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1.
Chemosphere ; 287(Pt 4): 132402, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34597642

RESUMO

Most previous studies have indicated inconsistent relationships between rice cadmium (Cd) and the soil properties of paddy fields at a regional scale under the adverse effects of confounding factors and spatial heterogeneity. In order to reduce these effects, this study integrates Geodetector, a stepwise regression model, and a hierarchical Bayesian method (collectively called GDSH). The GDSH framework is validated in a large typical rice production area in southeastern China. According to the results, significant stratified heterogeneity of the bioaccumulation factor is observed among different subregions and pH strata (q = 0.23, p < 0.01). Additionally, the soil-rice relationships and dominant factors vary by the subregions, and the available soil Cd and pH are found to be the dominant factors in 64% and 50% of subregions, respectively. In the entire region, when the pH < 6, the dominant factors are organic matter and available Cd, and when pH ≥ 6 they are organic matter, pH, and available Cd. Furthermore, these factors presented different sensitivity to the spatial heterogeneity. The results indicate that, at the subregional level, the GDSH framework can reduce the confounding effects and accurately identify the dominant factors of rice Cd. At the regional level, this model can evaluate the sensitivity of the dominant factors to spatial heterogeneity in a large area. This study provides a new scheme for the complete utilization of regional field survey data, which is conducive to formulating precise pollution control strategies.


Assuntos
Oryza , Poluentes do Solo , Teorema de Bayes , Cádmio/análise , Solo , Poluentes do Solo/análise
2.
Sensors (Basel) ; 21(23)2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34883948

RESUMO

The existing classification methods for Panax notoginseng taproots suffer from low accuracy, low efficiency, and poor stability. In this study, a classification model based on image feature fusion is established for Panax notoginseng taproots. The images of Panax notoginseng taproots collected in the experiment are preprocessed by Gaussian filtering, binarization, and morphological methods. Then, a total of 40 features are extracted, including size and shape features, HSV and RGB color features, and texture features. Through BP neural network, extreme learning machine (ELM), and support vector machine (SVM) models, the importance of color, texture, and fusion features for the classification of the main roots of Panax notoginseng is verified. Among the three models, the SVM model performs the best, achieving an accuracy of 92.037% on the prediction set. Next, iterative retaining information variables (IRIVs), variable iterative space shrinkage approach (VISSA), and stepwise regression analysis (SRA) are used to reduce the dimension of all the features. Finally, a traditional machine learning SVM model based on feature selection and a deep learning model based on semantic segmentation are established. With the model size of only 125 kb and the training time of 3.4 s, the IRIV-SVM model achieves an accuracy of 95.370% on the test set, so IRIV-SVM is selected as the main root classification model for Panax notoginseng. After being optimized by the gray wolf optimizer, the IRIV-GWO-SVM model achieves the highest classification accuracy of 98.704% on the test set. The study results of this paper provide a basis for developing online classification methods of Panax notoginseng with different grades in actual production.

3.
Cell Signal ; 88: 110167, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34628002

RESUMO

Artesunate (ART), a water-soluble derivative of artemisinin, has been reported to exert antineoplastic effects via diverse mechanisms in various types of cancer. Therefore, understanding the underlying mechanism of action of ART in distinct cancer types is indispensable to optimizing the therapeutic application of ART for different types of cancer. The present study aimed to investigate the cellular and molecular mechanisms responsible for the antineoplastic effects of ART in diffuse large B cell lymphoma (DLBCL) cells. Cell proliferation was measured using Cell Counting Kit-8 and colony formation assays. The levels of apoptosis and cell cycle distribution were investigated using flow cytometry. In addition, western blotting was used to analyze the expression levels of ART-induced apoptosis-, autophagy- and ferroptosis-related proteins. Monodansylcadaverine staining was performed to determine the levels of autophagy. Moreover, malondialdehyde and reactive oxygen species assays were used to determine the levels of ferroptosis. The results of the present study revealed that ART inhibited proliferation, and induced apoptosis, cell cycle arrest, autophagy and ferroptosis in DLBCL cells. Pharmacological inhibition of autophagy and ferroptosis alleviated the increased levels of apoptosis induced by ART. Notably, ART was found to exert its effects via inhibition of STAT3 activation. The genetic knockdown of STAT3 enhanced ART-induced autophagy and ferroptosis, and concomitantly upregulated the expression levels of apoptosis- and cell cycle-related proteins. In conclusion, the findings of the current study suggested that ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in DLBCL cells.

