Publications by authors named "Ting Qi"

79 Publications

Long non-coding RNA DUXAP8 elevates RCN2 expression and facilitates cell malignant behaviors and angiogenesis in cervical cancer via sponging miR-1297.

Diagn Pathol 2021 Nov 14;16(1):105. Epub 2021 Nov 14.

Department of Gynecology, the First People's Hospital of Lianyungang, No.6 Zhenhua East Road, Jiangsu, 222000, Lianyungang, China.

Background: Cervical cancer (CC) endangers women's health in the world range. Accumulating studies have revealed the crucial regulatory role of long non-coding RNAs (lncRNAs) in multiple malignancies, including CC. Our study aimed to explore the role of lncRNA double homeobox A pseudogene 8 (DUXAP8) in cervical carcinogenesis.

Methods: Gene expressions in CC were assessed by RT-qPCR. Function experiments and tube formation assays were performed to evaluate the role of DUXAP8 in CC cells. Subcellular fractionation and FISH assays were conducted to determine the subcellular location of DUXAP8. Luciferase reporter, RNA pull down and RIP assays were conducted to investigate the mechanism of DUXAP8.

Results: DUXAP8 was notably upregulated in CC cells. Downregulation of DUXAP8 repressed cell malignant behaviors and angiogenesis in CC. Mechanically, DUXAP8 boosted the expression of reticulocalbin-2 (RCN2) through relieving the binding of miR-1297 to RCN2 3'-UTR. Moreover, miR-1297 inhibition and RCN2 overexpression could counteract the inhibitory effects of DUXAP8 knockdown on the malignant phenotypes of CC cells. Besides, enhanced RCN2 expression restored the tumor growth in vivo that was inhibited by DUXAP8 repression.

Conclusions: DUXAP8 promotes malignant behaviors in CC cells via regulating miR-1297/RCN2 axis.
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http://dx.doi.org/10.1186/s13000-021-01145-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590774PMC
November 2021

Correlation and Diagnostic Value of Serum RBP4 and sRAGE and the Condition of Patients with Chronic Kidney Disease.

Evid Based Complement Alternat Med 2021 27;2021:6166528. Epub 2021 Oct 27.

Department of Nephrology, Central Theater General Hospital of PLA, Wuhan, Hubei 430070, China.

Chronic kidney disease (CKD) is a progressive damage of renal structure and function caused by various reasons. Its course is long and irreversible. CKD can be divided into 5 stages according to the glomerular filtration rate (GFR). Early detection and early intervention of CKD can reduce the complications of patients and improve the survival rate. Retinol-binding protein 4 (RBP4) is a small molecule transporter. Receptor for advanced glycation end products (RAGE) is a multi-ligand transmembrane signal transduction receptor discovered in recent years. Soluble RAGE (sRAGE) is a new splicing heterogeneity of RAGE. Our results show that serum RBP4 is increased while sRAGE is decreased in CKD patients, both of which are closely related to the severity of CKD. The combined use of serum RBP4 and sRAGE has a high diagnostic value for CKD and can provide a reliable diagnostic basis for the clinic.
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http://dx.doi.org/10.1155/2021/6166528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566031PMC
October 2021

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 09 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 2021

The Evolution of G-quadruplex Structure in mRNA Untranslated Region.

Evol Bioinform Online 2021 21;17:11769343211035140. Epub 2021 Jul 21.

State Key Laboratory of Bioelectronics, School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, Jiangsu, China.

The RNA G-quadruplex (rG4) is a kind of non-canonical high-order secondary structure with important biological functions and is enriched in untranslated regions (UTRs) of protein-coding genes. However, how rG4 structures evolve is largely unknown. Here, we systematically investigated the evolution of RNA sequences around UTR rG4 structures in 5 eukaryotic organisms. We found universal selection on UTR sequences, which facilitated rG4 formation in all the organisms that we analyzed. While -rich sequences were preferred in the rG4 structural region, -rich sequences were selectively not preferred. The selective pressure acting on rG4 structures in the UTRs of genes with higher content was significantly smaller. Furthermore, we found that rG4 structures experienced smaller evolutionary selection near the translation initiation region in the 5' UTR, near the polyadenylation signals in the 3' UTR, and in regions flanking the miRNA targets in the 3' UTR. These results suggest universal selection for rG4 formation in the UTRs of eukaryotic genomes and the selection may be related to the biological functions of rG4s.
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http://dx.doi.org/10.1177/11769343211035140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299884PMC
July 2021

Associated functional network development and language abilities in children.

