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Dietary phenolic compounds and vitamin E bioavailability : model studies in rats and humans /Frank, Jan, January 2004 (has links) (PDF)
Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2004. / Härtill 7 uppsatser.
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Transcriptional responses during the pathogenic interaction between Heterobasidion Annosum s. l. and conifers /Karlsson, Magnus, January 2005 (has links) (PDF)
Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2005. / Härtill 4 uppsatser.
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Sesame seed lignans : diversity, human metabolism and bioactivities /Moazzami, Ali A., January 2006 (has links) (PDF)
Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2006. / Härtill 6 uppsatser.
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Cytochrome P450 3A and ABC-transport proteins in horse /Tydén, Eva, January 2008 (has links) (PDF)
Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2008. / Härtill 5 uppsatser.
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Alterações farmacocinéticas de drogas pelo citocromo P450 na leishmaniose visceral humanaSouza, Tânia Maria Vieira 12 June 2014 (has links)
Studies in humans and laboratory animals have shown that inflammation and infectious processes are associated with changes in expression and activity of cytochrome P450 (CYP), which are responsible for the metabolism of most drugs in clinical use. In this context, the objectives of this work were: observe pharmacokinetic changes of CYP450 during human visceral leishmaniasis, describe the epidemiological, clinical and laboratory characteristics of patients with visceral leishmaniasis and evaluate the activity of the isoenzymes CYP3A4, CYP2C9 and CYP2C19 in patients with visceral leishmaniasis before and after treatment. This is a cross-sectional study, developed into an inpatient unit of a school hospital linked to the Federal University of Sergipe, reference in the diagnosis and treatment of visceral leishmaniasis in the state, which involved 24 patients. The study was conducted in four phases: before treatment, immediately after treatment, ninety and one hundred and eighty days after the end of treatment. In each phase, patients ingested the medication omeprazole (CYP2C19 substrate), losartan (CYP2C9 substrate) and midazolam (CYP3A4 substrate), which were used as evidence of the enzymes for which are substrates. Collecting blood samples (5 mL) of the patients before the administration of these drugs and 15, 30, 45 minutes and 1, 2, 3, 4, 5 and 6 hours after administration of those drugs. It was also collected all urine produced in 8 hours after the ingestion of drugs and separate a aliquot of 20 mL for analysis. Liquid chromatography coupled to mass spectrometry high efficiency (LC-MS) was used for the quantification of drugs and metabolites in the samples. The reason omeprazol/5-hidróxi-omeprazol plasma concentrations obtained 4 h after drug administration was used to evaluate the activity of CYP2C19, and the CYP2C9 enzyme activity was estimated by the ratio of concentrations losartano/E-3174 in urine collected 8h after administration of the drug. To estimate the activity of CYP3A4 was calculated the apparent clearance (CL / F) of midazolam. The results showed a prevalence of the disease in males and that most cases occurred in patients residing in urban areas. In relation to the clinical findings were present weight loss, fever, malaise and hepatomegaly in 100% of participants, and 50% were diagnosed between 90 and 180 days the onset of symptoms. On laboratory changes, anemia, leukopenia, thrombocytopenia, hypoalbuminemia, normal or slightly altered transaminases were found. As the enzymatic activity, the apparent clearance of midazolam found himself reduced during illness and increased after treatment; the metabolic ratio of