Publications by authors named "Feng Yue"

632 Publications

Synthesis, molecular docking and mosquitocidal efficacy of lawsone and its derivatives against the dengue vector Aedes aegypti L. (Diptera: Culicidae).

Med Chem 2021 Jul 27. Epub 2021 Jul 27.

State Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou 311300, China.

Background: Aedes aegypti is the primary dengue vector, a significant public health problem in many countries. Controlling the growth of Ae. aegypti is the biggest challenge in the mosquito control program, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission.

Objective: To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1-phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis.

Methods: All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects.

Results: Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC50 and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM).

Conclusion: The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programme.
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http://dx.doi.org/10.2174/1573406417666210727121654DOI Listing
July 2021

F-PEG1-Vinyl Sulfone-Labeled Red Blood Cells as Positron Emission Tomography Agent to Image Intra-Abdominal Bleeding.

Front Med (Lausanne) 2021 5;8:646862. Epub 2021 Jul 5.

Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

F-Labeled blood pool agents (BPAs) have attracted great attention for identifying bleeding sites. However, many BPAs are not sufficiently evaluated partially due to the limitations of labeling methods. In our previous work, we noticed that F-PEG1-vinyl sulfone (F-VS) could efficiently label red blood cells (RBCs) and . However, its application as BPA is not fully evaluated. In this study, we systematically explored the feasibility of using F-VS-labeled RBCs as a positron emission tomography (PET) BPA for intra-abdominal bleeding diagnosis. In brief, we first optimized the labeling conditions, which lead to an 80% labeling yield of RBCs after incubating with F-VS in phosphate-buffered saline (PBS) at 37°C for 20 min. F-VS-labeled RBCs were found to be stable , which could simplify its transportation/storage for applications. In normal rat PET study, the cardiovascular system could be clearly imaged up to 5 h post injection (p.i.). An intra-abdominal hemorrhage rat model demonstrated that the F-VS-labeled RBCs clearly showed the dynamic changes of extravascular radioactivity due to intra-abdominal hemorrhage. Validation in the model of gastrointestinal bleeding clearly demonstrated the great potential of using F-VS-labeled RBCs as a BPA, which could be further evaluated in future studies.
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http://dx.doi.org/10.3389/fmed.2021.646862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287037PMC
July 2021

Closed-loop geometric multi-scale heart-coronary artery model for the numerical calculation of fractional flow reserve.

Comput Methods Programs Biomed 2021 Jul 6;208:106266. Epub 2021 Jul 6.

Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address:

Background And Objectives: Fractional flow reserve (FFR) is considered to be the "gold standard" for the clinical diagnosis of functional myocardial ischemia. With the development of medical imaging and computational fluid dynamics (CFD), noninvasive computation of FFR has been developed. The most representative calculation method is the noninvasive FFR derived from coronary CT angiography (FFR), but it cannot thoroughly simulate the real physiological structure of the cardiovascular system. In this study, we propose a noninvasive closed-loop FFR derived from coronary CT angiography (FFR).

Methods: The closed-loop multi-scale model includes three parts: the heart module, the coronary artery module with microcirculation structure and the systemic circulation module. The proposed structure was formed by coupling a lumped parameter model (0D) with a 3D model, such that the 0D model provides the boundary conditions for the 3D model. We enrolled 100 patients through a prospective multi-center clinical trial and calculated their FFR. Then, we extracted the pressure and flow waveforms of the coronary stenosis vessels through closed-loop geometric multi-scale CFD calculations. We evaluated the accuracy of FFR in diagnosing myocardial ischemia using the clinical measurement of FFR as the standard.

Results: The results of FFR calculation in all patients showed a good correlation between FFR and FFR (r = 0.64, p < 0.05). The AUC (95% CI) of FFR was 0.819 [0.72, 0.91]. The accuracy, specificity, sensitivity, positive predictive value and negative predictive value of FFR were 86%, 95%, 62%, 86% and 83%, respectively.

Conclusions: The closed-loop multi-scale model proposed in this study can simulate the physiological cycle in a more realistic way. FFR is a reliable diagnostic index for myocardial ischemia.
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http://dx.doi.org/10.1016/j.cmpb.2021.106266DOI Listing
July 2021

Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis.

Ann Med 2021 12;53(1):1118-1128

Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Circulating white blood cell (WBC) counts have been related to lung function impairment, but causal relationship was not established. We aimed to evaluate independent effects and causal relationships of WBC subtypes with lung function.

Methods: The 19,159 participants from NHANES 2011-2012 ( = 3570), coke-oven workers (COW,  = 1762) and Dongfeng-Tongji (DFTJ,  = 13,827) cohorts were included in the observational studies. The associations between circulating counts of WBC subtypes and prebronchodilator lung function were evaluated by linear regression models and LASSO regression was used to select effective WBC subtypes. Summary statistics for WBC-associated SNPs were extracted from literature, and Mendelian randomization (MR) analysis with inverse-variance weighted (IVW) method was applied to estimate the causal effects of total WBC and subtypes on lung function among 4012 subjects from COW ( = 1126) and DFTJ cohorts ( = 2886).

Results: Total WBC counts were negatively associated with lung function among three populations and their pooled analysis indicated that per 1 × 10 cells/L increase in total WBC was associated with 36.13 (95% CI: 30.35, 41.91) mL and 25.23 (95% CI: 19.97, 30.50) mL decrease in FVC and FEV, respectively. Independent associations with lung function were found for neutrophils, monocytes, eosinophils and basophils (all  < .05), except lymphocytes. Besides, IVW MR analysis showed that genetically predicted total WBC and neutrophil counts were associated with reduced FVC ( = .017 and .021, respectively) and FEV ( = .048 and .043, respectively).

