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1.
J Nanosci Nanotechnol ; 20(3): 1425-1433, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492303

RESUMO

We aimed to develop antimicrobial agents that satisfy biosafety considerations while exhibiting efficient antimicrobial activity. Peptide-capped silver nanoclusters (peptide@AgNCs) were designed. In addition, the antimicrobial activity and mechanism of peptide@AgNCs were studied. The hemolysis and cytotoxicity tests on mammalian cells were used to confirm the biocompatibility of peptide@ AgNCs. KLA@AgNCs exhibited dramatic antimicrobial activity without inducing significant cytotoxicity in mammalian cells. The KLA@AgNCs destroyed the integrity of the bacterial membrane and induced ROS accumulation, causing oxidative damage to biomolecules. The malfunction of the respiratory chain complexes I and V completely suppresses the energy production, ultimately accelerating the death of the bacteria. Our findings may advance the development of Ag-based nanomaterials with enhanced bactericidal activity and improved biocompatibility.

2.
J Nanosci Nanotechnol ; 20(2): 659-667, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383060

RESUMO

As a new kind of two-dimensional nanomaterial, black phosphorus (BP) nanosheets have attracted significant interests in diverse bioapplications due to their unique structure and physicochemical properties. Despite BP nanosheets' advantages in cancer diagnosis and therapy applications, their biosafety issues are still unclear. Herein, we report a systematic study on the In Vitro and In Vivo toxicity of BP nanosheets. In Vitro experiments showed that BP nanosheets decrease the viability of human bronchial epithelial cells in a time- and dose-dependent manner. The mechanism study showed that BP nanosheets interfere with mitochondrial membrane potential, leading to an increase in intracellular ROS. These responses further initiated the activation of the caspase-3 and ultimately dictated cells to undergo apoptosis. Then, the In Vivo experiments of BP nanosheets revealed that single injection of BP nanosheets does not cause toxicity to mice in a short period of time, whereas multiple injections of BP nanosheets exert adverse effects on liver and renal function of mice. Interestingly, the liver and renal function of the mice returned to normal after a recovery period. Our findings provide insights into the rational design of BP nanosheets and guide their applications in biomedical fields.

4.
EBioMedicine ; 46: 160-169, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395503

RESUMO

BACKGROUND: We aimed to investigate whether pre-therapeutic radiomic features based on magnetic resonance imaging (MRI) can predict the clinical response to neoadjuvant chemotherapy (NACT) in patients with locally advanced cervical cancer (LACC). METHODS: A total of 275 patients with LACC receiving NACT were enrolled in this study from eight hospitals, and allocated to training and testing sets (2:1 ratio). Three radiomic feature sets were extracted from the intratumoural region of T1-weighted images, intratumoural region of T2-weighted images, and peritumoural region of T2-weighted images before NACT for each patient. With a feature selection strategy, three single sequence radiomic models were constructed, and three additional combined models were constructed by combining the features of different regions or sequences. The performance of all models was assessed using receiver operating characteristic curve. FINDINGS: The combined model of the intratumoural zone of T1-weighted images, intratumoural zone of T2-weighted images,and peritumoural zone of T2-weighted images achieved an AUC of 0.998 in training set and 0.999 in testing set, which was significantly better (p < .05) than the other radiomic models. Moreover, no significant variation in performance was found if different training sets were used. INTERPRETATION: This study demonstrated that MRI-based radiomic features hold potential in the pretreatment prediction of response to NACT in LACC, which could be used to identify rightful patients for receiving NACT avoiding unnecessary treatment.

