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1.
PLoS Biol ; 18(3): e3000686, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32226015

RESUMO

Compact CRISPR/Cas9 systems that can be packaged into an adeno-associated virus (AAV) hold great promise for gene therapy. Unfortunately, currently available small Cas9 nucleases either display low activity or require a long protospacer adjacent motif (PAM) sequence, limiting their extensive applications. Here, we screened a panel of Cas9 nucleases and identified a small Cas9 ortholog from Staphylococcus auricularis (SauriCas9), which recognizes a simple NNGG PAM, displays high activity for genome editing, and is compact enough to be packaged into an AAV for genome editing. Moreover, the conversion of adenine and cytosine bases can be achieved by fusing SauriCas9 to the cytidine and adenine deaminase. Therefore, SauriCas9 holds great potential for both basic research and clinical applications.

2.
Sci Rep ; 10(1): 4502, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161360

RESUMO

Malachite green is a common environmental pollutant that poses a great threat to non-target organisms, including humans. This study reports the characterization of a bacterial strain, Pseudomonas veronii JW3-6, which was isolated from a malachite green enrichment culture. This strain degraded malachite green efficiently in a wide range of temperature and pH levels. Under optimal degradation conditions (32.4 °C, pH 7.1, and inoculum amount of 2.5 × 107 cfu/mL), P. veronii JW3-6 could degrade 93.5% of 50 mg/L malachite green within seven days. Five intermediate products from the degradation of malachite green were identified: leucomalachite green, 4-(dimethylamino) benzophenone, 4-dimethylaminophenol, benzaldehyde, and hydroquinone. We propose a possible degradation pathway based on these findings. The present study is the first to report the degradation of malachite green by P. veronii and the identification of hydroquinone as a metabolite in the degradation pathway.

3.
Sci Transl Med ; 12(535)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188725

RESUMO

Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and N-acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of N-acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N-acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.

4.
Nat Commun ; 11(1): 680, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015344

RESUMO

Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is one of the most destructive diseases that pose a great threat to wheat production. Wheat landraces represent a rich source of powdery mildew resistance. Here, we report the map-based cloning of powdery mildew resistance gene Pm24 from Chinese wheat landrace Hulutou. It encodes a tandem kinase protein (TKP) with putative kinase-pseudokinase domains, designated WHEAT TANDEM KINASE 3 (WTK3). The resistance function of Pm24 was validated by transgenic assay, independent mutants, and allelic association analyses. Haplotype analysis revealed that a rare 6-bp natural deletion of lysine-glycine codons, endemic to wheat landraces of Shaanxi Province, China, in the kinase I domain (Kin I) of WTK3 is critical for the resistance function. Transgenic assay of WTK3 chimeric variants revealed that only the specific two amino acid deletion, rather than any of the single or more amino acid deletions, in the Kin I of WTK3 is responsible for gaining the resistance function of WTK3 against the Bgt fungus.

5.
Nucleic Acids Res ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32064513

RESUMO

REV3L, the catalytic subunit of DNA polymerase ζ (Pol ζ), is indispensable for translesion DNA synthesis, which protects cells from deleterious DNA lesions resulting from various intrinsic and environmental sources. However, REV3L lacks a proofreading exonuclease activity and consequently bypasses DNA lesions at the expense of increased mutations, which poses a severe threat to genome stability. Here we report a site-specific proteolytic event of human REV3L. We show that REV3L is cleaved by a threonine aspartase, Taspase1 (TASP1), to generate an N-terminal 70-kDa fragment (N70) and a polypeptide carrying the C-terminal polymerase catalytic domain in human cells. Strikingly, such a post-translational cleavage event plays a vital role in controlling REV3L stability by preventing ubiquitination and proteasome-mediated degradation of REV3L. Indicative of the biological importance of the above REV3L post-translational processing, cellular responses to UV and cisplatin-induced DNA lesions are markedly impaired in human HCT116 cell derivatives bearing defined point mutations in the endogenous REV3L gene that compromise REV3L cleavage. These findings establish a new paradigm in modulating the abundance of REV3L through site-specific proteolysis in human cells.