Conclusions: WBC subtypes were independently associated with lower lung function except lymphocytes. Our findings suggest that circulating neutrophils may be causal factors in lung function impairment.KEY MESSAGESWhite blood cell (WBC) subtypes were negatively associated with lung function level except lymphocytes in the observational studies.Associations of WBC subtypes with lung function may be modified by sex and smoking.Mendelian randomization analysis shows that neutrophils may be causal factors in lung function impairment.
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http://dx.doi.org/10.1080/07853890.2021.1948603DOI Listing
December 2021

Recapitulating Zika Virus Infection in Vagina of Tree Shrew .

Front Cell Infect Microbiol 2021 25;11:687338. Epub 2021 Jun 25.

Faculty of Life Science and Technology, Yunnan Provincial Center for Molecular Medicine, Kunming University of Science and Technology, Kunming, China.

Sexual transmission of Zika Virus (ZIKV) elevates the risk of its dissemination in the female reproductive tract and causes a serious threat to the fetus. However, the available animal models are not appropriate to investigate sexual transmission, dynamics of ZIKV infection, replication, and shedding. The use of tree shrew as a small animal model of ZIKV vaginal infection was assessed in this study. A total of 23 sexually mature female tree shrews were infected with ZIKV GZ01 the intravaginal route. There was no significant difference in change of body weight, and the temperature between ZIKV infected and control animals. Viral RNA loads were detected in blood, saliva, urine, and vaginal douching. ZIKV RNA was readily detected in vaginal lavage of 22 animals (95.65%, 22/23) at 1 dpi, and viral load ranged from 104.46 to 107.35 copies/ml, and the peak of viral load appeared at 1 dpi. The expression of key inflammatory genes, such as IL6, 8, CCL5, TNF-a, and CXCL9, was increased in the spleen of ZIKV infected animals. In the current study, female tree shrews have been successfully infected with ZIKV through the vaginal route for the first time. Interestingly, at first, ZIKV replicates at the local site of infection and then spreads throughout the host body to develop a robust systemic infection and mounted a protective immune response. This small animal model is not only valuable for exploring ZIKV sexual transmission and may also help to explain the cause of debilitating manifestations of the fetus .
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http://dx.doi.org/10.3389/fcimb.2021.687338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270636PMC
July 2021

Intraoperative Swept-Source OCT-Based Corneal Topography for Measurement and Analysis of Stromal Surface After Epithelial Removal.

J Refract Surg 2021 Jul 1;37(7):484-492. Epub 2021 Jul 1.

Purpose: To assess intraoperative stromal topography measurements using swept-source optical coherence tomography (OCT)-based topography/tomography after epithelial removal and to analyze the epithelial contribution to the corneal topography and optics.

Methods: This was a prospective series of 22 eyes of 19 patients referred to receive phototherapeutic keratotomy (PTK) for treatment of recurrent corneal erosion and a control group of 22 virgin eyes. Swept-source OCT corneal topography/tomography was obtained immediately before and immediately after mechanical deepithelialization before PTK. Epithelial thickness maps were obtained before the surgery using spectral-domain OCT in the control group and as a reference in the group with anterior basement membrane dystrophy. Topographic and optical characteristics, including the curvature, astigmatism, asphericity, and higher order aberrations of the cornea before and after deepithelialization were compared, and their differences correlated with the measurements derived from the epithelial thickness maps.

Results: Stromal topography measurements after deepithelialization were easily obtained and showed excellent repeatability. Assessment of corneal edema induced by deepithelialization revealed that it did not significantly affect the measured parameters. The stromal surface was steeper by 1.28 diopters, had higher with-the-rule astigmatism by 0.41 diopters, was more prolate, and had more higher order aberrations compared to the intact epithelialized corneal surface. These differences correlated well with the parameters derived from epithelial thickness maps.

Conclusions: Measurement of stromal topography using swept-source OCT immediately after mechanical deepithelialization may be a viable method in therapeutic refractive surgery, where stromal topography-guided ablation is needed. A significant epithelial contribution to anterior corneal topography and optics was confirmed. .
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http://dx.doi.org/10.3928/1081597X-20210405-01DOI Listing
July 2021

Tumor invasive ability of papillary thyroid carcinomas is not conferred by acquired gene mutations.

J Investig Med 2021 Jul 7. Epub 2021 Jul 7.

Department of Ultrasound, First Affiliated Hospital of Dalian Medical University, Dalian, China

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The ability to predict whether a carcinoma would exhibit invasive ability in patients with PTC is important and has clinical implications for the selection of therapeutic strategies. Although several studies have focused on the genetic characterization of invasive cancer cells, the factors critical to the origination of invasive cancer cells are still unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of the tumor invasion phenotype and to investigate the genetic features of invasive cancer cells in patients with PTC. We performed customized 48-gene deep exon sequencing in samples obtained from 88 patients with PTC via fine needle aspiration; the results revealed that no genetic changes were specifically associated with the tumor aggressiveness phenotype. Our results indicate that genetic mutations do not cause indolent PTCs to become invasive.
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http://dx.doi.org/10.1136/jim-2021-001971DOI Listing
July 2021

Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex.

FEBS J 2021 Jul 7. Epub 2021 Jul 7.

Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, 2050, Australia.

The combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1, and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodeling module of the Nucleosome Remodeling and Deacetylase (NuRD) complex. To date, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential in defining underlying mechanisms of gene regulation. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS) we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodeling activity into both the ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the Nuclear Receptor Co-Repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.
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http://dx.doi.org/10.1111/febs.16112DOI Listing
July 2021

Classification of type 2 diabetes mellitus with or without cognitive impairment from healthy controls using high-order functional connectivity.

Hum Brain Mapp 2021 Jul 2. Epub 2021 Jul 2.

School of Biomedical Engineering, ShanghaiTech University, Shanghai, China.