Neuroimage 2021 11 4;242:118452. Epub 2021 Aug 4.

Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

During childhood, the brain is gradually converging to the efficient functional architecture observed in adults. How the brain's functional architecture evolves with age, particularly in young children, is however, not well understood. We examined the functional connectivity of the core language regions, in association with cortical growth and language abilities, in 175 young children in the age range of 4 to 9 years. We analyzed the brain's developmental changes using resting-state functional and T1-weighted structural magnetic resonance imaging data. The results showed increased functional connectivity strength with age between the pars triangularis of the left inferior frontal gyrus and left temporoparietal regions (cohen's d = 0.54, CI: 0.24 - 0.84), associated with children's language abilities. Stronger functional connectivity between bilateral prefrontal and temporoparietal regions was associated with better language abilities regardless of age. In addition, the stronger functional connectivity between the left inferior frontal and temporoparietal regions was associated with larger surface area and thinner cortical thickness in these regions, which in turn was associated with superior language abilities. Thus, using functional and structural brain indices, coupled with behavioral measures, we elucidate the association of functional language network development, language ability, and cortical growth, thereby adding to our understanding of the neural basis of language acquisition in young children.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463838PMC
November 2021

Expression and significance of let-7a and tumor necrosis factor-alpha in placenta of severe preeclampsia.

J Matern Fetal Neonatal Med 2021 Jul 21:1-5. Epub 2021 Jul 21.

Department of Obstetrics, Lianyungang First People's Hospital, Lianyungang, China.

Objective: To investigate the expression and clinical significance of let-7a and tumor necrosis factor-alpha (TNF-α) in placental tissue of patients with severe preeclampsia (SPE).

Methods: From January 2018 to October 2019, 64 cases of puerperal delivery at the First People's Hospital of Lianyungang City, 44 cases of SPE (SPE group), and 20 cases of healthy pregnant women (NC group) were selected. QRT-PCR and Western-blot were used to detect the expression levels of let-7a, TNF-αmRNA, and protein in the two groups of placental tissues. The correlation and the clinical significance of the two were statistically analyzed.

Results: The relative expression of let-7a in the SPE group was significantly lower than that in the control group (0.06 ± 0.02 versus 0.25 ± 0.04,  < .05); the expression of TNF-αmRNA in the SPE group was significantly higher than that in the control group (0.48 ± 0.04 versus 0.17 ± 0.03,  < .05); TNF-α protein expression was significantly increased in the SPE group (1.09 ± 0.12 versus 0.56 ± 0.03,  < .05); let-7a and TNF-α were significantly negatively correlated ( = -0.41,  < .05); the blood pressure and birth weight of the pregnant women in the SPE group and the control group were significantly different [systolic blood pressure (164.27 ± 4.62) mmHg versus (125.01 ± 2.23)] mmHg, diastolic blood pressure (109.24 ± 2.97) mmHg versus (75.94 ± 2.74) mmHg, neonatal birth weight (2507.02 ± 161.46) g versus (3592.12 ± 153.05) g,  < .05]; the expression of TNF-α in placental tissue of SPE group was significantly positively correlated with systolic and diastolic blood pressure ( = 0.93 and 0.89,  < .05).

Conclusion: let-7a may participate in the occurrence and development of SPE by negatively regulating the expression of TNF-α.
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http://dx.doi.org/10.1080/14767058.2021.1949276DOI Listing
July 2021

Assembly and optical properties of 1D helical bundles induced by triphenylamine, side chains and solvents in crystals.

Org Biomol Chem 2021 Jun;19(25):5555-5562

School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.

