Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
J Hematol Oncol ; 13(1): 128, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32977829

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate integrative analysis on the hierarchy of different AML subtypes. METHODS: Using Microwell-seq, a high-throughput single-cell mRNA sequencing platform, we analyzed the cellular hierarchy of bone marrow samples from 40 patients and 3 healthy donors. We also used single-cell single-molecule real-time (SMRT) sequencing to investigate the clonal heterogeneity of AML cells. RESULTS: From the integrative analysis of 191727 AML cells, we established a single-cell AML landscape and identified an AML progenitor cell cluster with novel AML markers. Patients with ribosomal protein high progenitor cells had a low remission rate. We deduced two types of AML with diverse clinical outcomes. We traced mitochondrial mutations in the AML landscape by combining Microwell-seq with SMRT sequencing. We propose the existence of a phenotypic "cancer attractor" that might help to define a common phenotype for AML progenitor cells. Finally, we explored the potential drug targets by making comparisons between the AML landscape and the Human Cell Landscape. CONCLUSIONS: We identified a key AML progenitor cell cluster. A high ribosomal protein gene level indicates the poor prognosis. We deduced two types of AML and explored the potential drug targets. Our results suggest the existence of a cancer attractor.

2.
Water Environ Res ; 92(12): 2129-2139, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32585773

RESUMO

In order to explain the effect of anionic surfactants on aerobic denitrification in the urban river, sodium dodecyl benzene sulfonate (SDBS) and sodium dodecyl sulfonate (SDS) were added in aerobic denitrifier and the efficiency of nitrogen removal, microbial mechanisms, and enzyme activity was investigated in this study. The results showed that the total nitrogen (TN) and the nitrate nitrogen ( NO 3 - - N ) removal efficiency decreased as an increase of SDBS concentration. In contrast, 59.70% of the TN and 75.12% of NO 3 - - N were removed as the SDBS was 0 mg/L (Control). When SDBS was 200 mg/L (SDBS-200), the removal efficiency of TN and NO 3 - - N was reduced to 4.92% and 4.00%, respectively. However, the denitrification efficiency was significantly accelerated when the concentration of SDS increased, except for 200 mg/L treatment (SDS-200). As the SDS increased from 0 to 100 mg/L (SDS-100), the removal efficiency of TN and NO 3 - - N raised from 59.70% to 70.8% and from 75.12% to 85.08%, respectively. The community structure of aerobic denitrifiers was significantly affected in the SDBS and SDS. While the Cupriavidus and Achromobacter were dominant genera in the group of Control (39.59%, and 42.45%) and SDS-100 (44.40% and 34.86%), the relative abundance of Cupriavidus increased to 84.06% and 59.45% in the group of SDBS-200 and SDS-200, respectively. Enzyme activity assays proved that the nitrite reductase (NiR) relative activity of aerobic denitrification was suppressed by both SDBS and SDS. The increase in the SDS concentrations (from 0 to 50 mg/L) resulted in sharp growth of the nitrate reductase (NR) relative activities (from 100% to 146.86%). These findings demonstrated that SDBS and SDS affected aerobic denitrification efficiency of the aerobic denitrifiers by changing its microbial community structure and enzyme activity. PRACTITIONER POINTS: SDS strengthened aerobic denitrification at low concentration, but the aerobic denitrifiers were inhibited in SDBS. The variation of community structure played a vital role in the aerobic denitrification system. The enzyme activity was seriously affected by SDBS and SDS. Microorganisms and enzyme activity were synergistically involved in the aerobic denitrification.

3.
Nature ; 581(7808): 303-309, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32214235

RESUMO

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems1. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.


Assuntos
Células/citologia , Células/metabolismo , Análise de Célula Única/métodos , Adulto , Animais , Grupo com Ancestrais do Continente Asiático , Diferenciação Celular , Linhagem Celular , Separação Celular , China , Bases de Dados Factuais , Corpos Embrioides/citologia , Corpos Embrioides/metabolismo , Grupos Étnicos , Feto/citologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunidade , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Camundongos , Especificidade de Órgãos , RNA Mensageiro/análise , RNA Mensageiro/genética , Análise de Sequência de RNA , Análise de Célula Única/instrumentação , Processos Estocásticos
4.
Cell Discov ; 4: 59, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30393564

RESUMO

Identification of effective culture conditions to maintain and possibly expand human HSPCs in vitro is an important goal. Recent advances highlight the efficacy of chemicals in maintaining and converting cell fates. We screened 186 chemicals and found that a combination of CHIR-99021, Forskolin and OAC1 (CFO) maintained human CD34-positive cells in vitro. Efficiency of the culture system was characterized using flow cytometry for CD34-positive cells, a colony-forming assay and xeno-transplants. We found that human CD34-positive cells treated with this combination had enhanced expression of human HSPC markers and increased haematopoietic re-populating ability in immune-deficient mice. Single-cell RNA-seq analyses showed that the in vitro cultured human CD34-positive cells were heterogeneous. We found that CFO supports maintenance of human CD34-positive cells by activating HOXA9, GATA2 and AKT-cAMP signaling pathway. These data have implications in therapies requiring maintenance and/or expansion of human HSPCs.