5.
BMC Cancer ; 21(1): 955, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433456

RESUMO

BACKGROUND: The improved prognosis of classic Hodgkin lymphoma (cHL) has been accompanied by elevated risks of non-cancer-specific death (non-CSD). The aim of this study was to verify the occurrence of non-CSD and its effect on rates of overall survival among adult patients with cHL. METHODS: To ensure sufficient follow-up time, we analyzed retrospective data from patients aged ≥20 years with cHL that was diagnosed between 1983 and 2005 in the Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was applied to analyze the non-CSD occurrence in relation to all factors. Using Fine-Gray's method, we calculated the cumulative incidences of CSD and non-CSD. Stacked cumulative incidence plots and ratio of non-CSD to all causes of death were applied to evaluate the effect of non-CSD on rates of overall survival. Finally, we analyzed long-term mortality through Cox proportional hazard regression analysis and competing risk regression analysis to emphasize a more appropriate model of survival for patients with cHL. RESULTS: Among the 18,518 patients included, there were 3768 cases of CSD (20.3%) and 3217 of non-CSD (17.4%). Older age, earlier period, male sex, unmarried status, mixed cellularity (MC) and lymphocyte-depletion (LD) histological subtype, and patients received radiotherapy (RT) only were associated with more non-CSD according to binary logistic analysis. The cumulative incidence of non-CSD exceeded CSD after approximately 280 months follow-up. The most common causes of non-CSDs were cardiovascular disease, subsequent primary neoplasms, infectious diseases, accidents, and suicide. In a Cox proportional hazards model, patients who were black, unmarried, at an advanced stage or underwent chemotherapy (CT) alone were at greater risk of mortality than were white patients, who were married, at an early stage, and underwent combined modality; these populations were also found to be at greater risk for CSD in a competing risk model, but the risk of non-CSD did not differ significantly according to race and marital status, patients with early-stage disease and who underwent RT only were found to be at higher risk of non-CSD instead. CONCLUSIONS: Lymphoma was the cause of death in most patients who died, but non-CSD was not unusual. Patients with cHL should be monitored closely for signs of cardiovascular disease and malignant tumors. Rates of overall survival of patients were diminished by non-CSD, and a competing risk model was more suitable for establishing the prognosis than was the Cox proportional hazards model.


Assuntos
Causas de Morte/tendências , Doença de Hodgkin/mortalidade , Programa de SEER/estatística & dados numéricos , Adulto , Terapia Combinada , Feminino , Seguimentos , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
6.
Comput Struct Biotechnol J ; 19: 1684-1693, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897976

RESUMO

Recent studies have shown that the three-dimensional (3D) structure of chromatin is associated with cancer progression. However, the roles of the 3D genome structure and its dynamics in cancer remains largely unknown. In this study, we investigated hierarchical topologically associating domain (TAD) structures in cancers and defined a "TAD hierarchical score (TH score)" for genes, which allowed us to assess the TAD nesting level of all genes in a simplified way. We demonstrated that the TAD nesting levels of genes in a tumor differ from those in normal tissue. Furthermore, the hierarchical TAD level dynamics were related to transcriptional changes in cancer, and some of the genes in which the hierarchical level was altered were significantly related to the prognosis of cancer patients. Overall, the results of this study suggest that the folding dynamics of TADs are closely related to transcriptional abnormalities in cancers, emphasizing that the function of hierarchical chromatin organization goes beyond simple chromatin packaging efficiency.