5.
J Clin Invest ; 129(9): 3864-3876, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31424425

RESUMO

The expression of the transmembrane protein 25 gene (Tmem25) is strongly influenced by glutamate ionotropic receptor kainate type subunit 4, and its function remains unknown. Here, we showed that TMEM25 was primarily localized to late endosomes in neurons. Electrophysiological experiments suggested that the effects of TMEM25 on neuronal excitability were likely mediated by N-methyl-d-aspartate receptors. TMEM25 affected the expression of the N-methyl-d-aspartate receptor NR2B subunit and interacted with NR2B, and both were colocalized to late endosome compartments. TMEM25 induced acidification changes in lysosome compartments and accelerated the degradation of NR2B. Furthermore, TMEM25 expression was decreased in brain tissues from patients with epilepsy and epileptic mice. TMEM25 overexpression attenuated the behavioral phenotypes of epileptic seizures, whereas TMEM25 downregulation exerted the opposite effect. These results provide some insights into TMEM25 biology in the brain and the functional relationship between TMEM25 and epilepsy.

6.
Hum Mol Genet ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31384951

RESUMO

Germ cell-derived genomic structure variants not only drive the evolution of species but also induce developmental defects in offspring. The genomic structure variants have different types, but most of them are originated from DNA double-strand breaks (DSBs). It is still not well known whether DNA DSBs exist in adult mammalian oocytes and how the growing and fully-grown oocytes repair their DNA DSBs induced by endogenous or exogenous factors. In this study we detected the endogenous DNA DSBs in the growing and fully-grown mouse oocytes, and found that the DNA DSBs mainly localized at the centromere-adjacent regions which are also copy number variation hotspots. When the exogenous DNA DSBs were introduced by Etoposide, we found that Rad51-mediated homologous recombination (HR) was used to repair the broken DNA. However, the HR repair caused the chromatin intertwined and impaired the homologous chromosome segregation in oocytes. Although we hadn't detected the indication about HR repair of endogenous centromere-adjacent DNA DSBs, we found that Rad52 and RNA:DNA hybrids colocalized with these DNA DSBs, indicating a Rad52 dependent DNA repair might exist in oocytes. In summary, our results not only demonstrated an association between endogenous DNA DSBs with genomic structure variants, but also revealed one specific DNA DSB repair manner in oocytes.

7.
ACS Chem Neurosci ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369236

RESUMO

Lanosterol, an amphipathic molecule, was discovered only very recently to effectively hinder the aggregation of lens proteins and dissolve the extremely stable fibrillar aggregates in cataracts. Here, we combined computational and experimental approaches to study how lanosterol disrupts the aggregation of another important peptide, amyloid-ß (Aß) peptide, associated with the Alzheimer's Disease (AD). Molecular dynamics simulations using the core amyloidogenic segment (KLVFFA) of Aß peptide revealed that lanosterol exhibits at least two types of inhibition mechanism on the self-assembly of Aß peptides. First, lanosterol entangles with peptides and forms a hydrophobic core with residues Phe-19 and Phe-20 in particular. Second, it interferes with the steric zipper interaction at the ß-sheet-ß-sheet interface. These simulation data suggest that lanosterol induces the unfolding of the Aß peptide and the separation of the ß-sheet layers. This predicted inhibition effect of lanosterol was then confirmed by an in vitro ThT fluorescence assay and AFM imaging. The cell toxicity assay also showed that the treatment of lanosterol indeed mitigates the cytotoxicity of the Aß peptide in PC-12 cells. Moreover, lanosterol shows a stronger suppression effect on Aß peptides' aggregation than cholesterol because of its higher hydrophobicity. This result establishes a foundation for the development of lanosterol-based potential therapies for AD and other protein conformational diseases.