omeprazole plasma concentration of 5-hydroxy-omeprazole and the ratio of the concentration urine losartano/E-3174 were increased during illness, and reduced after treatment, indicating a reduction in the activity of CYP3A4, 2C9 and 2C19 during LV and increase after treatment. The knowledge that occur changes on the activity of the cytochromes P450 and, consequently, on the pharmacokinetics of drugs during visceral leishmaniasis, may contribute to better understanding of the response to drugs during the disease. / Estudos realizados em seres humanos e animais de laboratório têm demonstrado que a inflamação e os processos infecciosos estão associados a alterações na expressão e na atividade dos citocromos P450 (CYP), os quais são responsáveis pelo metabolismo da maioria dos fármacos de uso clínico. Nesse contexto, os objetivos deste trabalho foram: observar as alterações farmacocinéticas dos CYP450 durante a LV humana, descrever as características epidemiológicas, clínicas e laboratoriais dos pacientes com leishmaniose visceral e avaliar a atividade das isoenzimas CYP3A4, CYP2C9 e CYP2C19 em pacientes com leishmaniose visceral antes e após o tratamento. Trata-se de um estudo transversal, desenvolvido em uma unidade de internamento de um hospital escola vinculado à Universidade Federal de Sergipe, referência no diagnóstico e tratamento da leishmaniose visceral no Estado, do qual participaram 24 pacientes. O estudo foi realizado em quatro fases: antes do início do tratamento, imediatamente após o término do tratamento, noventa e cento e oitenta dias após o término do tratamento. Em cada fase, os pacientes ingeriram os medicamentos omeprazol (substrato do CYP2C19), losartano (substrato do CYP2C9) e midazolam (substrato do CYP3A4), os quais foram usados como prova da atividade das enzimas para as quais são substratos. Foi realizada coleta de amostras de sangue (5 mL) dos pacientes antes da administração desses medicamentos, e 15, 30, 45 minutos e 1, 2, 3, 4, 5 e 6 horas após a administração dessas drogas. Também foi coletada toda a urina produzida nas 8h seguintes à ingestão dos medicamentos e separada uma alíquota de 20 mL para análise. A cromatografia líquida de alta eficiência acoplada à espectrometria de massas (LC-MS-MS) foi utilizada para quantificação dos medicamentos e seus metabólitos nas amostras coletadas. A razão das concentrações plasmáticas omeprazol/5-hidróxi-omeprazol obtidas 4h após a administração do fármaco foi usada para avaliar a atividade do CYP2C19, e a atividade da enzima CYP2C9 foi estimada pela razão das concentrações losartano/E-3174 na urina coletada nas 8h seguintes à administração do fármaco. Para estimar a atividade do CYP3A4 foi calculado o clearence aparente (CL/F) do midazolam. Os resultados mostraram que houve predomínio da doença no sexo masculino e que a maioria dos casos ocorreu em pacientes residentes na zona urbana. Em relação ao quadro clínico, estiveram presentes emagrecimento, febre, hepatomegalia e mal estar em 100% dos participantes, e 50% deles foram diagnosticados entre 90 e 180 dias do início dos sintomas. Sobre as alterações laboratoriais, foram encontradas anemia, leucopenia, plaquetopenia, hipoalbuminemia, transaminases normais ou levemente alteradas. Quanto à atividade enzimática, o clearence aparente do midazolam encontrava-se reduzido durante a doença e aumentado após o tratamento; a razão metabólica da concentração plasmática de omeprazol-5-hidróxi-omeprazol e a razão da concentração losartano/E-3174 na urina encontravam-se aumentadas durante a doença e reduzidas após o tratamento, indicando uma redução da atividade dos CYP3A4, 2C9 e 2C19 durante a LV e um aumento após o tratamento. O conhecimento de que ocorrem alterações na atividade dos citocromos P450 e, consequentemente, na farmacocinética das drogas durante a LV, pode contribuir para um melhor entendimento da resposta aos medicamentos durante a doença.