7.
Am J Blood Res ; 11(1): 100-110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796397

RESUMO

INTRODUCTION: The inflammatory and immune cells have an important impact on Hodgkin lymphoma (HL). The derived neutrophil-lymphocyte ratio (dNLR) has been confirmed to have a similar prognostic value as the neutrophil-lymphocyte ratio (NLR) in many kinds of tumors, but it has not been explored as a prognostic marker for Hodgkin lymphoma patients. OBJECTIVE: The aim of the study is to evaluate the prognostic value of dNLR and NLR in HL. METHODS: This retrospective study included 213 newly diagnosed HL patients from 2008 to 2019. Then, the prognostic significance of dNLR and NLR in these patients was evaluated. Meanwhile, subgroup analyses based on the Ann Arbor stage and histotype were also carried out. Finally, propensity score matching was used to reduce selection bias. RESULTS: Patients with dNLR ≥ 2.1 showed shorter overall survival (OS) (P = 0.006). Also, patients with NLR ≥ 3.0 showed worse OS (P = 0.005) and progression-free survival (PFS) (P = 0.031). These results were also found in patients with early-stage and mixed cellularity subtype HL. Besides, high dNLR represented an independent prognostic marker for OS and high NLR remained an independent prognostic factor for OS and PFS on multivariable analysis. CONCLUSION: Elevated dNLR and NLR were related to worse survival in HL patients. For the first time, the dNLR has shown the potential to be a new prognostic factor for patients with HL.

8.
J Clin Invest ; 131(7)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33661763

RESUMO

Autophagy modulates lipid turnover, cell survival, inflammation, and atherogenesis. Scavenger receptor class B type I (SR-BI) plays a crucial role in lysosome function. Here, we demonstrate that SR-BI regulates autophagy in atherosclerosis. SR-BI deletion attenuated lipid-induced expression of autophagy mediators in macrophages and atherosclerotic aortas. Consequently, SR-BI deletion resulted in 1.8- and 2.5-fold increases in foam cell formation and apoptosis, respectively, and increased oxidized LDL-induced inflammatory cytokine expression. Pharmacological activation of autophagy failed to reduce lipid content or apoptosis in Sr-b1-/- macrophages. SR-BI deletion reduced both basal and inducible levels of transcription factor EB (TFEB), a master regulator of autophagy, causing decreased expression of autophagy genes encoding VPS34 and Beclin-1. Notably, SR-BI regulated Tfeb expression by enhancing PPARα activation. Moreover, intracellular macrophage SR-BI localized to autophagosomes, where it formed cholesterol domains resulting in enhanced association of Barkor and recruitment of the VPS34-Beclin-1 complex. Thus, SR-BI deficiency led to lower VPS34 activity in macrophages and in atherosclerotic aortic tissues. Overexpression of Tfeb or Vps34 rescued the defective autophagy in Sr-b1-/- macrophages. Taken together, our results show that macrophage SR-BI regulates autophagy via Tfeb expression and recruitment of the VPS34-Beclin-1 complex, thus identifying previously unrecognized roles for SR-BI and potentially novel targets for the treatment of atherosclerosis.


Assuntos
Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Células Espumosas/metabolismo , PPAR alfa/metabolismo , Receptores Depuradores Classe B/metabolismo , Transcrição Genética , Animais , Doenças da Aorta/genética , Aterosclerose/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteína Beclina-1/genética , Classe III de Fosfatidilinositol 3-Quinases/genética , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , PPAR alfa/genética , Receptores Depuradores Classe B/deficiência
9.
Brief Bioinform ; 22(5)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33454752

RESUMO

The exploration of three-dimensional chromatin interaction and organization provides insight into mechanisms underlying gene regulation, cell differentiation and disease development. Advances in chromosome conformation capture technologies, such as high-throughput chromosome conformation capture (Hi-C) and chromatin interaction analysis by paired-end tag (ChIA-PET), have enabled the exploration of chromatin interaction and organization. However, high-resolution Hi-C and ChIA-PET data are only available for a limited number of cell lines, and their acquisition is costly, time consuming, laborious and affected by theoretical limitations. Increasing evidence shows that DNA sequence and epigenomic features are informative predictors of regulatory interaction and chromatin architecture. Based on these features, numerous computational methods have been developed for the prediction of chromatin interaction and organization, whereas they are not extensively applied in biomedical study. A systematical study to summarize and evaluate such methods is still needed to facilitate their application. Here, we summarize 48 computational methods for the prediction of chromatin interaction and organization using sequence and epigenomic profiles, categorize them and compare their performance. Besides, we provide a comprehensive guideline for the selection of suitable methods to predict chromatin interaction and organization based on available data and biological question of interest.


