rats. All rats were randomly divided into four groups (n=8 in each group) after crush injury and were intraperitoneally administrated daily for 4 weeks with 1mg/kg, or 5mg/kg GRg1 (low or high dose GRg1 groups), or 100mug/kg mecobalamin or normal saline, respectively. The axonal regeneration was investigated by retrograde labeling and morphometric analysis. The motor functional recovery was evaluated by electrophysiological studies, behavioral tests and histological appearance of the target muscles. Our data showed that high dose GRg1 achieved better axonal regeneration and functional recovery than those achieved by low dose GRg1 and mecobalamin. The final outcome of low dose GRg1 and mecobalamin was similar in both morphological and functional items, which was significantly better than that in saline group. These findings show that GRg1 is capable of promoting nerve regeneration after nerve injuries, suggesting the possibility of developing GRg1 a neuroprotective drug for peripheral nerve repair applications.


Assuntos
Ginsenosídeos/uso terapêutico , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Eletrofisiologia , Masculino , Compressão Nervosa , Degeneração Neural/fisiopatologia , Panax , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia
13.
Brain Res ; 1336: 98-102, 2010 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-20388496

RESUMO

14-3-3 proteins comprise a large family of highly conserved, acidic polypeptides, expressed in all eukaryotic organisms, with highest concentration found in the brain. Multiple isoforms of 14-3-3 proteins have been shown to play an essential role in regulating differentiation, proliferation and transformation. In the previous study, the expression levels of all seven 14-3-3 isoforms were examined in astrocytoma. However, the expression of seven 14-3-3 isoforms in meningioma still remains unknown. This study is the first examination of 14-3-3 isoforms in three grades of meningioma by immunohistochemistry. 14-3-3epsilon, zeta and theta were specifically expressed in meningioma, and their expression levels increased with the increase of pathological grade of meningioma. The 14-3-3 eta, beta, gamma and sigma isoforms were negatively expressed in meningioma. In conclusion, The 14-3-3 epsilon, zeta and theta may be involved in tumorigenesis of meningioma and be efficient markers for predicting the degree of malignancy in meningioma.


Assuntos
Proteínas 14-3-3/biossíntese , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Meningioma/metabolismo , Meningioma/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/biossíntese , Adulto Jovem
14.
Brain Res ; 1304: 149-54, 2009 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-19782666

RESUMO

HIF-1alpha plays an indispensable role in tumor formation and histogenesis. Target genes involved in glucose transport are acutely transactivated by HIF-1alpha. GLUT-3 protein is the rate-limiting factor related to glucose transport, which is classified as brain-type glucose transporter. This study was the initial one aiming to probe into the co-expression and clinical significance of HIF-1alpha and GLUT-3 in glioma. One hundred and twenty cases of glioma tissues and ten human normal cerebral tissues decompressed in glioma excision were examined using immunohistochemistry and Western blot. The expression of HIF-1alpha and GLUT-3 increased gradually with the increase of pathological grade of glioma, respectively. There was significant difference in the expression of HIF-1alpha and GLUT-3 in every two groups, respectively. There was a positive correlation between HIF-1alpha and GLUT-3. In conclusion, the expression of HIF-1alpha and GLUT-3 in glioma was correlated significantly with tumors' pathological grade, which can be taken as a pair of useful markers for predicting the biological behavior of glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioma/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Actinas/metabolismo , Adolescente , Adulto , Idoso , Western Blotting , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Núcleo Celular/metabolismo , Criança , Feminino , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Adulto Jovem
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