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Caracterização molecular de isoformas do citocromo P450 em pacientes com malária por Plasmodium vivaxJesus, Jaquelane Silva de 30 August 2013 (has links)
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Previous issue date: 2013-08-30 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / High prevalence in Brazil, specifically in the Amazon Region, malária is a parasitic infectious disease with socioeconomic impact sin endemic areas. Plasmodium vivax is the most prevalent agent and has been associated with cases of severe malária before attributed only to Plasmodium falciparum. Genetic variability in host metabolism of antimalárial drugs, influenced by the polymorphism of cytochrome P450(CYP), could lead to significant changes in antimalárial treatment response. Little is known about the influence of genetic factors in the increase of the individual susceptibility of the host to development of severe disease. Therefore, this project aimed to determine the frequency of alleles CYP2B6*6, CYP2C8*3 and CYP2D6*4 in patients with vivax malária, to evaluate the relationship between the alleles found and the occurrence of severe malária and further establish the hematological and biochemical profile among carriers of alleles found. Therefore, we used peripheral blood samples of patients with vivax malária treated at a health care reference in Manaus-AM. Which were extracted leukocyte DNA, which in turn were amplified by real-time PCR using TaqMan ® system for allelic discrimination. The frequencies of the alleles CYP2B6*6, CYP2C8*3 and CYP2D6*4 were 28.26%, 6.7%, 8.87%, respectively. The CYP2D6*4 allele was more prevalent among patients diagnosed with severe vivax malária, and was associated with normal levels of reticulocytes, erythrocytes and hematocrit. Future studies are needed to understand the clinical implications of the polymorphisms found in patients with vivax malária. / De elevada prevalência no Brasil, especificamente na Região Amazônica, a malária é uma doença infecto-parasitária com impactos socioeconômicos em áreas endêmicas. O Plasmodium vivax é o agente de maior prevalência e tem sido associado a casos graves de malária antes atribuída apenas ao Plasmodium falciparum. A variabilidade genética do hospedeiro no metabolismo de fármacos antimaláricos, influenciada pelo polimorfismo de isoformas do citocromo P450 (CYP), poderia levar a alterações significativas na resposta terapêutica antimalárica. Pouco se conhece sobre a influência dos fatores genéticos no aumento da susceptibilidade individual do hospedeiro ao desenvolvimento de formas graves da doença. Portanto este projeto objetivou determinar a frequência dos alelos CYP2B6*6, CYP2C8*3 e CYP2D6*4 em pacientes com malária vivax, avaliar a relação entre os alelos encontrados e a ocorrência de malária grave e ainda estabelecer o perfil hematológico e bioquímico entre os portadores dos alelos encontrados. Para tanto foram utilizadas amostras de sangue periférico de pacientes com malária vivax atendidos numa unidade de saúde de referência na cidade de Manaus-AM. Dos quais foram extraídos o DNA leucocitário, que por sua vez foram amplificado por PCR em tempo real usando o sistema TaqMan® para a discriminação alélica. As freqüências dos alelos CYP2B6*6, CYP2C8*3 e CYP2D6*4 foram 28,26%, 6,7%, 8,87%, respectivamente. O alelo CYP2D6*4 foi o mais prevalente entre os pacientes diagnosticados com malária vivax grave, e também foi associado a níveis normais de reticulócitos, eritrócitos e hematócrito. Estudos futuros são necessários para compreender as implicações clínicas dos polimorfismos encontrados em pacientes com malária vivax.
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Estudos de modelagem molecular para previsão In Silico dos prováveis metabólitos de fase I de flavonóides / Studies of molecular modeling to in silico prediction of probalby phase 1 metabolites of flavonoidsSousa, Mariana Côrtes de 28 February 2012 (has links)
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Previous issue date: 2012-02-28 / Flavonoids are an important class of natural products candidate drugs, and low molecular
weight polyphenols, widely distributed throughout the plant kingdom. Investigations on its