Two novel helical aromatic foldamer derivatives TPA-Q6(n-He) and TPA-Q6(i-Bu) were synthesized and characterized by introducing n-hexyloxy and isobutoxy side chains, respectively, and modifying quinoline amide foldamers with the triphenylamine (TPA) moiety at the N-terminus. X-ray single crystal diffraction analyses and theoretical calculations showed that the quinoline amide hexamer derivative TPA-Q6(i-Bu) enabled one-dimensional (1D) helical self-assembly in solids due to the synergistic interaction of the flexible π units of TPA, the steric hindrance of the alkyl groups, and methanol molecules. The chemical modification of the TPA end group significantly enhanced the fluorescence due to the intramolecular charge transfer. Steady-state fluorescence spectra and transient decay curves showed that TPA-Q6(i-Bu) forming a 1D helical assembly obviously exhibited a redshift of the emission wavelength and an increase of phosphorescence lifetimes in crystals compared with TPA-Q6(n-He) adopting the alternating insertion arrangement induced by the long alkyl chains. The results offered a new way to explore the intrinsic relationship among molecular structures, packing modes and optical properties for foldamers.
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http://dx.doi.org/10.1039/d1ob00389eDOI Listing
June 2021

Spectroscopic insight into the pH-dependent interactions between atmospheric heavy metals (Cu and Zn) and water-soluble organic compounds in PM.

Sci Total Environ 2021 May 20;767:145261. Epub 2021 Jan 20.

College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address:

Taking Cu and Zn as examples, the pH-dependent interactions between atmospheric heavy metals (AHMs) and water-soluble organic compounds (WSOCs) in PM were analyzed by a combination of UV-vis absorption, Fourier transform infrared (FTIR) spectroscopy and excitation-emission matrix (EEM) fluorescence spectroscopy coupled with parallel factor analysis (PARAFAC). We found metal-H ion exchange, complexation and electrostatic adsorption might occur between AHMs and WSOCs, and were generally enhanced with the increase of pH. Furthermore, these interactions were strengthened with the stepwise addition of [Cu] (from 0 to 500 μmol·L), but had a relatively slight change with the stepwise addition of [Zn] (from 0 to 500 μmol·L) generally. This indicated that the above interactions depended on the types and the concentrations of AHMs. Carboxyl, hydroxyl, carbonyl and aromatic structures of WSOCs were the major binding sites with AHMs. Humic acid-like substances were the dominant components of WSOCs binding with AHMs. The ratios of the apparent fluorescence quantum yields of the low and the high conjugation fractions of WSOCs (Q) declined by more than 28% as adding [Cu], indicating the formers had more strong complexing capacity with AHMs. AHMs might significantly impact the light absorption capacity and the wavelength dependence of WSOCs. The humification index (HIX) declined more than 15% as adding [Cu] at pH 5.6 and 7.5, indicating AHMs might weaken the oxidation capacity of WSOCs. These results implied the interactions between AHMs and WSOCs might play a profound role in atmospheric environment, human health, and global climate change.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145261DOI Listing
May 2021

Diastereoselective [3 + 1] Cyclization Reaction of Oxindolyl Azaoxyallyl Cations with Sulfur Ylides: Assembly of 3,3'-Spiro[β-lactam]-oxindoles.

Org Lett 2021 02 1;23(4):1451-1456. Epub 2021 Feb 1.

Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610052, China.

Oxindoles and β-lactams are attractive structural motifs because of their unique biological importance. However, the fusion of the two moieties featuring 3,3'-spirocyclic scaffolds is a challenging task in organic synthesis. Herein we designed a novel type of oxindole-based azaoxyallyl cation synthons, which could readily participate in the [3 + 1] cyclization with sulfur ylides. With this protocol, a collection of 3,3-spiro[β-lactam]-oxindoles were facilely produced in up to 94% yield with perfect diastereoselectivity.
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http://dx.doi.org/10.1021/acs.orglett.1c00130DOI Listing
February 2021

Highly Chemoselective [2+1] Annulation of α-Alkylidene Pyrazolones with α-Bromonitroalkenes: Synthesis of Pyrazolone-Based Vinylcyclopropanes and Computational Studies.

J Org Chem 2021 Feb 10;86(3):2582-2592. Epub 2021 Jan 10.

State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, People's Republic of China.