6.
Exp Neurol ; 327: 113223, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32032565

RESUMO

AIMS: Ischemic stroke has become one of the main causes of death worldwide. MicroRNAs (miRNAs) have been implicated in cerebral ischemia-reperfusion (I/R) injury and could serve as therapeutic targets. 5-Lipoxygenase (5-LOX) is a key enzyme in the biosynthesis of leukotrienes and has been implicated in inflammatory central nerve system disorders. The objective of this study was to explore the neuroprotective effects of miR-193b-3p against focal cerebral I/R injury in rats by regulating 5-LOX expression. METHODS AND MATERIALS: Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion injury. The level of miR-193b-3p expression was observed in the rat cortical peri-infarct region after focal cerebral I/R injury. Bioinformatics analysis was used to predict the binding sites of miR-193b-3p, and a dual-luciferase reporter gene assay was applied to verify the potential interaction between 5-LOX mRNA and miR-193b-3p. Then, rats were injected with a miR-193b-3p agomir (modified and enhanced mimic) or antagomir (modified and enhanced inhibitor) in the right lateral ventricle of the brain. Neurological deficit scores, infarct volumes, neuron damage and 5-LOX enzymatic activity and expression were measured. In an in vitro experiment, cultured PC12 cells were exposed to oxygen-glucose deprivation and reperfusion (OGD/R). OGD/R-induced cells were treated with a miR-193b-3p mimic or inhibitor and 5-LOX siRNA. Cell viability, lactate dehydrogenase release, apoptosis rate and 5-LOX expression were evaluated. RESULTS: The level of miR-193b-3p expression was increased in the cortical peri-infarct region of rats with cerebral focal I/R injury. The results of the dual-luciferase reporter gene assay showed that a miR-193b-3p binding site was located in the 3' untranslated region (3'UTR) of 5-LOX mRNA. Neurological deficit scores, infarct volumes and neuronal injury were alleviated by miR-193b-3p agomir treatment but aggravated by miR-193b-3p antagomir. Furthermore, leukotriene B4, cysteinyl-leukotrienes and 5-LOX expression in the cortical peri-infarct region of rats with focal cerebral I/R injury were also downregulated by miR-193b-3p agomir treatment but upregulated by miR-193b-3p antagomir. In PC12 cells, miR-193b-3p mimic significantly decreased OGD/R-induced cell death and reduced lactate dehydrogenase release and 5-LOX expression. In contrast, miR-193b-3p inhibitor exacerbated OGD/R-induced injury in PC12 cells. Additionally, the in vitro effects of miR-193b-3p inhibitor on OGD/R-induced cell injury were partially reversed by 5-LOX siRNA treatment. CONCLUSION: MiR-193b-3p has a potentially neuroprotective effect on focal cerebral I/R-induced injury by inhibiting 5-LOX expression.

7.
J Sci Food Agric ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32077484

RESUMO

BACKGROUND: The carbohydrates in beer play an important role as they are essential for fermentation. Any change in their composition may influence the sensory characteristics of the beer and so their determination is of great interest. This study compares the carbohydrates in three types of commercial beer - barley malt beer, wheat beer, and barley malt beer with adjuncts - and examines their influence on beer quality, which is important for selecting raw ingredients and production conditions, and for quality control. RESULTS: Among the oligosaccharides in three types of beer, raffinose was the most, followed by maltotetraose, maltotriose and maltose. Monosaccharides were only present in small amounts. Dextrin, oligosaccharides with 2-6 polymerization degree and non-starch polysaccharides (NSP) make up 15.90-34.83%, 17.59-38.63%, and 2.33-7.47% of the total carbohydrates in beer, respectively. The dextrin content and NSP content were significantly (P < 0.05) different in wheat beer and barley malt beer, and their content was significantly (P < 0.01) correlated with the content of extracts in beer. Non-starch polysaccharide, dextrin, trisaccharide, and tetrasaccharide content significantly (P < 0.05) correlated with beer viscosity. These beer samples could be categorized clearly into three groups by principal component analysis. CONCLUSION: The oligosaccharides in beer reflect yeast utilization, depending on the type of beer. Dextrin, oligosaccharides with 2-4 polymerization, and NSP, were major carbohydrates in beer. Their composition and concentration influenced its characteristics and quality, and played an important role in the discrimination of different beer types. © 2020 Society of Chemical Industry.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32086196