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and may progress to dementia. However, the brain functional mechanism of T2DM-related dementia is still less understood. Recent resting-state functional magnetic resonance imaging functional connectivity (FC) studies have proved its potential value in the study of T2DM with cognitive impairment (T2DM-CI). However, they mainly used a mass-univariate statistical analysis that was not suitable to reveal the altered FC "pattern" in T2DM-CI, due to lower sensitivity. In this study, we proposed to use high-order FC to reveal the abnormal connectomics pattern in T2DM-CI with a multivariate, machine learning-based strategy. We also investigated whether such patterns were different between T2DM-CI and T2DM without cognitive impairment (T2DM-noCI) to better understand T2DM-induced cognitive impairment, on 23 T2DM-CI and 27 T2DM-noCI patients, as well as 50 healthy controls (HCs). We first built the large-scale high-order brain networks based on temporal synchronization of the dynamic FC time series among multiple brain region pairs and then used this information to classify the T2DM-CI (as well as T2DM-noCI) from the matched HC based on support vector machine. Our model achieved an accuracy of 79.17% in T2DM-CI versus HC differentiation, but only 59.62% in T2DM-noCI versus HC classification. We found abnormal high-order FC patterns in T2DM-CI compared to HC, which was different from that in T2DM-noCI. Our study indicates that there could be widespread connectivity alterations underlying the T2DM-induced cognitive impairment. The results help to better understand the changes in the central neural system due to T2DM.
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http://dx.doi.org/10.1002/hbm.25575DOI Listing
July 2021

Multifaceted Regulation of MicroRNA Biogenesis: Essential Roles and Functional Integration in Neuronal and Glial Development.

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 Jun 23.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.

MicroRNAs (miRNAs) are small, non-coding RNAs that function as endogenous gene silencers. Soon after the discovery of miRNAs, a subset of brain-enriched and brain-specific miRNAs were identified and significant advancements were made in delineating miRNA function in brain development. However, understanding the molecular mechanisms that regulate miRNA biogenesis in normal and diseased brains has become a prevailing challenge. Besides transcriptional regulation of miRNA host genes, miRNA processing intermediates are subjected to multifaceted regulation by canonical miRNA processing enzymes, RNA binding proteins (RBPs) and epitranscriptomic modifications. Further still, miRNA activity can be regulated by the sponging activity of other non-coding RNA classes, namely circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Differential abundance of these factors in neuronal and glial lineages partly underlies the spatiotemporal expression and function of lineage-specific miRNAs. Here, we review the continuously evolving understanding of the regulation of neuronal and glial miRNA biogenesis at the transcriptional and posttranscriptional levels and the cooperativity of miRNA species in targeting key mRNAs to drive lineage-specific development. In addition, we review dysregulation of neuronal and glial miRNAs and the detrimental impacts which contribute to developmental brain disorders.
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http://dx.doi.org/10.3390/ijms22136765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269442PMC
June 2021

Physical activity attenuates the associations of systemic immune-inflammation index with total and cause-specific mortality among middle-aged and older populations.

Sci Rep 2021 Jun 15;11(1):12532. Epub 2021 Jun 15.

Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China.

Systemic immune-inflammation index (SII) emerged as a biomarker of chronic inflammation and an independent prognostic factor for many cancers. We aimed to investigate the associations of SII level with total and cause-specific mortality risks in the general populations, and the potential modification effects of lifestyle-related factors on the above associations. In this study, we included 30,521 subjects from the Dongfeng-Tongji (DFTJ) cohort and 25,761 subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2014. Cox proportional hazards regression models were used to estimate the associations of SII with mortality from all-cause, cardiovascular diseases (CVD), cancer and other causes. In the DFTJ cohort, compared to subjects in the low SII subgroup, those within the middle and high SII subgroups had increased risks of total mortality [hazard ratio, HR (95% confidence interval, CI) = 1.12 (1.03-1.22) and 1.26 (1.16-1.36), respectively) and CVD mortality [HR (95%CI) = 1.36 (1.19-1.55) and 1.50 (1.32-1.71), respectively]; those within the high SII subgroup had a higher risk of other causes mortality [HR (95%CI) = 1.28 (1.09-1.49)]. In the NHANES 1999-2014, subjects in the high SII subgroup had higher risks of total, CVD, cancer and other causes mortality [HR (95%CI) = 1.38 (1.27-1.49), 1.33 (1.11-1.59), 1.22 (1.04-1.45) and 1.47 (1.32-1.63), respectively]. For subjects with a high level of SII, physical activity could attenuate a separate 30% and 32% risk of total and CVD mortality in the DFTJ cohort, and a separate 41% and 59% risk of total and CVD mortality in the NHANES 1999-2014. Our study suggested high SII level may increase total and CVD mortality in the general populations and physical activity exerted a beneficial effect on the above associations.
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http://dx.doi.org/10.1038/s41598-021-91324-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206152PMC
June 2021

Selenium mitigated aflatoxin B1-induced cardiotoxicity with potential regulation of 4 selenoproteins and ferroptosis signaling in chicks.

Food Chem Toxicol 2021 Aug 8;154:112320. Epub 2021 Jun 8.

Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. Electronic address:

The aim of the present study was to explore the underlying mechanism of selenium (Se)-mediated detoxification of aflatoxin B (AFB)-induced cardiotoxicity in chicks. A Se-deficient, corn-soybean meal-basal diet (36 μg Se/kg, BD) and three test diets (BD+1.0 mg AFB/kg, 0.3 mg Se/kg, or 1.0 mg AFB/kg+0.3 mg Se/kg) were used in a 3-wk 2 × 2 factorial design trial (n = 30 chicks/group). Dietary AFB led to induced (P < 0.05) serum creatine kinase and creatine kinase MB isoenzyme activities and heart histopathologic lesions. However, Se deficiency aggravated most of these alterations induced by AFB. Moreover, mRNA levels of two ferroptosis activators (solute carrier family 11 Member 2 and transferrin) were upregulated (P < 0.05) in the AFB-treated groups. Additionally, Se deficiency reduced (P < 0.05) glutathione peroxidase (GPX) 3 and thioredoxin reductase 3 mRNA and GPX activity but increased (P < 0.05) selenoprotein M and selenophosphate synthetase 2 mRNA in the heart in AFB-administered groups. The in vitro study showed that Se alleviated (P < 0.05) AFB-reduced cell viability and induced (P < 0.05) ROS and ferroptosis in H9C2 cardiac cells. It also downregulated (P < 0.05) two ferroptosis activators (long-chain acyl-CoA synthetase 4 and solute carrier family 11 Member 2) in the AFB-treated groups in the H9C2 cells. In conclusion, this study illustrated that Se alleviates AFB-induced cardiotoxicity and cardiomyocyte damage potentially related to the regulation of redox status, 4 selenoproteins, and ferroptosis-related signaling.
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http://dx.doi.org/10.1016/j.fct.2021.112320DOI Listing
August 2021

HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics.