9.
Clin Rheumatol ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31428886

RESUMO

INTRODUCTION: Contrast-enhanced ultrasound (CEUS) was recently used to evaluate vascularization within the carotid artery wall, and this process of vascularization was correlated with arteritis activity. We aimed to use CEUS to evaluate disease activity in Takayasu arteritis (TAK) patients. METHOD: We used CEUS to analyze 28 consecutive TAK patients. Disease activity was assessed according to the NIH criteria. We measured CEUS grades and assessed the correlation between contrast features and disease activity. RESULTS: Higher erythrocyte sedimentation rates (ESRs) were found (35 ± 28.7 vs. 13 ± 7.4 mm/h, p < 0.01), and CEUS carotid wall enhancement was more frequently (100% vs. 36.6%, p < 0.01) seen in TAK patients in the active phase than in those in the inactive phase. With increasing CEUS grades, both the artery wall thickness and ESR increased, and patients were more likely to be in the active phase (0 in grade 0, 42.9% in grade 1, and 75% in grade 2). Receiver operating characteristic (ROC) curve analysis showed that CEUS had an area under the ROC curve (AUC) of 0.872 (95% CI 0.785-0.959, p < 0.01), demonstrating good diagnostic accuracy. CONCLUSIONS: Higher CEUS grades reliably identify patients with active TAK. Key Points • No CEUS vascularization is obviously relative with the inactive disease of TAK patients. • Obvious CEUS vascularization is obviously relative with the active disease of TAK patients.

10.
J Affect Disord ; 257: 662-668, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377602

RESUMO

OBJECTIVE: Suicide ideation (SI) and suicide plan (SP) can be seen as immediate precursors of suicide. The major aim of this study is to estimate the severity of SI and SP among LBC, and explore their associated factors. METHOD: A population-based random sampling survey of 2898 LBC was performed. Self-developed structured questionnaire was used to collect relevant information. The prevalence of one-week and lifetime SI and SP was estimated, univariate and multivariate logistic regression model were used to analyze the associated factors of SI in LBC, as well as the associated factors of SP in LBC who reported SI. RESULTS: For surveyed LBC, the one-week prevalence rates of SI and SP were 6.76% (95%CI: 5.30-8.00%) and 2.31% (95%CI: 1.80-2.93%), the lifetime prevalence rates of SI and SP were 20.8% (95%CI: 17.2-25.0%) and 7.69% (95%CI: 4.84-11.0%). Girls reported higher prevalence of SI, while SP severity showed insignificant gender difference. Sex, grade, SH behaviors, depression and psychological resilience were consistently associated with both one-week and lifetime SI. Age and depression were prominent influencing factors of SP in one-week suicide ideators, grade, self-harm history, depression, mother's education level were associated factors of SP in lifetime suicide ideators. CONCLUSIONS: The prevalence of SI and SA in Chinese LBC is high. Girls, junior high school students, self-harmed, depressed, less psychologically resilient individuals were observed increased prevalence of SI, depression may play a significant role in facilitating the transition from SI to SP.

11.
J Am Soc Nephrol ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451534

RESUMO

BACKGROUND: PKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known. METHODS: To examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity. RESULTS: We found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD. CONCLUSIONS: These data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.

12.
Nat Prod Res ; : 1-8, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31359801

RESUMO

Astragali Radix (Huangqi) is one of the well-known traditional Chinese medicines and has been used in China for more than two thousand years. As a close species, Astragalus dolichochaete Diels was found to possess cytotoxicity during our preliminary study of Astragalus plants from Yunnan Province, China. To better understand the chemical foundation of the cytotoxicity, the major constituents of A. dolichochaete were studied. As a result, two new 8-isopentenyl isoflavane derivatives, dolichochaeteins A and B (1 and 2), together with ten known constituents were isolated, and their structures were elucidated by means of spectroscopy, mainly 1D and 2D NMR techniques. The cytotoxic activities were evaluated for the raw extract, ethyl acetate fraction, compound 2 and glyasperin H (3) against human gastric carcinoma cell line SGC-7901, human hepatoma cell line SMMC-7721 and human leukemic cell line K562. All the samples exhibited significant cytotoxicity.