RESUMO

Incomplete multi-view clustering (IMVC) optimally combines multiple pre-specified incomplete views to improve clustering performance. Among various excellent solutions, the recently proposed multiple kernel k-means with incomplete kernels (MKKM-IK) forms a benchmark, which redefines IMVC as a joint optimization problem where the clustering and kernel matrix imputation tasks are alternately performed until convergence. Though demonstrating promising performance in various applications, we observe that the manner of kernel matrix imputation in MKKM-IK would incur intensive computational and storage complexities, over-complicated optimization and limitedly improved clustering performance. In this paper, we firstly propose an Efficient and Effective Incomplete Multi-view Clustering (EE-IMVC) algorithm to address these issues. Instead of completing the incomplete kernel matrices, EE-IMVC proposes to impute each incomplete base matrix generated by incomplete views with a learned consensus clustering matrix. Moreover, we further improve this algorithm by incorporating prior knowledge to regularize the learned consensus clustering matrix. Two three-step iterative algorithms are carefully developed to solve the resultant optimization problems with linear computational complexity, and their convergence is theoretically proven. After that, we theoretically study the generalization bound of the proposed algorithms. Furthermore, we conduct comprehensive experiments to study the proposed algorithms in terms of clustering accuracy, evolution of the learned consensus clustering matrix and the convergence. As indicated, our algorithms deliver their effectiveness by significantly and consistently outperforming some state-of-the-art ones.

9.
Endokrynol Pol ; 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32096550

RESUMO

BACKGROUND: Thyroid dysgenesis (TD) is the main cause of congenital hypothyroidism (CH) affecting nearly 1 in 2000 newborn worldwide as the most common neonatal endocrine disorder. Paired box gene 8 (PAX8), expressed during all stages of thyroid follicular cell, plays a key role in thyroid morphogenesis by a complex regulatory network. In conclusion, the genetic mechanism of PAX8 mutant in TD is still ambiguity, therefore, more research are needed for further study. METHODS: Blood samples were collected from 289 TD patients in Shandong Province, China. Genetic DNA was extracted from peripheral blood. All the exons of PAX8 along with their exon-intro boundaries were amplified by PCR and analyzed by Sanger sequencing. RESULTS: We identified three novel PAX8 nonsense mutations in three patients by sequence analysis of PAX8: Patient 1 (c.C285G p.Y95X), Patient 2 (c.T747G p.Y249X) and Patient 3 (c.C786A p.Y262X). All the three patients carrying PAX8 variants have obvious clinical phenotype of thyroid anomaly, such as hypoplasia and athyreosis. CONCLUSION: We conducted the largest PAX8 mutation screening so far in TD patients for the first time worldwide. Three presumably pathogenic PAX8 mutations were detected in 289 TD cases for the first time, showing the mutation rate of PAX8 is 1.04% in Chinese TD patients. In addition, our study expands the gene mutation spectrum of TD.

10.
Public Health Genomics ; : 1-6, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31982877

RESUMO

OBJECTIVE: Accumulated evidence suggests that ATP-binding cassette A1 transporter (ABCA1) contributes to secreting insulin in pancreatic ß-cells and amyloid beta formation. This study aimed to investigate the association between three single nucleotide polymorphisms (SNPs) of ABCA1 and susceptibility to type 2 diabetes mellitus (T2DM) in a Han Chinese population. METHODS: A total of 996 T2DM patients and 1,002 controls were included in the study. Three SNPs in the ABCA1 gene, i.e., rs2230806 (R219K), rs1800977 (C69T), and rs9282541 (R230C), were genotyped by SNaPshot. A genotype model, an allele model, a dominant model, and a recessive model were used to assess susceptibility to T2DM. RESULTS: There were significant associations between rs1800977 and T2DM in different genetic models (TT vs. CC, OR = 0.591 [0.446-0.793], p < 0.001; T vs. C, OR = 0.835 [0.735-0.949], p = 0.006; recessive model, OR = 0.583 [0.449-0.756], p < 0.001). There were also significant associations between rs9282541 and T2DM in different genetic models (CT vs. CC, OR = 1.690 [0.807-1.005], p = 0.048; T vs. C, OR = 1.756 [0.694-1.060], p = 0.029; dominant model, OR = 1.735 [0.715-1.034], p = 0.037). CONCLUSION: Our case-control study showed that the two SNPs rs1800977 and rs9282541 in the ABCA1 gene are significantly associated with susceptibility to T2DM in our Han Chinese population. Study of further mechanisms should be performed before application to clinical therapy.