Assuntos
Cromatina/química , Epigênese Genética , Aprendizado de Máquina Supervisionado , Aprendizado de Máquina não Supervisionado , Sequência de Bases , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Genoma Humano , Humanos , Análise de Sequência de DNA
10.
Ecotoxicol Environ Saf ; 207: 111521, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254396

RESUMO

Phthalates (PAEs), bisphenol A (BPA), and oestrogenic compounds have become major concerns due to their endocrine-disrupting effect. However, few studies related to the occurrence of PAEs, BPA, and oestrogen in food and compost from different growth age livestock have been conducted. In this study, faeces, urine and food samples were collected from a typical livestock (cow) and a special livestock (pigeon) from concentrated animal feeding operations (CAFOs). The daily total oestrogen excretion of a single cow ranged from 192 µg/day to 671 µg/day, which was significantly higher than that of a single pigeon (0-0.01 µg/day). Conjugated oestrogens represented 22.0-46.0% of the total oestrogens excreted from cow faeces and 80.7-91.8% of those from cow urine, indicating that the form of the excreted oestrogens depends on the livestock species and type of excrement. BPA was all detected in all livestock manure and food, and the concentration in pigeon was 9.2-40.2 ng/g and 23.1 ng/g respectively, while that in cattle was 50.5-72.0 ng/g and 41.1 ng/g respectively. The results indicated that the food is significant sources of BPA entering the process of cow and pigeon breeding. Diethyl phthalate (DEP) was detected at high frequency in pigeon faeces samples, suggesting that pigeons were highly exposed to these plasticisers. The total oestradiol equivalent quantity (EEQt) of livestock origin in aquatic environments was estimated to be 2.99 ng/L, which was higher than the baseline hazard value (1 ng/L) (Xu et al., 2018). The study provides data on the emissions and sources of PAEs, BPA, and oestrogenic compounds from different livestock in CAFOs and demonstrates that food is a significant source of BPA entering livestock.


Assuntos
Ração Animal/análise , Compostos Benzidrílicos/análise , Poluentes Ambientais/análise , Estrogênios/análise , Contaminação de Alimentos/análise , Fenóis/análise , Ácidos Ftálicos/análise , Animais , Bovinos , China , Fezes/química , Feminino , Contaminação de Alimentos/estatística & dados numéricos , Humanos , Gado , Esterco/análise , Plastificantes
11.
Brief Bioinform ; 22(3)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32987404

RESUMO

Topologically associated domains (TADs) are spatial and functional units of metazoan chromatin structure. Interpretation of the interplay between regulatory factors and chromatin structure within TADs is crucial to understand the spatial and temporal regulation of gene expression. However, a computational metric for the sensitive characterization of TAD regulatory landscape is lacking. Here, we present the spatial density of open chromatin (SDOC) metric as a quantitative measurement of intra-TAD chromatin state and structure. SDOC sensitively reflects epigenetic properties and gene transcriptional activity in TADs. During mouse T-cell development, we found that TADs with decreased SDOC are enriched in repressed developmental genes, and the joint effect of SDOC-decreasing and TAD clustering corresponds to the highest level of gene repression. In addition, we revealed a pervasive preference for TADs with similar SDOC to interact with each other, which may reflect the principle of chromatin organization.


Assuntos
Algoritmos , Montagem e Desmontagem da Cromatina/genética , Cromatina/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Genoma/genética , Animais , Diferenciação Celular/genética , Linhagem Celular , Cromatina/metabolismo , Análise por Conglomerados , Epigenômica/métodos , Humanos , Células K562 , RNA-Seq/métodos , Reprodutibilidade dos Testes , Linfócitos T/classificação , Linfócitos T/citologia , Linfócitos T/metabolismo
12.
Heliyon ; 6(8): e04793, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32869005

RESUMO

The -1 ribosomal frameshifting is vital for the translation of the open reading frame (ORF)1b in SARS-CoV-2. The products of ORF1b participate in viral replication. Therefore, changing the frameshift frequency reduces the survival of the virus. This study aimed to successfully develop a toolkit for screening antiviral drugs. Finally, the FDA-approved drug library was screened, revealing that ivacaftor and (-)-Huperzine A worked well in changing the -1 ribosomal frameshifting of SARS-CoV-2 in vitro.