13.
Macromol Biosci ; : e1900124, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310440

RESUMO

Multivalent carbohydrate-lectin interactions play a crucial role in bacterial infection. Biomimicry of multivalent glycosystems represents a major strategy in the repression of bacterial growth. In this study, a new kind of glycopeptide (Naphthyl-Phe-Phe-Ser-Tyr, NMY) scaffold with mannose modification is designed and synthesized, which is able to perform supramolecular self-assembly with the assistance of catalytic enzyme, and present multiple mannose ligands on its self-assembled structure to target mannose-binding proteins. Relying on multivalent carbohydrate-lectin interactions, the glycopeptide hydrogel is able to bind Escherichia coli (E. coli) in high specificity, and result in bacterial adhesion, membrane disruption and subsequent cell death. In vivo wound healing assays reveal that this glycopeptide hydrogel exhibits considerable potentials for promoting wound healing and preventing E. coli infection in a full-thickness skin defect mouse model. Therefore, through a specific mannose-lectin interaction, a biocompatible hydrogel with inherent antibacterial activity against E. coli is achieved without the need to resort to antibiotic or antimicrobial agent treatment, highlighting the potential role of sugar-coated nanomaterials in wound healing and control of bacterial pathogenesis.

14.
Sci Total Environ ; 689: 258-268, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280149

RESUMO

Urban pluvial flooding is one of the most costly natural hazards worldwide. Risks of flooding are expected to increase in the future due to global warming and urbanization. The complexity of the involved processes and the lack of long-term field observations means that many crucial aspects related to urban flood risks still remain poorly understood. In this paper, the possibility to gain new insight into urban pluvial flooding using citizen flood observations is explored. Using a ten-year dataset of radar rainfall maps and 70,000 citizen flood reports for the city of Rotterdam, we derive critical thresholds beyond which urban pluvial flooding is likely to occur. Three binary decision trees are trained for predicting flood occurrences based on peak rainfall intensities across different temporal scales. Results show that the decision trees correctly predict 37%-52% of all flood occurrences and 95%-97% of all non-flood occurrences, which is a fair performance given the uncertainties associated with citizen data. More importantly, all models agree on which rainfall features are the most important for predicting flooding, reaching optimal performance whenever short- and long-duration rainfall peak intensities are combined together to make a prediction. Additional feature selection using principal component analysis shows that further improvement is possible when critical rainfall thresholds are calculated using a linear combination of peak rainfall intensities across multiple temporal scales. The encouraging results suggest that citizen observatories, although prone to larger errors and uncertainties, constitute a valuable alternative source of information for gaining insight into urban pluvial flooding.

15.
Brain Res ; 1721: 146332, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301272

RESUMO

BACKGROUND: To explore the causative genes and pathogenesis of autosomal dominant partial epilepsy with auditory features in a large Chinese family that includes 7 patients over four generations. METHODS: We used targeted exome sequencing and Sanger sequencing to validate the mutation. Zebrafish were used to explore the epileptic behavior caused by the mutation. Primary cortical neuronal culturing and in utero electroporation were used to observe the influences of the mutation on neuronal polarity and migration. RESULTS: We report the identification of a novel missense mutation, c.128C > G (p. Pro43Arg), in exon 1 of LGI1. The heterozygous missense mutation, which cosegregated with the syndrome, was absent in 300 unrelated and matched-ancestor controls. The mutation inhibited the secretion of LGI1 and could not rescue the hyperactivity caused by lgi1a knockdown in zebrafish. In vitro, mutant LGI1 interrupts normal cell polarity. In agreement with these findings, dysfunctional cortical neuron migration was observed using in utero electroporation technology, which is reminiscent of the subtle structural changes in the lateral temporal region observed in the proband of this family. CONCLUSION: Our findings enrich the spectrum of LGI1 mutations and support the pathogenicity of the mutation. Furthermore, additional information regarding the role of LGI1 in the development of temporal lobe epilepsy was elucidated, and a potential relationship was established between cortical neuronal migration dysfunction and autosomal dominant partial epilepsy with auditory features.