11.
J Invertebr Pathol ; 170: 107331, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31972173

RESUMO

Ophiocordyceps sinensis is an entomopathogenic fungus that infects ghost moth larva, forming the most valuable and rare traditional Chinese medicine, Chinese cordyceps. Our knowledge of the basic morphology and developmental biology of Chinese cordyceps is limited. In this study, morphological and ultrastructural observations of O. sinensis development in the hemocoel of Thitarodes xiaojinensis were obtained by multiple light and electron microscopy techniques, and the host immune reaction activities were determined. Our results indicated that fungal cells in the host hemocoel underwent morphotype transformations from blastospores to prehyphae to hyphae in sequence. The fusiform yeast-like blastospores were the initial cell type present in the host hemocoel and remained for 5 months or more; the encapsulation reaction and phenoloxidase activity of T. xiaojinensis hemolymph were inhibited during this period. When larvae entered the last instar, the blastospores switched to prehyphae and expanded throughout the host tissues, and then hyphae germinated from the prehyphae and mycelia formed, which finally led to host death. Considering the distinct differences between blastospores and hyphae, we identified prehyphae, which play important roles in fungal expansion, hyphae germination, and fusion formation among filaments. Notably, the elongation of prehyphae was strongly presumed to occur through fission but without separation of the two sister cells, in contrast to blastospore budding. During the morphotype transformation, the amount and composition of lipid droplets changed greatly, suggesting their important roles in these events. Overall, we provide a morphological and ultrastructural characterization of O. sinensis vegetative development within the hemocoel of T. xiaojinensis, identify and name the prehypha fungal cell type in entomopathogenic fungi for the first time, and conclude that O. sinensis infection causes sustained immunosuppression in T. xiaojinensis.

12.
ACS Appl Mater Interfaces ; 12(5): 6343-6350, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31939275

RESUMO

Solar-driven water evaporation is of great importance for freshwater production via solar distillation and has attracted growing attention recently by the development of heat localization strategies. Yet, when polluted water is used as the source water, solar-driven water evaporation might further deteriorate the pollution. In this study, we report the facile preparation of multifunctional Ag3PO4-reduced graphene oxide (Ag3PO4-rGO) nanocomposite-coated textiles for clean water production by solar-driven water evaporation, photocatalysis, and disinfection. The multifunctional textiles are obtained through coating Ag3PO4-rGO nanocomposites onto cotton textile substrates. The resulting textile can float on the water surface, absorb solar light, and convert it into heat, enhancing the water surface temperature and promoting water evaporation. We show that with Ag3PO4-rGO nanocomposite-coated textiles on the water surface, a high water evaporation rate of 1.31 kg/(m2 h) can be reached under solar light irradiation. Furthermore, the textiles can simultaneously decompose organic dyes and disinfect pathogenic microbes in water, purifying the raw water during solar-driven water evaporation. Such an all-in-one multifunctional textile provides a facile yet sustainable strategy for freshwater production.