A highly chemoselective [2+1] annulation of α-alkylidene pyrazolones with α-bromonitroalkenes has been achieved under mild conditions. α-Alkylidene pyrazolones were unprecedentedly used as a C1 synthon to participate in annulation reactions, providing access to diverse vinylcyclopropane-based pyrazolone products. In addition, a spectrum of pharmaceutically interesting pyrazole-fused pyranone oximes could be rapidly obtained through a [2+1] annulation/rearrangement sequential process. Computational studies disclosed the origin of the observed chemoselectivity of the [2+1] cycloaddition.
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http://dx.doi.org/10.1021/acs.joc.0c02674DOI Listing
February 2021

Tumor Mutational Burden Is Polygenic and Genetically Associated with Complex Traits and Diseases.

Cancer Res 2021 03 8;81(5):1230-1239. Epub 2021 Jan 8.

Institute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.

Tumor mutational burden (TMB) is an emerging biomarker of response to immunotherapy in solid tumors. However, the extent to which variation in TMB between patients is attributable to germline genetic variation remains elusive. Here, using 7,004 unrelated patients of European descent across 33 cancer types from The Cancer Genome Atlas, we show that pan-cancer TMB is polygenic with approximately 13% of its variation explained by approximately 1.1 million common variants altogether. We identify germline variants that affect TMB in stomach adenocarcinoma through altering the expression levels of and . Further analyses provide evidence that TMB is genetically associated with complex traits and diseases, such as smoking, rheumatoid arthritis, height, and cancers, and some of the associations are likely causal. Overall, these results provide new insights into the genetic basis of somatic mutations in tumors and may inform future efforts to use genetic variants to stratify patients for immunotherapy. SIGNIFICANCE: This study provides evidence for a polygenic architecture of tumor mutational burden and opens an avenue for the use of whole-genome germline genetic variations to stratify patients with cancer for immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3459DOI Listing
March 2021

SnRK1 Phosphorylates and Destabilizes WRKY3 to Enhance Barley Immunity to Powdery Mildew.

Plant Commun 2020 07 9;1(4):100083. Epub 2020 Jun 9.

State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Innovation Academy for Seed Design, Beijing 100101, China.

Plants recognize pathogens and activate immune responses, which usually involve massive transcriptional reprogramming. The evolutionarily conserved kinase, Sucrose non-fermenting-related kinase 1 (SnRK1), functions as a metabolic regulator that is essential for plant growth and stress responses. Here, we identify barley SnRK1 and a WRKY3 transcription factor by screening a cDNA library. SnRK1 interacts with WRKY3 in yeast, as confirmed by pull-down and luciferase complementation assays. Förster resonance energy transfer combined with noninvasive fluorescence lifetime imaging analysis indicates that the interaction occurs in the barley nucleus. Transient expression and virus-induced gene silencing analyses indicate that WRKY3 acts as a repressor of disease resistance to the fungus. Barley plants overexpressing have enhanced fungal microcolony formation and sporulation. Phosphorylation assays show that SnRK1 phosphorylates WRKY3 mainly at Ser83 and Ser112 to destabilize the repressor, and WRKY3 non-phosphorylation-null mutants at these two sites are more stable than the wild-type protein. SnRK1-overexpressing barley plants display enhanced disease resistance to . Transient expression of SnRK1 reduces fungal haustorium formation in barley cells, which probably requires SnRK1 nuclear localization and kinase activity. Together, these findings suggest that SnRK1 is directly involved in plant immunity through phosphorylation and destabilization of the WRKY3 repressor, revealing a new regulatory mechanism of immune derepression in plants.
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http://dx.doi.org/10.1016/j.xplc.2020.100083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747994PMC
July 2020

Peripheral blood non-canonical small non-coding RNAs as novel biomarkers in lung cancer.

Mol Cancer 2020 11 12;19(1):159. Epub 2020 Nov 12.

Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, 1664 North Virginia Street, Reno, Nevada, 89557, USA.

One unmet challenge in lung cancer diagnosis is to accurately differentiate lung cancer from other lung diseases with similar clinical symptoms and radiological features, such as pulmonary tuberculosis (TB). To identify reliable biomarkers for lung cancer screening, we leverage the recently discovered non-canonical small non-coding RNAs (i.e., tRNA-derived small RNAs [tsRNAs], rRNA-derived small RNAs [rsRNAs], and YRNA-derived small RNAs [ysRNAs]) in human peripheral blood mononuclear cells and develop a molecular signature composed of distinct ts/rs/ysRNAs (TRY-RNA). Our TRY-RNA signature precisely discriminates between control, lung cancer, and pulmonary TB subjects in both the discovery and validation cohorts and outperforms microRNA-based biomarkers, which bears the diagnostic potential for lung cancer screening.
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http://dx.doi.org/10.1186/s12943-020-01280-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659116PMC
November 2020

Effects of different drying methods on the structures and functional properties of phosphorylated Antarctic krill protein.