5.
Maturitas ; 111: 77-81, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29673835

RESUMO

OBJECTIVES: To observe the hearing function around menopause, to analyze the effects of ovarian reserve and hormone therapy on hearing, and to study factors related to hearing loss among women around menopause. STUDY DESIGN: In this cross-sectional study, we evaluated 109 women around menopause aged 45-55 years, including 40 women with ovarian failure, 48 with ovarian non-failure, and 21 receiving hormone therapy. All women underwent an audiologic evaluation, and hormone blood testing was performed. The general condition, reproductive history, medical history, lifestyle, and menopausal symptoms were collected through a questionnaire. MAIN OUTCOME MEASURE: The auditory threshold and anti-Mullerian hormone level. RESULTS: Women in the ovarian failure group presented with a decreased hearing level in all frequency bands compared with those in the ovarian non-failure group; the significant differences occurred at 8000 Hz, 10 000 Hz, 12 500 Hz, and 16 000 Hz in the right-ear air conduction. The auditory threshold was lower in the hormone therapy group than in the ovarian failure group, but the difference was statistically significant only in the right-ear air conduction at 10 000 Hz. There were two risk factors for hearing loss: an anti-Mullerian hormone level <0.01 ng/mL (odds ratio [OR] = 2.624) and frequent earphone use (OR = 3.846). CONCLUSIONS: A decline in ovarian function is associated with hearing loss in women, especially in relation to extended high-frequency air conduction of the right ear. Preserving ovarian function and reducing earphone use are important measures to protect women's hearing. However, the effect of hormone therapy on hearing requires further investigation.


Assuntos
Terapia de Reposição de Estrogênios , Perda Auditiva/fisiopatologia , Audição/efeitos dos fármacos , Menopausa/fisiologia , Reserva Ovariana/fisiologia , Insuficiência Ovariana Primária/fisiopatologia , Hormônio Antimülleriano/sangue , Limiar Auditivo , Estudos Transversais , Feminino , Perda Auditiva/etiologia , Humanos , Menopausa/efeitos dos fármacos , Pessoa de Meia-Idade , Pós-Menopausa/fisiologia , Pré-Menopausa/fisiologia , Insuficiência Ovariana Primária/complicações , Fatores de Risco
6.
PLoS Genet ; 14(1): e1007165, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29370161

RESUMO

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBN mutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7 ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN-associated ID.


Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteólise , Proteínas Ligases SKP Culina F-Box/antagonistas & inibidores , Complexos Ubiquitina-Proteína Ligase/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Células Cultivadas , Feminino , Células HEK293 , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Ligases SKP Culina F-Box/metabolismo , Complexos Ubiquitina-Proteína Ligase/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
7.
Cell Rep ; 18(6): 1499-1511, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28178526

RESUMO

Transcription from chromosomes is regulated by posttranslational modifications to histones, such as methylation and ubiquitination. Monoubiquitination of histones H2A and H2B influences H3 methylation to reinforce the activation or repression of gene expression. Here, we provide evidence that H3 polyubiquitination represses transcription of fetal and cell-cycle genes in postnatal mouse liver by crosstalk with H3K9 methylation. We found that the CRL4 ubiquitin ligase targets H3 for polyubiquitination at K79 via the DCAF8 substrate receptor in hepatocytes. Genetic inactivation of DCAF8 and overexpression of an H3K79 mutant in cells or inducible deletion of CRL4 in mouse liver abrogates H3 ubiquitination, reactivates the expression of fetal liver and cell-cycle genes by interfering with methylated H3K9 occupancy, and leads to cell senescence. Restoring CRL4DCAF8 expression in cells with decreased H3 ubiquitination reinstates the epigenetic gene silencing. Our results suggest that progressive H3 ubiquitination plays an important role in postnatal liver maturation.


Assuntos
Histonas/metabolismo , Fígado/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Ciclo Celular/fisiologia , Senescência Celular/fisiologia , Epigênese Genética , Inativação Gênica/fisiologia , Hepatócitos/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Metilação , Camundongos , Camundongos Transgênicos , Ubiquitina/metabolismo , Ubiquitinação/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...