13.
Nat Commun ; 11(1): 4084, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796843

RESUMO

Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. Humans with familial hypercholesterolemia (FH) have increased lipoprotein dicarbonyl adducts and dysfunctional HDL. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in Ldlr-/- mice, a model of FH. Compared to hypercholesterolemic Ldlr-/- mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in en face aortas, without changing plasma cholesterol. Ldlr-/- mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. Importantly, 2-HOBA reduces the MDA- and IsoLG-lysyl content in atherosclerotic aortas versus 4-HOBA. Furthermore, 2-HOBA reduces inflammation and plaque apoptotic cells and promotes efferocytosis and features of stable plaques. Dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects in a murine FH model, supporting its potential as a therapeutic approach for atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose/metabolismo , Benzilaminas/metabolismo , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Hiperlipoproteinemia Tipo II/metabolismo , Receptores de LDL/genética , Animais , Aorta , Apolipoproteínas E , Aterosclerose/tratamento farmacológico , Colesterol/sangue , Colesterol/metabolismo , Feminino , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/patologia , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos , Lipoproteínas HDL/metabolismo , Lipoproteínas IDL/sangue , Lipoproteínas IDL/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos
14.
Nutrients ; 12(7)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32629758

RESUMO

Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe-/- macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity. MDA modification of HDL reduced its anti-inflammatory function compared to native HDL. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and PON1 activity was also impaired in FH. Consistently, FH-HDL induced a pro-inflammatory response in Apoe-/- macrophages and had an impaired ability to promote cholesterol efflux. Interestingly, reactive dicarbonyl scavengers, including 2-hydroxybenzylamine (2-HOBA) and pentyl-pyridoxamine (PPM), effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers reduced MDA-HDL adduct formation and increased HDL cholesterol efflux capacity, supporting the therapeutic potential of reactive carbonyl scavenging for improving HDL function.


Assuntos
Arildialquilfosfatase/sangue , Sequestradores de Radicais Livres/farmacologia , Hipercolesterolemia/tratamento farmacológico , Lipoproteínas HDL/sangue , Oxirredução/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/sangue , Animais , Anti-Inflamatórios/farmacologia , Apolipoproteína A-I/sangue , Benzilaminas/farmacologia , Modelos Animais de Doenças , Humanos , Hipercolesterolemia/sangue , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Macrófagos/metabolismo , Malondialdeído/sangue , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/sangue , Piridoxina/farmacologia
15.
Biotechnol Lett ; 42(9): 1719-1726, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32318881

RESUMO

OBJECTIVE: To obtain a novel pullulanase with synthetic ability from a microorganism and characterize its substrates specificity. RESULTS: A novel pullulanase, PulY103A, from Bacillus megaterium Y103 was purified, characterized and expressed in Escherichia coli. PulY103A contained the signature sequences of type I pullulanases and showed 94.7% identity with a type I pullulanase (BmPul) from B. megaterium WW1210, showing similar molecular weight (110.8 kDa) and optimal pH (6.5). However, PulY103A had an optimal temperature of of 45 °C and exhibited relatively higher activity toward amylose (48.3%) compared with pullulan (100%), soluble starch (67.5%), and amylopectin (23.1%). The thin-layer chromatography results showed that the major pullulan hydrolysis products were maltotriose and maltohexaose, which differed from those reported in other pullulanases. On the basis of enzyme specificity, PulY103A was an amylopullulanase, which presented transglycosylation activity by forming α-1,4-glucosidic linkages. CONCLUSIONS: A novel amylopullulanase with transglycosylation activity was characterized. The features of this enzyme suggested its potential to produce maltohexaose.


Assuntos
Bacillus megaterium , Proteínas de Bactérias , Glicosídeo Hidrolases , Bacillus megaterium/enzimologia , Bacillus megaterium/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Clonagem Molecular , Escherichia coli , Glucanos/química , Glucanos/metabolismo , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Glicosilação , Hidrólise , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
16.
Cell Signal ; 72: 109643, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32320859