Elife 2021 Jun 9;10. Epub 2021 Jun 9.

Biology Department, University of Massachusetts Amherst, Amherst, United States.

Chromatin, which consists of DNA and associated proteins, contains genetic information and is a mechanical component of the nucleus. Heterochromatic histone methylation controls nucleus and chromosome stiffness, but the contribution of heterochromatin protein HP1α (CBX5) is unknown. We used a novel HP1α auxin-inducible degron human cell line to rapidly degrade HP1α. Degradation did not alter transcription, local chromatin compaction, or histone methylation, but did decrease chromatin stiffness. Single-nucleus micromanipulation reveals that HP1α is essential to chromatin-based mechanics and maintains nuclear morphology, separate from histone methylation. Further experiments with dimerization-deficient HP1α indicate that chromatin crosslinking via HP1α dimerization is critical, while polymer simulations demonstrate the importance of chromatin-chromatin crosslinkers in mechanics. In mitotic chromosomes, HP1α similarly bolsters stiffness while aiding in mitotic alignment and faithful segregation. HP1α is therefore a critical chromatin-crosslinking protein that provides mechanical strength to chromosomes and the nucleus throughout the cell cycle and supports cellular functions.
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http://dx.doi.org/10.7554/eLife.63972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233041PMC
June 2021

Genome-wide detection of enhancer-hijacking events from chromatin interaction data in rearranged genomes.

Nat Methods 2021 Jun 3;18(6):661-668. Epub 2021 Jun 3.

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.

Recent efforts have shown that structural variations (SVs) can disrupt three-dimensional genome organization and induce enhancer hijacking, yet no computational tools exist to identify such events from chromatin interaction data. Here, we develop NeoLoopFinder, a computational framework to identify the chromatin interactions induced by SVs, including interchromosomal translocations, large deletions and inversions. Our framework can automatically resolve complex SVs, reconstruct local Hi-C maps surrounding the breakpoints, normalize copy number variation and allele effects and predict chromatin loops induced by SVs. We applied NeoLoopFinder in Hi-C data from 50 cancer cell lines and primary tumors and identified tens of recurrent genes associated with enhancer hijacking. To experimentally validate NeoLoopFinder, we deleted the hijacked enhancers in prostate adenocarcinoma cells using CRISPR-Cas9, which significantly reduced expression of the target oncogene. In summary, NeoLoopFinder enables identification of critical oncogenic regulatory elements that can potentially reveal therapeutic targets.
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http://dx.doi.org/10.1038/s41592-021-01164-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191102PMC
June 2021

Epigenomic landscape and 3D genome structure in pediatric high-grade glioma.

Sci Adv 2021 Jun 2;7(23). Epub 2021 Jun 2.

Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are morbid brain tumors. Even with treatment survival is poor, making pHGG the number one cause of cancer death in children. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding histone H3. To investigate whether H3K27M is associated with distinct chromatin structure that alters transcription regulation, we generated the first high-resolution Hi-C maps of pHGG cell lines and tumor tissue. By integrating transcriptome (RNA-seq), enhancer landscape (ChIP-seq), genome structure (Hi-C), and chromatin accessibility (ATAC-seq) datasets from H3K27M and wild-type specimens, we identified tumor-specific enhancers and regulatory networks for known oncogenes. We identified genomic structural variations that lead to potential enhancer hijacking and gene coamplification, including , , and Together, our results imply three-dimensional genome alterations may play a critical role in the pHGG epigenetic landscape and contribute to tumorigenesis.
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http://dx.doi.org/10.1126/sciadv.abg4126DOI Listing
June 2021

Exploring the relationship between spiritual well-being and death anxiety in patients with gynecological cancer: a cross-section study.

BMC Palliat Care 2021 Jun 1;20(1):78. Epub 2021 Jun 1.

Department of Nursing, West China Second University Hospital, Sichuan University, Chengdu, China.

Background: In recent years, spiritual well-being has gradually gained the attention of health care providers in China, especially those in oncology departments, who have recognized the importance of improving spiritual well-being in cancer patients. Since most of the current research on spiritual well-being has been carried out in areas with religious beliefs, this study was conducted in the context of no development of formal religion. The purpose of this study was to explore the relationship between death anxiety and spiritual well-being and the related factors of spiritual well-being among gynecological cancer patients.

Methods: This cross-section study was conducted among 586 gynecological cancer patients. The European Organization for Research and Treatment for Cancer Quality of Life Questionnaire-spiritual well-being32 (EORTC QLQ-SWB32) and Templer's Death Anxiety Scale (T-DAS) were used to measure spiritual well-being and death anxiety. The Multiple Linear Regression Model was used to determine the relationship between spiritual well-being and death anxiety.

Results: For all participants, the highest QLQ-SWB32 centesimal score was 75.13 on the Relationship with Other scale, and the lowest was 60.33 on the Relationship with Someone or Something Greater Scale. The mean Death Anxiety score was 5.31 (SD 3.18). We found that Relationship with Someone or Something Greater was the only scale not associated with death anxiety. Overall, patients with lower death anxiety have a higher level of spiritual well-being. Besides, a high Relationship with Other score was associated with living with a partner (B = 2.471, P < 0.001) and married (B = -6.475, P = 0.001). Patients with higher Global-SWB were retired (B = 0.387, P = 0.019).