J Food Sci 2020 Nov 18;85(11):3690-3699. Epub 2020 Oct 18.

School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.

Antarctic krill protein (AKP) was extracted from Antarctic krill by an alkali dissolution-isoelectric precipitation method and then it was phosphorylated with sodium tripolyphosphate. The phosphorylated Antarctic krill protein (P-AKP) powder was obtained by spray-drying (SD), freeze-drying (FD), and hot-air drying (AD), and the effects of these drying methods on the structures and functional properties of proteins were investigated. The P-AKP powder dried by SD had the best sensory performance, and its particle size was much smaller than that of FD and AD. Scanning electron microscope displayed a uniform particle size of SD powder and the particles were uniformly dispersed. X-ray diffraction analysis showed a higher crystallinity of SD sample than AD and FD. Differential scanning calorimeter analysis revealed that SD sample had the best thermal stability and less protein denaturation (ΔH = 210.80 J/g), followed by FD (ΔH = 80.48 J/g) and AD (ΔH = 73.94 J/g; P < 0.05). Fourier transform infrared showed that SD sample contained more protein secondary structure. Compared with SD, the phosphorylated group-related chemical bonds in FD and AD samples were partially destroyed. SD sample had the highest protein solubility, oil absorption capacity, emulsifying, and foaming activities than FD and AD (P < 0.05). Although FD had the highest water absorption capacity, sample prepared with AD had the worst functional performance. Therefore, different drying methods used for preparation of the P-AKP can affect its physicochemical and associated functional properties, and SD could be an appropriate drying method for the industrial mass production of P-AKP powders with better functionalities. PRACTICAL APPLICATION: The optimal drying method for preparing the phosphorylated Antarctic krill protein (P-AKP) powder was proved to be spray-drying (SD), because the physicochemical and functional properties were better for P-AKP dried by SD than the other drying methods. Hence, SD was recommended for the industrial mass production of P-AKP powders with better functionalities. This research can provide theoretical guidance for the further processing and utilization of P-AKP, and offer technical reference for food processing and preservation.
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http://dx.doi.org/10.1111/1750-3841.15503DOI Listing
November 2020

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611474PMC
October 2020

Overexpression of Fatty Acid 2-Hydroxylase is Associated with an Increased Sensitivity to Cisplatin by Ovarian Cancer and Better Prognoses.

Genet Test Mol Biomarkers 2020 Oct;24(10):632-640

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.

Recent discoveries indicate that the enzyme fatty acid 2-hydroxylase (FA2H) is associated with biological behavior and can be used for outcome prediction in several types of cancers. Such relevancy, however, between FA2H and ovarian cancer is not clear. Therefore, we carried out this study to compare the expression of FA2H with the clinicopathological features of ovarian cancer. Using the Oncomine database, we examined the expression levels of the gene in ovarian cancer tissues and their adjacent noncancerous tissues that had been evaluated by quantitative reverse-transcription polymerase chain reaction (PCR) analyses. We performed Kaplan-Meier curve analyses for overall survival and progression-free survival. In addition, relationships between the FA2H expression levels and clinicopathological features of ovarian cancer were analyzed. Finally, FA2H small interfering RNAs (siRNAs) or negative control siRNAs were separately transfected into OVCAR-3 and SKOV-3 cells to explore the downstream effects. From these results, expression was tested by real-time PCR, and the effects of FA2H expression levels on the sensitivity of ovarian cancer cells to cisplatin chemotherapy was evaluated using sulforhodamine B assays. Compared with the adjacent tissues, FA2H was expressed at lower levels in the ovarian cancer tissues. In survival analyses, decreased FA2H was significantly associated with poorer survival outcome in multiple subtypes of ovarian cancer. In addition, FA2H expression was significantly associated with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage, differentiation, lymph node involvement, tumor size, ascites, CA125 levels, and pelvic involvement. Knockdown of FA2H expression by siRNAs in the OVCAR-3 and SKOV-3 cell lines reduced their sensitivity to cisplatin, via modulation of GLI Family Zinc Finger 1 () gene expression. Our results demonstrate that FA2H is a biomarker for ovarian cancer and it may serve as a useful prognostic factor.
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http://dx.doi.org/10.1089/gtmb.2019.0259DOI Listing
October 2020

The interaction laws of atmospheric heavy metal ions and water-soluble organic compounds in PM based on the excitation-emission matrix fluorescence spectroscopy.