activities over the past 30 years, demonstrated a potential to prevent several diseases, among them cardiovascular diseases, inflammatory disorders, viral infections, diabetes and neurological disorders, in addition to its known antioxidant. The family of cytochrome P450 (CYP) is composed of monooxygenases, which play a crucial role in the metabolism of endogenous and exogenous substances, and participates in the metabolism of flavonoids. In this paper we describe the application of a methodology for exploring combined in silico prediction of sites of metabolism of quercetin, rutin, naringin and naringenin, found in abundance in nature. A methodology used was ligand based drug design (LBDD) to predict the sites of metabolism (SOM) and the program MetaPrint2D most likely estimate of the metabolites, combined with the method structure based drug design (SBDD) by using molecular docking and energy minimization, to predict the interaction of quercetin, rutin, naringin and naringenin with the isoforms CYP2C9 and CYP1A2. Metabolites were found several Phase I with catalytically active distance (<5 Å) and interaction sites described in the literature, with hydroxylation reactions of aliphatic, aromatic hydroxylation, dealkylation and O-dealkylation. The proposed in silico metabolic hydroxylation at the position corresponding to the C3' were consistent with studies in vitro and in vivo experiments described in the literature for naringin and naringenin. Amino acids of the active site of CYP isoforms have been identified as important in the positioning of the flavonoids quercetin, rutin, naringin and naringenin toward the heme, confirming the involvement of these isoforms in the metabolism of flavonoids. / Os flavonóides representam uma importante classe de produtos naturais candidatos à
fármacos, sendo polifenóis de baixo peso molecular, amplamente distribuídos no reino
vegetal. Investigações sobre suas atividades, nos últimos 30 anos, demonstraram uma
prevenção potencial de diversas patologias, dentre elas doenças cardiovasculares, desordens
inflamatórias, infecções virais, diabetes e desordens neurológicas, além de sua conhecida ação
antioxidante. A família do citocromo P450 (CYP) é composta de monooxigenases, que
desempenham um papel crucial no metabolismo de substâncias endógenas e exógenas, e
participa do metabolismo de flavonóides. Neste trabalho, descrevemos a aplicação de uma
metodologia in silico combinada para explorar a previsão dos sítios de metabolismo dos
flavonóides quercetina, rutina, naringenina e naringina, encontrados em abundância na
natureza. Utilizou-se uma metodologia baseada nos ligantes (LBDD) para previsão dos sítios
de metabolismo (SOM) pelo programa MetaPrint2D e previsão dos metabólitos mais
prováveis, combinado à metodologia baseada na estrutura do receptor (SBDD) através da
utilização de docking molecular e minimização de energia, para prever a interação de
quercetina, rutina, naringenina e naringina com as isoformas CYP2C9 e CYP1A2. Foram
encontrados diversos metabólitos de Fase I, com distâncias cataliticamente ativas (< 5 Å) e
sítios de interação descritos na literatura, apresentando reações de hidroxilação alifática,
hidroxilação aromática, desalquilação e O-desalquilação. Os metabólitos propostos in silico
correspondentes à hidroxilação na posição C3’ foram com coerentes com estudos in vitro e in
vivo descritos na literatura para naringenina e naringina. Aminoácidos do sítio ativo das
isoformas de CYP foram identificados como importantes no posicionamento dos flavonóides
quercetina, rutina, naringenina e naringina em direção ao heme, confirmando a participação
dessas isoformas no metabolismo de flavonóides.
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Avaliação da capacidade esteroidogênica dos embriões de preá (Galea spixii): imunomarcação e expressão gênica das enzimas do complexo citocromo P450 / Steroidogenic capacity evaluation of spix yellow-toothed cavy embryos (Galea spixii): immunostaining and gene expression of cytochrome P450 complex enzymesFranceliusa Delys de Oliveira 04 November 2016 (has links)
A síntese dos hormônios esteroides é feita através da ação de um complexo enzimático chamado citocromo P450. As enzimas 3β-HSD (3β-hidroxiesteroide desidrogenase), P450c17 (citocromo P450 17α-hidroxilase/17,20-liase) e P450arom (citocromo P450 aromatase), fazem parte desse complexo e são responsáveis pela síntese dos hormônios progestágenos, andrógenos e estrógenos, espectivamente. Essas enzimas já foram identificadas em inúmeros tecidos, inclusive em embriões em período pré-implantação. Por isso, acredita-se que o blastocisto seja uma fonte de produção de progesterona e estrógeno, hormônios essenciais para implantação e manutenção da gestação. Em roedores, as informações sobre a capacidade esteroidogênica dos embriões são controversas e também restritas apenas a estudos com espécies laboratoriais. Para trazer mais informações sobre a capacidade esteroidogênica em blastocistos de roedores utilizamos o preá (Galea spixii), uma espécie de roedor silvestre encontrada nas