16.
BMC Genomics ; 20(1): 480, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185888

RESUMO

BACKGROUND: Plasmids play an vital role in driving the rapid global spread of antimicrobial resistance and adaptation to changing ambient conditions. It has been suggested that the presence of plasmids can pose tremendous impacts on the host physiology. However, little is known regarding the contributions of carbapenemase-encoding plasmid carriage on the physiology and pathogenicity of hypervirulent K. pneumoniae (hvKP). RESULTS: Here we performed a transcriptomic analysis of hvKP with or without carbapenemase-encoding plasmid p24835-NDM5. The results had shown 683 genes with differential expression (false discovery rate, ≤0.001; > 2-fold change), of which 107 were up-regulated and 576 were down-regulated. Gene groups with functions relating to carbohydrate metabolism and multidrug efflux system were increased in genes with increased expression, and those relating to capsule biosynthesis and virulence factors were increased in the genes with decreased expression. In agreement with these changes, survival rate of TfpNDM-hvKP in the presence of normal human serum decreased, and competitive index (CI values) indicated significant fitness defects in the plasmid-carrying hvKP strain when co-cultured with its plasmid-free isogenic ancestor and the ATCC control. Moreover, the p24835-NDM5-containing hvKP strain retained its high neutrophil-mediated phagocytosis and murine lethality. CONCLUSION: These data indicate that hvKP responds to carbapenemase-encoding plasmid by altering the expression of genes involved in carbohydrate metabolism, antibiotic resistance, capsule biosynthesis and virulence expression. Apart from antibiotic resistance selective advantages, carbapenemase-encoding plasmid carriage may also lead to virulence change or adaption to specific habitats in hvKP strain.

17.
Environ Sci Technol ; 53(13): 7887-7892, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31180653

RESUMO

Mercury emission is an important issue during in-situ gasification chemical-looping combustion ( iG-CLC) of coal. This work focused on experimentally "isolating" two elementary subprocesses (coal pyrolysis and char gasification) during iG-CLC of coal, identifying mercury distribution within the two subprocesses, and examining the effects of a hematite oxygen carrier (OC) on the mercury fate. The mercury measurement accuracy was carefully ensured by comparing online measurements (by a VM 3000 instrument) and benchmark measurements (by the standard Ontario Hydro Method, ASTM D6784) as well as repeated tests (10 times for each case). The mercury mass balance was 115% for the entire iG-CLC. A total of 44.7% of the mercury was released as the gas phase form within the coal pyrolysis process at a typical CLC operation temperature (950 °C), whereas 13.4% was released during the char gasification process. The release rate and amount of mercury were minimally affected by the presence of OC; however, the OC promoted the conversion of Hg0(g) to Hg2+(g). Only a small amount of mercury was absorbed by the OC and transported into the air reactor along with carbon residue, released as Hg0(g) and Hg2+(g) or remained in the OC and coal ash as particulate mercury.

18.
Epilepsy Res ; 154: 139-143, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31151073

RESUMO

PURPOSE: Valproic acid (VPA) is frequently used in the treatment of epilepsy. The adverse effects of VPA include hyperammonemia (HA) which is characterized by abnormally elevated blood ammonia level. Carbamoyl-Phosphate Synthase 1 (CPS1) is an enzyme catalyzing the initial step of removing ammonia from blood. Studies have demonstrated that the CPS1 polymorphism rs1047891-A allele carriers were susceptible to VPA-induced HA. However, the evidences remained controversial. In this study, we sought to validate the association between rs1047891 and VPA-induced HA by combining the association results from previous studies together. METHODS: We first conducted a systematic meta-analysis to determine whether rs1047891 was statistically significant. Then, we further evaluated the pleiotropic effects of rs1047891 using published genome-wide association studies (GWAS) and UKBB results. A conditional analysis was conducted to investigate whether the association between rs1047891 and VPA-induced HA was mediated by cardiovascular or renal disease risk factors or vice versa. RESULTS: The allelic, dominant and recessive ORs of rs1047891-A were all significant in our fixed-effect meta-analysis. In GWAS catalog and UKBB data, rs1047891 was associated with basal metabolic rate, adiposity and hematology traits, cardiovascular and renal disease risk factors. We further proved that plasma HDL cholesterol and homocysteine level, in addition to eGFR by serum creatinine, were associated with VPA-induced HA risk independently from rs1047891 polymorphism. CONCLUSION: In conclusion, the SNP rs1047891 was associated with VPA-induce HA among epilepsy patients. Meanwhile, plasma HDL cholesterol and homocysteine level had independent effects from it.