J Hazard Mater 2021 01 16;402:123497. Epub 2020 Jul 16.

College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

The excitation-emission matrix (EEM) fluorescence spectroscopy was used to characterize the fluorescence properties of water-soluble organic compounds (WSOCs) in PM coupled with parallel factor analysis (PARAFAC). Three main components of WSOCs were extracted from PM, i.e., humic-like (fulvic acid-like and humic acid-like) substances (HULIS), and soluble microbial by-product-like or aromatic protein-like, respectively. A fluorescence quenching experiment was designed to systematically analyze the interaction laws of atmospheric heavy metal ions and WSOCs in PM. Our study revealed HULIS, especially the humic acid-like substances, might be principal substances binding with metal ions and the strength of interactions was related to the types and concentrations of metal ions. Furthermore, EEM was a powerful tool to understand the interaction laws of atmospheric heavy metal ions and WSOCs in PM. This work implied that the interactions of atmospheric heavy metal ions and WSOCs might directly or indirectly play a significant role in atmospheric environment and public health.
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http://dx.doi.org/10.1016/j.jhazmat.2020.123497DOI Listing
January 2021

Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders.

Mol Psychiatry 2021 06 12;26(6):2070-2081. Epub 2020 May 12.

Institute for Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia.

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium-schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genome-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. We show that decreased expression of VPS29 in the brain may increase risk to SCZ only and increased expression of CSE1L is associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7 in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.
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http://dx.doi.org/10.1038/s41380-020-0705-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657979PMC
June 2021

Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data.

Nat Commun 2020 04 28;11(1):2061. Epub 2020 Apr 28.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Promoter-anchored chromatin interactions (PAIs) play a pivotal role in transcriptional regulation. Current high-throughput technologies for detecting PAIs, such as promoter capture Hi-C, are not scalable to large cohorts. Here, we present an analytical approach that uses summary-level data from cohort-based DNA methylation (DNAm) quantitative trait locus (mQTL) studies to predict PAIs. Using mQTL data from human peripheral blood ([Formula: see text]), we predict 34,797 PAIs which show strong overlap with the chromatin contacts identified by previous experimental assays. The promoter-interacting DNAm sites are enriched in enhancers or near expression QTLs. Genes whose promoters are involved in PAIs are more actively expressed, and gene pairs with promoter-promoter interactions are enriched for co-expression. Integration of the predicted PAIs with GWAS data highlight interactions among 601 DNAm sites associated with 15 complex traits. This study demonstrates the use of mQTL data to predict PAIs and provides insights into the role of PAIs in complex trait variation.
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http://dx.doi.org/10.1038/s41467-020-15587-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188843PMC
April 2020

Palladium-catalysed decarboxylative annulations of vinylethylene carbonates leading to diverse functionalised heterocycles.

Org Biomol Chem 2020 05 24;18(19):3638-3648. Epub 2020 Apr 24.

Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, PR China.

Heterocycles are the fundamental structural motifs found in natural products and biologically active compounds. The construction of these structures is therefore an important task in organic chemistry. Vinylethylene carbonates (VECs) are versatile building blocks that can undergo transition metal catalysed decarboxylation to enable various kinds of interesting transformations. This review provides an overview of the significant achievements of VECs in palladium-catalysed annulations over the past five years. The flexible reactivity of VECs is demonstrated by various [3 + 2], [5 + n] and other types of annulations, which could offer powerful protocols for accessing diverse functionalised heterocycles.
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http://dx.doi.org/10.1039/d0ob00458hDOI Listing
May 2020

Mechanistic study of cellobiose conversion to 5-hydroxymethylfurfural catalyzed by a Brønsted acid with counteranions in an aqueous solution.