regiões de Caatinga e Semiárido do Nordeste brasileiro e muito utilizado na alimentação de famílias de baixa renda como fonte proteica. Diante o exposto, o objetivo deste trabalho é fazer um apanhado histórico sobre os dados publicados a cerca da capacidade dos embriões de diversas espécies de produzir os hormônios esteroides além de identificar e quantificar a expressão das enzimas esteroidogênicas em embriões de preá através das técnicas de imunohistoquímica e PCR em tempo real. As análises morfológicas indicam que o desenvolvimento inicial do preá se assemelha com os demais roedores, porém o tempo de desenvolvimento difere das espécies usadas em laboratório. As marcações da imunohistoquímica foram positivas nos tecidos maternos, mas os embriões não tiveram marcação para nenhuma das três enzimas do estudo. No entanto, os dados obtidos pelo PCR indicam que os genes CYP11, CYP17 e CYP19 foram expressos nos embriões e, portanto, o concepto de G. spixii tem capacidade de produzir hormônios esteroides, assim como visto em várias outras espécies que já foram estudadas / The synthesis of steroid hormones is made through the action of an enzyme complex called cytochrome P450. 3β-HSD (3β-hydroxysteroid dehydrogenase), P450c17 (cytochrome P450 17 α-hydroxylase/17,20-lyase) and P450arom (cytochrome P450 aromatase), are present in this complex and are are responsible for the synthesis of progestins, androgens and estrogens hormones, respectively. These enzymes have been identified in numerous tissues, including embryos in pre-implantation period. Therefore, it is believed that the blastocyst is a source of production of progesterone and estrogen, hormones essential for the implementation and maintenance of pregnancy. In rodents, the information about the steroidogenic capacity of embryos are controversial and confined to studies with laboratory species. To get more information about the steroidogenic capacity in blastocysts of rodents we used the spix yellow-toothed cavy (Galea spixii), a species of wild rodent found in the northeastern of Brazil, and used in the feeding of low-income families as a source of protein. On the above, the aim of this work is to make a historic about the data published about the ability of embryos of various species to produce steroid hormones and identify and quantify the expression of steroidogenics enzymes in embryos of spix yellow-toothed cavy by immunohistochemical and real-time PCR techniques. The morphological analyses indicate that the G. spixii early development resembles other rodents, but development time differs from the species used in laboratory. The immunohistochemical stainning was positive in maternal tissues, but the embryos did not have stainnig for any of the three enzymes of the study. However, the data obtained by PCR indicate that CYP11, CYP17 and CYP19 genes were expressed in embryos and, therefore, the concept of G. spixii has capacity to produce steroid hormones, as seen in several other species that have been studied
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Investigating orphan cytochrome P450s in Mycobacterium tuberculosis : insights into enzyme structure, function and inhibitor designChenge, Jude January 2016 (has links)
The World Health Organization regards tuberculosis as a world pandemic disease. There is increased demand for new drugs to tackle this threat. This threat has been further elevated with the emergence of drug resistant strains of the causative pathogen, Mycobacterium tuberculosis (Mtb), thereby increasing the urgency for development of novel anti-tubercular drugs. Success in whole genome sequence determination of Mtb revealed a large cohort of cytochrome P450 (CYP) enzymes. Research on these Mtb P450s has shown that several of them are critical to the survival of the pathogen. CYP121A1 and CYP128A1 have been demonstrated to be essential using knockout experiments. CYP125A1 and CYP142A1 have been shown to play crucial roles in bacterial catabolism of host steroids, with CYP125A1 also shown to be located within a gene cluster highly important for bacterial virulence and infectivity. CYP144A1 was shown to be one of the genes whose expression is elevated when Mtb was exposed to macrophage-like conditions, and gene knockout studies using the H37Rv virulent strain of Mtb indicated the ΔCYP144A1 mutant to be more sensitive to the clotrimazole antifungal. CYP126A1 was shown to be located within a cluster of genes highly important for the de novo synthesis of purines in Mtb. These and other data suggested these enzymes to be important to the growth process of Mtb and thus potential drug targets for developing novel therapeutics. Findings in this