13.
J Agric Food Chem ; 68(3): 826-837, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31895558

RESUMO

A total of five strains of nicosulfuron-degrading bacteria were isolated from a continuously cultivated microbial consortium using culturomics. Among them, a novel Pseudomonas strain, LAM1902, with the highest degradation efficiency was investigated in detail. The characteristics of nicosulfuron-degradation by LAM1902 were investigated and optimized by response surface analysis. Furthermore, non-targeted metabolomic analysis of extracellular and intracellular biodegradation of nicosulfuron by LAM1902 was carried out by liquid chromatography/mass spectroscopy (LC-MS) and gas chromatography-time-of-flight/mass spectroscopy (GC-TOF/MS). It was found that nicosulfuron was degraded by LAM1902 mainly via breaking the sulfonylurea bridge, and this degradation might be attributed to oxalate accumulation. The results of GC-TOF/MS also showed that the intracellular degradation of nicosulfuron did not occur. However, nicosulfuron exerted a significant influence on the metabolism of inositol phosphate, pyrimidine, arginine/proline, glyoxylate, and dicarboxylate metabolism and streptomycin biosynthesis. The changes of myo-inositol, trehalose, and 3-aminoisobutanoic acid were proposed as a mechanism of self-protection against nicosulfuron stress.


Assuntos
Herbicidas/metabolismo , Pseudomonas/metabolismo , Piridinas/metabolismo , Compostos de Sulfonilureia/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biodegradação Ambiental , Herbicidas/química , Concentração de Íons de Hidrogênio , Metabolômica , Filogenia , Pseudomonas/classificação , Pseudomonas/genética , Pseudomonas/isolamento & purificação , Piridinas/química , Compostos de Sulfonilureia/química
14.
J Anim Physiol Anim Nutr (Berl) ; 104(1): 126-135, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31532044

RESUMO

Moringa stem meal (MSM) with a high level of crude fibre (CF) might be developed and utilized in herbivorous geese as an unconventional feedstuff. The aim of this study was to investigate the effect of the MSM level in the diet on the growth performance, slaughter performance, breast meat quality and serum biochemical parameters in geese from 22 to 70 days of age. A one-factor completely randomized design was adopted in our study. A total of one thousand eight 21-day-old geese were randomly divided into six groups, with six replicates per group and 28 birds per replicate. The geese were fed diets containing MSM levels of 0, 20, 40, 60, 80 or 100 g/kg during day 22-70. The dietary MSM level had no effect (p > .05) on the final body weight (BW), average daily gain (ADG) or average daily feed intake (ADFI). The feed/gain ratio (F/G) increased linearly (p < .001) as the dietary MSM level increased. No differences (p > .05) were observed in the slaughter performance, meat quality and the relative organ weight (except for thymus) of the geese (p > .05). The relative weight of the thymus in the geese fed diets with supplementation of MSM was higher than that in the non-supplemented MSM control group (p < .05). In addition, 100 g MSM/kg of diet decreased the serum glucose (GLU) level (p < .05) and increased the alanine transaminase (ALT) enzyme activity (p = .03). Dietary MSM levels of no more than 60 g/kg had no effects on the growth performance and slaughter performance, whereas diets with 100 g MSM/kg increased the F/G and serum ALT enzyme activity, as well as decreasing the serum GLU level. Therefore, MSM provided at a reasonable level could be developed as an unconventional feedstuff for geese at the finisher period.

15.
Mol Genet Genomic Med ; 8(2): e1076, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833240

RESUMO

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare genetically heterogeneous cutaneous disease predominantly characterized by erythroderma, generalized abnormal scaling of the whole body and a collodion membrane at birth. Numerous causative genes have been demonstrated to be responsible for ARCI including PNPLA1 which can cause ARCI type 10. The objectives of this study are to describe clinical features of three ARCI patients from two Chinese unrelated families and to identify the underlying causative mutations. METHODS: Genomic DNA was extracted from peripheral venous blood obtained from the two Chinese ARCI families in Shandong province. Subsequently, targeted regions sequencing (TRS) followed by Sanger sequencing was conducted to identify and validate the likely pathogenic mutations of the ARCI families. RESULTS: Genetic analyses revealed four novel PNPLA1 variants that are predicted to be probably to lead to ARCI in three patients of two families. Patient 1 in one family was in compound heterozygous status for c.604delC/p.Arg202Glyfs*27 and c.820dupC/p.Arg274Profs*15, whereas c.738_742delinsCCCACAGATCCTGC/ p.Gly247_Tyr248delinsProGlnIleLeuHis, and c.816dupC/p.Arg274Profs*15 were found in patient 2 and 3 of the other family. In addition, these variants cosegregate in the two pedigrees and are all within highly conserved regions of the PNPLA1 protein, which indicate that the four mutations are likely pathogenic. CONCLUSION: Our findings not only broaden the mutational spectrum of PNPLA1, but also contribute to establishing genotype-phenotype correlations for different forms of ARCI.