RESUMO

Transient Receptor Potential Melastatin Subfamily Member 4 (TRPM4) has been demonstrated to be aberrantly expressed in several cancers but seldom reported in acute leukemia. Based on database mining and validated experiments, our present data show that TRPM4 is selectively overexpressed in AML patients and cell lines with the MLL gene rearrangement. We analyzed the correlation between TRPM4 expression and clinical parameters in a validated cohort of AML patients. Increased TRPM4 expression was associated with significant leukocytosis (p = .028), M4/M5 subtype (p = .000), FLT3-ITD mutation (p = .034), MLL status (p = .007) and a higher risk stratification (p = .001). Knockdown of TRPM4 mediated by siRNA impaired proliferation and arrested the cell cycle at the G0/G1 phase in MLL-rearranged leukemia cells. We suggested that TRPM4 may be involved in the pathogenesis of MLL-rearranged leukemia through regulating the AKT/GLI1/Cyclin D1 pathway. The transcription factor HOXA9 was found to be responsible for upregulation of TRPM4 expression by binding to its promoter. In conclusion, TRPM4 is overexpressed in MLL-rearranged AML and blockade of TRPM4 may be an alternative therapeutic approach in AML patients with high TRPM4 expression.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Ciclina D1/metabolismo , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Canais de Cátion TRPM/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Adulto , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/metabolismo , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Canais de Cátion TRPM/metabolismo , Transcrição Genética , Regulação para Cima/genética
17.
Sci Total Environ ; 721: 137770, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32182465

RESUMO

This study quantified influences of interactions between anthropogenic and natural factors on trace element accumulation and pollution risk in karst soils at regional and local scales and identified the dominant interacting factors. A total of 513 soil samples were collected from Hechi, southern China to measure concentrations of arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), and lead (Pb), which were compared with published background values. Descriptive statistics and occurrence characteristics were developed with geostatistical methods and the comprehensive pollution risk was calculated using the Nemerow pollution index (NPI). Geo-detector models were used to further examine and quantify the influence of 14 factors (5 anthropogenic and 9 natural) on trace element concentrations and NPI, both individually and interacting with the other 13 factors. The results clearly demonstrate that anthropogenic factors interact with natural factors to enhance nonlinearly and significantly trace element accumulation in karst soils. Watershed was the natural factor that most enhanced trace element accumulation when interacting with anthropogenic factors. Land use and smelting industry were the anthropogenic factors that most enhanced trace element accumulation when interacting with natural factors. Land use-watershed interaction accounted for 56% of Cd accumulation and smelting industry-watershed interaction for 19% of As accumulation. Land use-watershed, land use-lithology, and pH-watershed interactions accounted for 51%, 19%, and 15%, respectively of NPI values. The findings indicate that changing land use and reducing pollutant discharge from the smelting industry should be considered.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32132977

RESUMO

Objective: The relationship between diabetes and all- and cause-specific mortality in individuals with common cancers (breast, colorectal, and prostate) remains both under-researched and poorly understood. Methods: Cancer survivors (N = 37,993) from the National Health Interview Survey with linked data retrieved from the National Death Index served as our study participants. Cox proportional-hazards models were used to assess associations between pre- and post-diabetes and all-cause and cause-specific mortality. Results: Over a median follow-up period of 13 years, 2,350 all-cause, 698 cancer, and 506 CVD deaths occurred. Among all cancer survivors, patients with diabetes had greater risk of: all-cause mortality [hazard ratio (HR) 1.35, 95% CI = 1.27-1.43], cancer-specific mortality (HR: 1.14, 95% CI = 1.03-1.27), CVD mortality (HR: 1.36, 95% CI = 1.18-1.55), diabetes related mortality (HR: 17.18, 95% CI = 11.51-25.64), and kidney disease mortality (HR: 2.51, 95% CI = 1.65-3.82), compared with individuals without diabetes. The risk of all-cause mortality was also higher amongst those with diabetes and specific types of cancer: breast cancer (HR: 1.28, 95% CI = 1.12-1.48), prostate cancer (HR: 1.20, 95% CI = 1.03-1.39), and colorectal cancer (HR: 1.29, 95% CI = 1.10-1.50). Diabetes increased the risk of cancer-specific mortality among colorectal cancer survivors (HR: 1.36, 95% CI = 1.04-1.78) compared to those without diabetes. Diabetes was associated with higher risk of diabetes-related mortality when compared to non-diabetic breast (HR: 9.20, 95% CI = 3.60-23.53), prostate (HR: 18.36, 95% CI = 6.01-56.11), and colorectal cancer survivors (HR: 12.18, 95% CI = 4.17-35.58). Both pre- and post-diagnosis diabetes increased the risk of all-cause mortality among all cancer survivors. Cancer survivors with diabetes had similar risk of all-cause and CVD mortality during the second 5 years of diabetes and above 10 years of diabetes as compared to non-diabetic patients. Conclusions: Diabetes increased the risk of all-cause mortality among breast, prostate, and colorectal cancer survivors, not for pre- or post-diagnosis diabetes. Greater attention on diabetes management is warranted in cancer survivors with diabetes.