19.
JACC Cardiovasc Interv ; 12(13): 1240-1252, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202947

RESUMO

OBJECTIVES: The BASILICA (Bioprosthetic or native Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction during TAVR) investigational device exemption trial was a prospective, multicenter, single-arm safety and feasibility study. BACKGROUND: Coronary artery obstruction is a rare but devastating complication of transcatheter aortic valve replacement (TAVR). Current stent-based preventative strategies are suboptimal. Bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction during TAVR (BASILICA) is a novel transcatheter technique performed immediately before TAVR to prevent coronary artery obstruction. METHODS: Subjects with severe native or bioprosthetic aortic valve disease at high or extreme risk for surgery, and at high risk of coronary artery obstruction, were included. The primary success endpoint was successful BASILICA and TAVR without coronary obstruction or reintervention. The primary safety endpoint was freedom from major adverse cardiovascular events. Data were independently monitored. Endpoints were independently adjudicated. A core laboratory analyzed computed tomography images. RESULTS: Between February 2018 and July 2018, 30 subjects were enrolled. Primary success was met in 28 (93%) subjects. BASILICA traversal and laceration was successful in 35 of 37 (95%) attempted leaflets. There was 100% freedom from coronary obstruction and reintervention. Primary safety was met in 21 (70%), driven by 6 (20%) major vascular complications related to TAVR but not BASILICA. There was 1 death at 30 days. There was 1 (3%) disabling stroke and 2 (7%) nondisabling strokes. Transient hemodynamic compromise was rare (7%) and resolved promptly with TAVR. CONCLUSIONS: BASILICA was feasible in both native and bioprosthetic valves. Hemodynamic compromise was uncommon. Safety was acceptable and needs confirmation in larger studies. BASILICA appears effective in preventing coronary artery obstruction from TAVR in subjects at high risk.

20.
J Sep Sci ; 42(16): 2668-2678, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31197931

RESUMO

Ribonucleic acid N6 -methyladenosine methylation plays an important role in a variety of biological processes and diseases. Acetaminophen-induced hepatotoxicity is one of the major challenges faced by clinicians. To date, the link between N6 -methyladenosine and acetaminophen-induced hepatotoxicity has not been studied. In this study, a simple ultra high performance liquid chromatography with tandem mass spectrometry method was developed for the simultaneous determination of five nucleosides (adenosine, uridine, cytidine, guanosine, and N6 -methyladenosine) in messenger ribonucleic acid. After enzymatic digestion of messenger ribonucleic acid, the nucleosides sample was separated on an Acquity UPLC column with gradient elution using methanol and 0.02% formic acid water, and detected by a Qtrap 4500 mass spectrometer with an electrospray ionization mode. The method was validated over the concentration ranges of 4-800 ng/mL for adenosine, uridine, cytidine, and guanosine and 0.1-20 ng/mL for N6 -methyladenosine. It was successfully applied to the determination of N6 -methyladenosine levels in liver messenger ribonucleic acid in an acetaminophen-induced hepatotoxicity mouse model and a control group. This study offers a method for the determination of nucleoside contents in epigenetic studies and constitutes the first step toward the investigation of ribonucleic acid methylation in acetaminophen-induced hepatotoxicity, which will facilitate the elucidation of its mechanism.

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