16.
Chem Biol Interact ; 316: 108925, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838054

RESUMO

Hemangioma is one of the commonest benign vascular tumors among children. Propranolol is the first-line therapeutic drug for hemangioma. However, the effects and mechanisms of propranolol in hemangioma have not been thoroughly elaborated. In this study, the effects and mechanisms of propranolol were explored using hemangioma-derived endothelial cells (HemECs). The expression of GLUT1 were determined by immunofluorescence staining. qRT-PCR assay was conducted to detect the mRNA expressions of angiopoietin-2 (Ang-2) and Tie-2. Western blot assay was carried out to measure the protein levels of Ang-2, Tie-2, protein kinase-B (Akt) and phospholyrated-Akt (p-Akt). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) assay and Western blot of Ki67 protein level. Cell apoptosis was measured by flow cytometry analysis and Western blot of Bax and Bcl-2 levels. We found that propranolol inhibited proliferation and induced apoptosis in human umbilical vein endothelial cells (HUVECs) and HemECs. Moreover, propranolol inhibited the expressions of Ang-2 and Tie-2 in HUVECs and HemECs. Functional analysis revealed that Ang-2 attenuated the effects of propranolol on HemEC proliferation and apoptosis. Mechanistical analysis showed that propranolol inhibited the Akt pathway by regulating Ang-2 expression in HemECs. Futhermore, inhibition of the Akt pathway attenuated the effects of Ang-2 on proliferation and apoptosis in HemECs. In conclusion, propranolol inhibited proliferation and induced apoptosis of HemECs via Akt pathway by down-regulating Ang-2 expression, which contributes to our understanding on the pathogenesis of hemangioma and promotes the development of therapeutic approaches for hemangioma.


Assuntos
Angiopoietina-2/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Propranolol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Angiopoietina-2/genética , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Hemangioma/metabolismo , Hemangioma/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
17.
Nat Genet ; 52(1): 48-55, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31844323

RESUMO

R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells1-4. Here we show that N6-methyladenosine (m6A) modification, contributing to different aspects of messenger RNA metabolism5,6, is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m6A-containing R-loops accumulate during G2/M and are depleted at G0/G1 phases of the cell cycle, and that the m6A reader promoting mRNA degradation, YTHDF2 (ref. 7), interacts with R-loop-enriched loci in dividing cells. Consequently, YTHDF2 knockout leads to increased R-loop levels, cell growth retardation and accumulation of γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m6A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.

18.
Zhongguo Zhong Yao Za Zhi ; 44(18): 4015-4020, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31872739

RESUMO

The present work was launched to study the chemical constituents from fermented Noni juice. Ten compounds were isolated by using silicagel,Sephadex LH-20 and pre-HPLC. The structures of these compounds were identified by 1D and 2D NMR. Their structures were established as norimester( 1),cyclo( R-Pro-S-Phe)( 2),cyclo-( L-Pro-L-Leu)( 3),trans-cyclo-( D-tryptophanyl-Ltyrosyl)( 4),cyclo( L-Trp-N-methyl-L-Ala-)( 5),4-allyl-2-hydroxyphenyl 1-O-ß-D-apiosyl-( 1 → 6)-ß-D-glucopyranoside( 6),2-methoxy-4-vinylphenyl ß-D-apiofuranosyl-( 1→6)-ß-D-glucopyranoside( 7),( +)-lirioresinol A( 8),( ±)-syringaresinol( 9),and2-formyl-1 H-pyrrole-1-butanoic acid( 10). All compounds were tested for their antibacterial activity and α-glucosidase inhibitory activity. Compound 1 was a new compound. All compounds were isolated from fermented Noni juice for the first time. Compound 1 showed significant inhibitory activity against α-glucosidase [IC50 value of( 4. 22±0. 03) µmol·L-1].