Conclusions: Our study found that the spiritual well-being of patients with gynecological cancer in China was no worse than in other countries with religious beliefs and patients with lower death anxiety have a higher level of spiritual well-being. Clinical staff should pay attention to the spiritual health of cancer patients, and spiritual care should be regarded as an essential element in cancer care.
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http://dx.doi.org/10.1186/s12904-021-00778-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170730PMC
June 2021

Coma Influence on Manifest Astigmatism in Coma-Dominant Irregular Corneal Optics.

J Refract Surg 2021 Apr 1;37(4):274-282. Epub 2021 Apr 1.

Purpose: To evaluate the influence of coma on manifest refractive cylinder (MRC) in eyes with coma-dominated corneal optics and suggest alternative guidelines for surgical planning of astigmatism correction in topography-guided ablation and toric intraocular lens (IOL) exchange surgery.

Methods: Twelve eyes with coma-dominant corneal optics and low lenticular astigmatism were selected. The astigmatism remaining after subtraction of total corneal astigmatism (TCA) and lenticular astigmatism from MRC, termed discrepant astigmatism, was calculated and correlated to corneal coma at the anterior surface. Refractive and topography data were then used to simulate topography-guided refractive surgery (topography-guided group) in 7 eyes and lenticular exchange surgery with toric intraocular lens (IOL) implantation (toric IOL group) in 5 eyes. The estimated postoperative MRC after correction of TCA or MRC for each group was compared.

Results: The axis and amplitude of discrepant astigmatism correlated strongly with the axis and amplitude of coma. In the topography-guided group, where topography-guided ablation eliminated corneal higher order aberrations (HOAs), TCA-based correction led to less estimated postoperative manifest astigmatism than MRC-based correction. In the toric IOL group, where removal of the crystalline lens did not affect corneal HOAs, MRC-based correction via toric IOL implantation led to less estimated postoperative astigmatism than TCA-based correction.

Conclusions: Discrepant astigmatism in eyes with coma-dominant corneal optics correlates with coma. In such eyes, treating TCA, along with corneal HOAs, instead of MRC, seems appropriate in topography-guided treatments, whereas treating MRC may be a better choice in lenticular exchange surgery with toric IOL implantation, where corneal HOAs are not treated. .
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http://dx.doi.org/10.3928/1081597X-20210119-02DOI Listing
April 2021

Validation of a QTL for Grain Size and Weight Using an Introgression Line from a Cross between Oryza sativa and Oryza minuta.

Rice (N Y) 2021 May 20;14(1):43. Epub 2021 May 20.

Chinese National Center for Rice Improvement and State Key Laboratory of Rice Biology, China National Rice Research Institute, Hangzhou, 310006, China.

Background: Grain size and weight are important target traits determining grain yield and quality in rice. Wild rice species possess substantial elite genes that can be served as an important resource for genetic improvement of rice. In this study, we identify and validate a novel QTL on chromosome 7 affecting the grain size and weight using introgression lines from cross of Oryza sativa and Oryza minuta.

Results: An introgression line 'IL188' has been achieved from a wild species Oryza minuta (2n = 48, BBCC, W303) into O. sativa japonica Nipponbare. The F and F populations derived from a cross between IL188 and Nipponbare were used to map QTLs for five grain size traits, including grain length (GL), grain width (GW), grain length to width ratio (LWR), grain thickness (GT) and thousand grain weight (TGW). A total of 12 QTLs for the five grain traits were identified on chromosomes 1, 2, 3, 6, 7, and 8. The QTL-qGL7 controlling GL on chromosome 7 was detected stably in the F and F populations, and explained 15.09-16.30% of the phenotypic variance. To validate the effect of qGL7, eight residual heterozygous line (RHL) populations were developed through selfing four F and four F plants with different heterozygous segments for the target region. By further developing SSR and Indel markers in the target interval, qGL7 was delimited to a ~ 261 kb region between Indel marker Y7-12 and SSR marker Y7-38, which also showed significant effects on grain width and thousand grain weight. Comparing with the reference genome of Nipponbare, stop or frameshift mutations in the exon of the three putative genes LOC_Os07g36830, LOC_Os07g36900 and LOC_Os07g36910 encoding F-box domain-containing proteins may be the candidate genes for qGL7. Scanning electron microscopy analysis of the glume's epidermal cells showed that the cell length and width of NIL-qGL7 was higher than NIL-qGL7, indicating that qGL7 increases grain size and weight by regulating cell expansion.

Conclusions: In this study, we detected 12 QTLs regulating grain size and weight using an introgression line from a cross between Oryza sativa and Oryza minuta. Of these loci, we confirmed and delimited the qGL7 to a ~ 261 kb region. Three putative genes, LOC_Os07g36830, LOC_Os07g36900 and LOC_Os07g36910 encoding F-box domain-containing proteins may be the candidate genes for qGL7. These results provide a basis for map-based cloning of the qGL7 gene and useful information for marker assisted selection in rice grain quality improvement.
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http://dx.doi.org/10.1186/s12284-021-00472-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137761PMC
May 2021

Genetic characteristics of a New HIV-1 subtype B/C intersubtype circulating recombinant form (CRF118_BC) identified in Yunnan, China.

J Infect 2021 Aug 16;83(2):237-279. Epub 2021 May 16.

Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2021.05.007DOI Listing
August 2021

METTL3/METTL14 Transactivation and mA-Dependent TGF-β1 Translation in Activated Kupffer Cells.

Cell Mol Gastroenterol Hepatol 2021 May 13. Epub 2021 May 13.

MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China. Electronic address:

Background And Aims: Transforming growth factor β1 (TGF-β1) secreted from activated Kupffer cells (KCs) promotes the progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis. N6-methyladenosine (mA) RNA modification participates in various cell stress responses, yet it remains unknown whether it plays a role in TGF-β1 upregulation in activated KCs.