PhD have revealed that many characteristics of CYP144A1 and CYP126A1 are comparable to previous Mtb P450s reported to date. CYP144A1 is highly conserved within the Mycobacterium genus and specifically within pathogenic species. Transcriptomic analysis has revealed an alternative truncated transcript leading to the production of two physiologically relevant versions of CYP144A1. Our comparative biophysical characterization of both versions (CYP144A1-FLV and -TRV) show both enzymes to be similar in their binding tightly to azole antifungals. EPR and DSC studies show that the 30 amino acid truncation (to form CYP144A1-TRV) does not affect the heme electronic environment and the overall thermal stability of the enzymes. X-ray crystallography was utilized to determine the first crystal structure of a Mtb CYP144 family enzyme. The structure reveals that CYP144A1 possesses a large hydrophobic active site primed for accommodating large hydrophobic substrates. Further chemoproteomic profiling identified novel compounds, which bind in both inhibitor-like and substrate-like modes to CYP144A1, resulting in the development of novel CYP144A1 compounds for use as chemical probes for this P450. Fragment and compound screening identified several ligands with varying binding affinities for CYP126A1, suggesting that this P450 is capable of binding and catalyzing reactions with a wide range of substrates. Turnover experiments proved catalytic activity of CYP126A1 on one of these compounds (Compound 4). Crystallization of CYP126A1 with various compound “hits” (compounds 1 and 7, the azole drug ketoconazole) revealed involvement of several important residues within the active site of CYP126A1 in interactions with these molecules, thus providing important information for designing inhibitors for this enzyme. Both CYP144A1 and CYP126A1 display important characteristics that contribute to our general understanding of cytochromes P450 as a whole, and of Mtb P450s in particular. This PhD project has established the first instance of leaderless transcripts in Mtb P450s and has presented the first crystal structures of both CYP144A1 and CYP126A1, as well as identifying novel, useful chemicals that can be used as mechanistic probes for these enzymes as well as providing the basis for Mtb P450 isoform-specific inhibitors.
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Metabolism and interactions of pesticides in human and animal <em>in vitro</em> hepatic modelsAbass, K. M. (Khaled M.) 16 November 2010 (has links)
Abstract
Risk assessment of chemicals needs reliable scientific information and one source of information is the characterization of the metabolic fate and toxicokinetics of a chemical. Metabolism is often the most important factor contributing to toxicokinetics. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal proteins playing a pivotal role in xenobiotic metabolism.
In the present study, pesticides were used as representative xenobiotics since exposure to pesticides is a global challenge to risk assessment. Human and animal in vitro hepatic models were applied with the advantage of novel analytical techniques (LC/TOF-MS and LC/MS-MS) to elucidate the in vitro metabolism and interaction of selected pesticides.
The results of these studies demonstrate that CYP enzymes catalyze the bioactivation of profenofos, diuron and carbosulfan into their more toxic metabolites desthiopropylprofenofos, N-demethyldiuron and carbofuran, respectively. The suspected carcinogenic metabolite of metalaxyl, 2,6-dimethylaniline, was not detected. CYP3A4 and CYP2C19 activities may be important in determining the toxicity arising from exposure to profenofos and carbosulfan. Individuals with high CYP1A2 and CYP2C19 activities might be more susceptible to diuron toxicity.
Qualitative results of in vitro metabolism were generally in agreement with the results obtained from the published in vivo data, at least for the active chemical moiety and major metabolites. Considerable differences in the quantities of the metabolites produced within the species, as well as in the ratios of the metabolites among the species, were observed.
These findings illustrate that in vitro screening of qualitative and quantitative differences are needed to provide a firm basis for interspecies and in vitro-in vivo extrapolations. Based on our findings, in vitro-in vivo extrapolation based on the elucidation of the in vitro metabolic pattern of pesticides in human and animal hepatic models could be a good model for understanding and extending the results of pesticides metabolism studies to human health risk assessment.
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