Assuntos
/análise , Sucos de Frutas e Vegetais/análise , Morinda/química , Compostos Fitoquímicos/análise , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética
19.
BMC Cancer ; 19(1): 1037, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684910

RESUMO

BACKGROUND: SMAD4 is frequently inactivated and associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Abnormal SMAD4 expression also plays an important role in the malignant progression of PDAC. METHODS: We investigated SMAD4 status in PDAC by immunohistochemical methods to explore the relationships between SMAD4 expression and clinicopathological features and then detected SMAD4 mutations by Sanger sequencing in 95 patients with PDAC to identify new mutation sites in PDAC. We further evaluated the effects of a missense mutation, Y353C, in the SMAD4 MH2 domain, on cell proliferation and migration in vitro. RESULTS: Immunohistochemistry showed that the expression of SMAD4 in PDAC carcinoma tissue was significantly lower than that in normal pancreatic tissue, and negative SMAD4 expression was closely related to tumour diameter, staging, lymph node metastasis and differentiation. Sanger sequencing analysis showed that the rate of SMAD4 mutation was 11.8% in 85 PDAC cases, and the novel SMAD4 Y353C missense mutation identified in this study promoted cell migration and invasion without affecting cell proliferation in vitro. Furthermore, SMAD4 Y353C resulted in reduced expression of E-cadherin and increased expression of Vimentin compared with wild-type SMAD4 overexpression. CONCLUSION: This study supports the key role of SMAD4 as a tumour suppressor gene in PDAC and shows that SMAD4 Y353C is associated with poor progression of PDAC.

20.
Int J Syst Evol Microbiol ; 69(12): 3910-3916, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31693472

RESUMO

A Gram-stain-negative, aerobic, motile, rod-shaped bacterium, designated strain LAM9072T, was isolated from a sample of a sulfonylurea herbicide-degrading consortium enriched with saline soil. The optimal temperature and pH for the growth of strain LAM9072T were 35 °C and 7.0, respectively. Strain LAM9072T could grow in the presence of NaCl up to 9 % (w/v). Comparative analysis of the 16S rRNA gene sequences revealed that strain LAM9072T was closely related to members of the family Vibrionaceae, with the highest similarities to Photobacterium halotolerans MACL01T (97.7 %) and Photobacterium galatheae S2753T (97.7 %). Strain LAM9072T formed a distinct phylogenetic subclade within the genus Photobacterium in the 16S rRNA gene phylogenetic trees. The results of multi-locus sequence analysis revealed a distinct lineage with P. halotolerans MACL01T as its closest relative. The genomic G+C content was 50.2 mol%. The DNA-DNA hybridization values between strain LAM9072T and P. halotolerans LMG 22194T and P. galatheae LMG 28894T were 41.6 and 22.2 %, respectively. The average nucleotide identity values were 90.9 and 78.8 %, respectively, by comparing the draft genome sequences of strain LAM9072T and P. halotolerans LMG 22194T and P. galatheae LMG 28894T. The major fatty acids were summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c), C16 : 0 and summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c). Ubiquinone 8 was detected as the predominant respiratory quinone. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, aminophospholipid and four unidentified lipids. Based on its phenotypic characteristics and the results of genotypic analyses, we propose that strain LAM9072T represents a novel species, for which the name Photobacteriumsalinisoli sp. nov. is proposed. The type strain is LAM9072T (=ACCC 19961T=JCM 30852T).


Assuntos
Herbicidas/metabolismo , Photobacterium/classificação , Filogenia , Microbiologia do Solo , Compostos de Sulfonilureia/metabolismo , Técnicas de Tipagem Bacteriana , Composição de Bases , Biodegradação Ambiental , China , DNA Bacteriano/genética , Ácidos Graxos/química , Hibridização de Ácido Nucleico , Fosfolipídeos/química , Photobacterium/isolamento & purificação , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Ubiquinona/química
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