Methods: Western blot, dot blot, and liquid chromatography with tandem mass spectrometry were used to determine the expression of mA methyltransferase, METTL3, and METTL14, as well as global mA modification. RNA-sequencing and mA-seq were employed to screen differentially expressed genes and responsive mA peaks. Nuclear factor κB (NF-κB)-mediated METTL3/METTL14 transactivation were validated with chromatin immunoprecipitation polymerase chain reaction and dual-luciferase reporter system, and the role of mA in TGF-β1 upregulation was further verified in METTL3/METTL14-deficient KCs and myeloid lineage cell-specific METTL14 knockout mice.

Results: Serum lipopolysaccharide (LPS) concentration is increased in high-fat diet-induced NASH rats. TGF-β1 upregulation is closely associated with METTL3/METTL14 upregulation and global mA hypermethylation, in both NASH rat liver and LPS-activated KCs. LPS-responsive mA peaks are identified on the 5' untranslated region (UTR) of TGF-β1 messenger RNA (mRNA). NF-κB directly transactivates METTL3 and METTL14 genes. LPS-stimulated TGF-β1 expression is abolished in METTL3/METTL14-deficient KCs and myeloid lineage cell-specific METTL14 knockout mice. Mutation of mA sites on the 5'UTR of TGF-β1 mRNA blocks LPS-induced increase of luciferase reporter activity.

Conclusions: NF-κB acts as transcription factor to transactivate METTL3/METTL14 genes upon LPS challenge, leading to global RNA mA hypermethylation. Increased mA on the 5'UTR of TGF-β1 mRNA results in mA-dependent translation of TGF-β1 mRNA in a cap-independent manner. We identify a novel role of mA modification in TGF-β1 upregulation, which helps to shed light on the molecular mechanism of NASH progression.
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http://dx.doi.org/10.1016/j.jcmgh.2021.05.007DOI Listing
May 2021

DNA methylome analysis identifies BMI-related epigenetic changes associated with non-small cell lung cancer susceptibility.

Cancer Med 2021 Jun 3;10(11):3770-3781. Epub 2021 May 3.

Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Background: Body mass index (BMI) has been reported to be inversely associated with incident risk of non-small cell lung cancer (NSCLC). However, the underlying mechanism is still unclear. This study aimed to investigate the role of DNA methylation in the relationship between BMI and NSCLC.

Methods: We carried out a genome-wide DNA methylation study of BMI in peripheral blood among 2266 Chinese participants by using Illumina Methylation arrays. For the BMI-related DNA methylation changes, their associations with NSCLC risk were further analyzed and their mediation effects on BMI-NSCLC association were also evaluated.

Results: The methylation levels of four CpGs (cg12593793, cg17061862, cg11024682, and cg06500161, annotated to LMNA, ZNF143, SREBF1, and ABCG1, respectively) were found to be significantly associated with BMI. Methylation levels of cg12593793, cg11024682, and cg06500161 were observed to be inversely associated with NSCLC risk [OR (95%CI) =0.22 (0.16, 0.31), 0.39 (0.30, 0.50), and 0.66 (0.53, 0.82), respectively]. Additionally, cg11024682 in SREBF1 and cg06500161 in ABCG1 mediated 45.3% and 19.5% of the association between BMI and decreased NSCLC risk, respectively.

Conclusions: In this study, we identified four DNA methylation sites associated with BMI in the Chinese populations at the genome-wide significant level. We also found that the BMI-related methylations of SREBF1 and ABCG1 could mediate about a quintile-to-half of the effect of BMI on reduced NSCLC risk, which adds a potential mechanism underlying this association.
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http://dx.doi.org/10.1002/cam4.3906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178488PMC
June 2021

Mitochondrial ATP-Dependent Proteases-Biological Function and Potential Anti-Cancer Targets.

Cancers (Basel) 2021 Apr 22;13(9). Epub 2021 Apr 22.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.

Cells must eliminate excess or damaged proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the ubiquitin-proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria proteases, including four core ATP-dependent proteases, m-AAA, i-AAA, LonP, and ClpXP, located in the mitochondrial membrane and matrix. This review will discuss the function of mitochondrial proteases, with a focus on ClpXP as a novel therapeutic target for the treatment of malignancy. ClpXP maintains the integrity of the mitochondrial respiratory chain and regulates metabolism by degrading damaged and misfolded mitochondrial proteins. Inhibiting ClpXP genetically or chemically impairs oxidative phosphorylation and is toxic to malignant cells with high ClpXP expression. Likewise, hyperactivating the protease leads to increased degradation of ClpXP substrates and kills cancer cells. Thus, targeting ClpXP through inhibition or hyperactivation may be novel approaches for patients with malignancy.
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http://dx.doi.org/10.3390/cancers13092020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122244PMC
April 2021

Plasminogen activator inhibitor-1 gene promoter 4G/5G polymorphism and risks of peripherally inserted central catheter-related venous thrombosis in patients with lung cancer: a prospective cohort study.

Support Care Cancer 2021 Apr 24. Epub 2021 Apr 24.

Department of Thoracic Oncology, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, 610041, China.

Purpose: This study investigated the influence of plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms and other contributing clinical factors on peripherally inserted central catheter-related venous thrombosis (PICC-RVT) in Chinese patients with lung cancer.

Methods: We conducted a prospective study of 237 participants. Blood samples were collected to detect the PAI-1 4G/5G genotype. Venous thromboembolism risk was calculated by the Caprini risk assessment model. Color Doppler ultrasonography was performed every 7 days for 3 weeks to confirm PICC-RVT.

Results: The rate of PICC-RVT was 13.50% (32/237). The 5G/5G, 4G/5G, and 4G/4G genotypes were found in 12.50% vs 17.56%, 59.38% vs 49.27%, and 28.12% vs 34.17% in the thrombus group and the non-thrombus group of the participants. No difference was observed in the distribution frequency of the three genotypes between the thrombus and non-thrombus groups. A higher fibrinogen level (OR 1.194, 95% CI 1.004-1.420, P = 0.045) and a higher Caprini score (OR 1.698, 95% CI 1.103-2.614, P = 0.016) were statistically significant risk factors for PICC-RVT. Compared with patients who underwent a pemetrexed/cisplatin regimen, those who were administered paclitaxel/cisplatin (OR 18.332, 95% CI 2.890-116.278, P = 0.002) or gemcitabine/cisplatin (OR 6.617, 95% CI 1.210-36.180, P = 0.029) were at increased risk of PICC-RVT.