Assuntos
Neoplasias da Mama/mortalidade , Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Colorretais/mortalidade , Diabetes Mellitus/fisiopatologia , Neoplasias da Próstata/mortalidade , Adolescente , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Causas de Morte , China/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Diabetes Mellitus/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Fatores de Risco , Adulto Jovem
19.
PLoS Comput Biol ; 16(2): e1007287, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32084131

RESUMO

Hi-C is commonly used to study three-dimensional genome organization. However, due to the high sequencing cost and technical constraints, the resolution of most Hi-C datasets is coarse, resulting in a loss of information and biological interpretability. Here we develop DeepHiC, a generative adversarial network, to predict high-resolution Hi-C contact maps from low-coverage sequencing data. We demonstrated that DeepHiC is capable of reproducing high-resolution Hi-C data from as few as 1% downsampled reads. Empowered by adversarial training, our method can restore fine-grained details similar to those in high-resolution Hi-C matrices, boosting accuracy in chromatin loops identification and TADs detection, and outperforms the state-of-the-art methods in accuracy of prediction. Finally, application of DeepHiC to Hi-C data on mouse embryonic development can facilitate chromatin loop detection. We develop a web-based tool (DeepHiC, http://sysomics.com/deephic) that allows researchers to enhance their own Hi-C data with just a few clicks.


Assuntos
Genoma , Modelos Biológicos , Cromatina/química , Conjuntos de Dados como Assunto , Análise de Sequência/métodos
20.
Clin Drug Investig ; 40(1): 41-53, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31586305

RESUMO

BACKGROUND AND OBJECTIVE: Because of the narrow therapeutic window and huge inter-individual variation, the individual precision on anticoagulant therapy of warfarin is challenging. In our study, we aimed to construct a Back Propagation Neural Network (BPNN) model to predict the individual warfarin maintenance dose among Chinese patients who have undergone heart valve replacement, and validate its prediction accuracy. METHODS: In this study, we analyzed 13,639 eligible patients extracted from the Chinese Low Intensity Anticoagulant Therapy after Heart Valve Replacement database, which collected data on patients using warfarin after heart valve replacement from 15 centers all over China. Ten percent of patients who were finally enrolled in the database were used as the external validation, while the remaining were randomly divided into the training and internal validation groups at a ratio of 3:1. Input variables were selected by univariate analysis of the general linear model; 2.0, the mean value of the international normalized ratio (INR) range 1.5-2.5, was used as the mandatory variable. The BPNN model and the multiple linear regression (MLR) model were constructed by the training group and validated through comparisons of the mean absolute error (MAE), mean squared error (MSE), root mean squared error (RMSE), and ideal predicted percentage. RESULTS: Finally, 10 input variables were selected and a three-layer BPNN model was constructed. In the BPNN model, the value of MAE (0.688 mg/day and 0.740 mg/day in internal and external validation, respectively), MSE (0.580 mg/day and 0.599 mg/day in internal and external validation, respectively), and RMSE (0.761 mg/day and 0.774 mg/day in internal and external validation, respectively) were achieved. Ideal predicted percentages were high in both internal (63.0%) and external validation (59.7%), respectively. Compared with the MLR model, the BPNN model showed a higher ideal prediction percentage in the external validation group (59.7% vs. 56.6%), and showed the best prediction accuracy in the intermediate-dose subgroup (internal validation group: 85.2%; external validation group: 84.7%) and a high predicted percentage in the high-dose subgroup (internal validation group: 36.2%; external validation group: 39.8%), but poor performance in the low-dose subgroup (internal validation group: 0%; external validation group: 0.3%). Meanwhile, the BPNN model showed better ideal prediction percentage in the high-dose group than the MLR model (internal validation: 36.2% vs. 31.6%; external validation: 42.8% vs. 37.8%). CONCLUSION: The BPNN model shows promise for predicting the warfarin maintenance dose after heart valve replacement.


Assuntos
Anticoagulantes/administração & dosagem , Implante de Prótese de Valva Cardíaca , Varfarina/administração & dosagem , Adulto , Algoritmos , China , Feminino , Valvas Cardíacas/cirurgia , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Varfarina/uso terapêutico
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