Conclusion: Our finding suggested that there is no statistically significant influence of the PAI-1 4G/5G gene variant on PICC-RVT in Chinese patients with lung cancer. However, patients with higher Caprini scores and higher fibrinogen levels are at increased risk for PICC-RVT, as are patients receiving chemotherapy. Clinical staff should carefully perform a risk assessment for patients with PICC. Those with the above risk factors should pay close attention and take timely and effective preventive measures.
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http://dx.doi.org/10.1007/s00520-021-06207-8DOI Listing
April 2021

Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development.

J Hazard Mater 2021 08 8;416:125839. Epub 2021 Apr 8.

Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

Benzo[a]pyrene (B[a]P) is a typical carcinogen associated with increased lung cancer risk, but the underlying mechanisms remain unclear. This study aimed to investigate epigenome-wide DNA methylation associated with B[a]P exposure and their mediation effects on B[a]P-lung cancer association in two lung cancer case-control studies of 462 subjects. Their plasma levels of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) adducts and genome-wide DNA methylations were separately detected in peripheral blood by using enzyme-linked immunosorbent assay (ELISA) and genome-wide methylation arrays. The epigenome-wide meta-analysis was performed to analyze the associations between BPDE-Alb adducts and DNA methylations. Mediation analysis was applied to assess effect of DNA methylation on the B[a]P-lung cancer association. We identified 15 CpGs associated with BPDE-Alb adducts (P < 1.0 × 10), among which the methylation levels at five loci (cg06245338, cg24256211, cg15107887, cg02211741, and cg04354393 annotated to UBE2O, SAMD4A, ACBD6, DGKZ, and SLFN13, respectively) mediated a separate 38.5%, 29.2%, 41.5%, 47.7%, 56.5%, and a joint 58.2% of the association between BPDE-Alb adducts and lung cancer risk. Compared to the traditional factors [area under the curve (AUC) = 0.788], addition of these CpGs exerted improved discriminations for lung cancer, with AUC ranging 0.828-0.861. Our results highlight DNA methylation alterations as potential mediators in lung tumorigenesis induced by B[a]P exposure.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125839DOI Listing
August 2021

YM155 inhibits retinal pigment epithelium cell survival through EGFR/MAPK signaling pathway.

Int J Ophthalmol 2021 18;14(4):489-496. Epub 2021 Apr 18.

First Affiliated Hospital of Northwest University, Northwest University, Xi'an 710069, Shaanxi Province, China.

Aim: To investigate YM155's effect on retinal pigment epithelium (RPE) cells' viability and the potential regulatory mechanisms.

Methods: Human immortalized RPE cell lines (ARPE-19 cell line) were processed with YM155 and epidermal growth factor (EGF). ARPE-19 cell viability was detected by methyl thiazolyl tetrazolium assay, and apoptosis was tested by flow cytometry assay. ARPE-19 cell proliferation was assessed with bromodeoxyuridine tagged incorporation assay, and migration ability was evaluated a wound-healing assay. Epidermal growth factor receptor (EGFR)/MAPK pathway proteins were tested immunoblotting. EGFR localization was examined by immunofluorescence assay.

Results: YM155 suppressed ARPE-19 cells' viability in a time and concentration-dependent manner. A high dose of YM155 caused a small amount of ARPE-19 cell death. YM155 significantly diminished the ARPE-19 cells' proliferative and migrative capacity. YM155 down-regulated total EGFR and phosphorylated external signal-regulated protein kinase (ERK), and it up-regulated the phosphorylation of P38MAPK and c-Jun N-terminal kinase (JNK). YM155 induced endocytosis of EGFR in ARPE-19 cell. YM155 also attenuated EGF-induced ARPE-19 cells' proliferative and migrative capacity. Moreover, YM155 significantly decreased the expression of phosphorylated EGFR and ERK after treated by EGF.

Conclusion: YM155 inhibits RPE cell survival, the cell proliferative and migrative capacity, and it effectuates a small amount of cell death through the EGFR/MAPK signaling pathway. YM155 might, therefore, be an agent to prevent and treat abnormal RPE cell survival in proliferative vitreoretinopathy.
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http://dx.doi.org/10.18240/ijo.2021.04.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025172PMC
April 2021

Exposure to constant light impairs cognition with FTO inhibition and mA-dependent TrκB repression in mouse hippocampus.

Environ Pollut 2021 Aug 30;283:117037. Epub 2021 Mar 30.

MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, PR China; Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, PR China. Electronic address:

N6-methyladenosine (mA) mRNA methylation plays a role in various brain functions. Exposure to chronic constant light (CCL) has been reported to impair cognition, yet whether the underlying mechanism involves mA remains unknown. In this study, mice exposed to CCL for 3 weeks show impaired cognitive behavior, which was associated with increased mA level in hippocampus. Accordingly, the mA demethylase FTO was inhibited while the methyltransferases METTL3, METTL14 and WTAP, as well as the reader protein YTHDF2, were elevated in the hippocampus of CCL-exposed mice. CCL exposure significantly activated hippocampal expression of circadian regulator cryptochrome 1 and 2 (CRY1 and 2). Meanwhile, hippocampal neurogenesis was impaired with suppression of BDNF/TrκB/ERK pathway. To further delineate the signaling pathway and the role of mA, we altered the expression of CRY1/2 in hippocampus neuron cells. CRY1/2 overexpression inhibited FTO and increased mA levels, while CRY1/2 knockdown led to opposite results. Luciferase reporter analysis further confirmed CRY1/2-induced FTO suppression. Furthermore, FTO knockdown increased mA on 3'UTR of TrκB mRNA, and decreased TrκB mRNA stability and TrκB protein expression, in a YTHDF2-dependent manner. These results indicate that CCL-activated CRY1/2 causes transcriptional inhibition of FTO, which suppresses TrκB expression in hippocampus via mA-dependent post-transcriptional regulation and contributes to impaired cognitive behavior in mice exposed to constant light.
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http://dx.doi.org/10.1016/j.envpol.2021.117037DOI Listing
August 2021

Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer.

Genome Biol 2021 Apr 15;22(1):105. Epub 2021 Apr 15.

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA.

Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. RESULT: We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. CONCLUSION: In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.
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http://dx.doi.org/10.1186/s13059-021-02325-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048365PMC
April 2021

The identification of neutrophils-mediated mechanisms and potential therapeutic targets for the management of sepsis-induced acute immunosuppression using bioinformatics.

Medicine (Baltimore) 2021 Mar;100(12):e24669

General Practice Department, Zhejiang Hospital, Hangzhou, Zhejiang, China.

Abstract: Neutrophils have crucial roles in defensing against infection and adaptive immune responses. This study aimed to investigate the genetic mechanism in neutrophils in response to sepsis-induced immunosuppression.The GSE64457 dataset was downloaded from the Gene Expression Omnibus database and the neutrophil samples (D3-4 and D6-8 post sepsis shock) were assigned into two groups. The differentially expressed genes (DEGs) were identified. The Short Time-series Expression Miner (STEM) clustering analysis was conducted to select the consistently changed DEGs post sepsis shock. The overlapping genes between the DEGs and the deposited genes associated with immune, sepsis, and immunosuppression in the AmiGO2 and Comparative Toxicogenomics Database were screened out and used for the construction of the protein-protein interaction (PPI) network. The expression of several hub genes in sepsis patients was validated using the PCR analysis. The drugs targeting the hub genes and the therapy strategies for sepsis or immunosuppression were reviewed and used to construct the drug-gene-therapy-cell network to illustrate the potential therapeutic roles of the hub genes.A total of 357 overlapping DEGs between the two groups were identified and were used for the STEM clustering analysis, which generated four significant profiles with 195 upregulated (including annexin A1, ANXA1; matrix metallopeptidase 9, MMP9; and interleukin 15, IL-15) and 151 downregulated DEGs (including, AKT1, IFN-related genes, and HLA antigen genes). Then, a total of 34 of the 151 downregulated DEGs and 39 of the 195 upregulated DEGs were shared between the databases and above DEGs, respectively. The PPI network analysis identified a downregulated module including IFN-related genes. The deregulation of DEGs including AKT1 (down), IFN-inducible protein 6 (IFI6, down), IL-15 (up), and ANXA1 (up) was verified in the neutrophils from patients with sepsis-induced immunosuppression as compared with controls. Literature review focusing on the therapy showed that the upregulation of IL-15, IFN, and HLA antigens are the management targets. Besides, the AKT1 gene was targeted by gemcitabine.These findings provided additional clues for understanding the mechanisms of sepsis-induced immunosuppression. The drugs targeting AKT1 might provide now clues for the management strategy of immunosuppression with the intention to prevent neutrophil infiltration.
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http://dx.doi.org/10.1097/MD.0000000000024669DOI Listing
March 2021

A homogeneous split-luciferase assay for rapid and sensitive detection of anti-SARS CoV-2 antibodies.

Nat Commun 2021 03 22;12(1):1806. Epub 2021 Mar 22.

Donnelly Centre, University of Toronto, Toronto, ON, Canada.

Better diagnostic tools are needed to combat the ongoing COVID-19 pandemic. Here, to meet this urgent demand, we report a homogeneous immunoassay to detect IgG antibodies against SARS-CoV-2. This serological assay, called SATiN, is based on a tri-part Nanoluciferase (tNLuc) approach, in which the spike protein of SARS-CoV-2 and protein G, fused respectively to two different tNLuc tags, are used as antibody probes. Target engagement of the probes allows reconstitution of a functional luciferase in the presence of the third tNLuc component. The assay is performed directly in the liquid phase of patient sera and enables rapid, quantitative and low-cost detection. We show that SATiN has a similar sensitivity to ELISA, and its readouts are consistent with various neutralizing antibody assays. This proof-of-principle study suggests potential applications in diagnostics, as well as disease and vaccination management.
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http://dx.doi.org/10.1038/s41467-021-22102-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985487PMC
March 2021

Reduced electron transport chain complex I protein abundance and function in Mfn2-deficient myogenic progenitors lead to oxidative stress and mitochondria swelling.

FASEB J 2021 04;35(4):e21426

Department of Animal Sciences, Purdue University, West Lafayette, IN, USA.

Mitochondrial remodeling through fusion and fission is crucial for progenitor cell differentiation but its role in myogenesis is poorly understood. Here, we characterized the function of mitofusin 2 (Mfn2), a mitochondrial outer membrane protein critical for mitochondrial fusion, in muscle progenitor cells (myoblasts). Mfn2 expression is upregulated during myoblast differentiation in vitro and muscle regeneration in vivo. Targeted deletion of Mfn2 gene in myoblasts (Mfn2 ) increases oxygen-consumption rates (OCR) associated with the maximal respiration and spare respiratory capacity, and increased levels of reactive oxygen species (ROS). Skeletal muscles of Mfn2 mice exhibit robust mitochondrial swelling with normal mitochondrial DNA content. Additionally, mitochondria isolated from Mfn2 muscles have reduced OCR at basal state and for complex I respiration, associated with decreased levels of complex I proteins NDUFB8 (NADH ubiquinone oxidoreductase subunit B8) and NDUFS3 (NADH ubiquinone oxidoreductase subunit S3). However, Mfn2 has no obvious effects on myoblast differentiation, muscle development and function, and muscle regeneration. These results demonstrate a novel role of Mfn2 in regulating mitochondrial complex I protein abundance and respiratory functions in myogenic progenitors and myofibers.
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http://dx.doi.org/10.1096/fj.202002464RDOI Listing
April 2021
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