Phys Chem Chem Phys 2020 May 20;22(17):9349-9361. Epub 2020 Apr 20.

College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, P. R. China.

The fundamental understanding of the cooperativity of a Brønsted acid together with its anion for cellulose conversion in an aqueous solution is limited at present, in which cellobiose has usually been regarded as a bridge that connects monosaccharides and cellulose. The mechanism of β-cellobiose conversion to 5-hydroxymethylfurfural (HMF) catalyzed by a Brønsted acid (HO) accompanied by counteranions in an aqueous solution has been studied using quantum chemical calculations at the M06-2X/6-311++G(d,p) level under a polarized continuum model (PCM-SMD). For the formation of the first HMF from cellobiose, there are three reaction pathways, i.e., through cellobiulose and glycosyl-HMF (C/H), through cellobiulose and fructose (C/F/H), and through glucose (C/G/H). For these three reaction pathways, the rate-determining steps are associated with the intramolecular [1,2]-H shift in the aldose-ketose tautomerization. C/H is the thermodynamically predominant pathway, while C/G/H is the kinetically dominant pathway. From cellobiose, the origin of the first HMF results kinetically from a small proportion of both C/H and C/F/H and from a large proportion of C/G/H. For the role of the counteranion in the catalytic activity of HO, the halide anions (Cl and Br) act as promoters, whereas both NO anions and carboxylate-containing anions behave as inhibitors. The roles of these anions in β-cellobiose conversion to HMF can be correlated with their electrostatic potential and atomic number, which may cause a decrease in the relative enthalpy energy and the value of entropy on interacting with the cation moiety. These insights may advance the novel design of sustainable conversion systems for cellulose conversion into HMF.
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http://dx.doi.org/10.1039/c9cp06944eDOI Listing
May 2020

Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease.

Nat Commun 2020 03 6;11(1):1238. Epub 2020 Mar 6.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
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http://dx.doi.org/10.1038/s41467-020-15065-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060318PMC
March 2020

Tissue specific regulation of transcription in endometrium and association with disease.

Hum Reprod 2020 02;35(2):377-393

The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.

Study Question: Are genetic effects on endometrial gene expression tissue specific and/or associated with reproductive traits and diseases?

Summary Answer: Analyses of RNA-sequence data and individual genotype data from the endometrium identified novel and disease associated, genetic mechanisms regulating gene expression in the endometrium and showed evidence that these mechanisms are shared across biologically similar tissues.

What Is Known Already: The endometrium is a complex tissue vital for female reproduction and is a hypothesized source of cells initiating endometriosis. Understanding genetic regulation specific to, and shared between, tissue types can aid the identification of genes involved in complex genetic diseases.

Study Design, Size, Duration: RNA-sequence and genotype data from 206 individuals was analysed and results were compared with large publicly available datasets.

Participants/materials, Setting, Methods: RNA-sequencing and genotype data from 206 endometrial samples was used to identify the influence of genetic variants on gene expression, via expression quantitative trait loci (eQTL) analysis and to compare these endometrial eQTLs with those in other tissues. To investigate the association between endometrial gene expression regulation and reproductive traits and diseases, we conducted a tissue enrichment analysis, transcriptome-wide association study (TWAS) and summary data-based Mendelian randomisation (SMR) analyses. Transcriptomic data was used to test differential gene expression between women with and without endometriosis.

Main Results And The Role Of Chance: A tissue enrichment analysis with endometriosis genome-wide association study summary statistics showed that genes surrounding endometriosis risk loci were significantly enriched in reproductive tissues. A total of 444 sentinel cis-eQTLs (P < 2.57 × 10-9) and 30 trans-eQTLs (P < 4.65 × 10-13) were detected, including 327 novel cis-eQTLs in endometrium. A large proportion (85%) of endometrial eQTLs are present in other tissues. Genetic effects on endometrial gene expression were highly correlated with the genetic effects on reproductive (e.g. uterus, ovary) and digestive tissues (e.g. salivary gland, stomach), supporting a shared genetic regulation of gene expression in biologically similar tissues. The TWAS analysis indicated that gene expression at 39 loci is associated with endometriosis, including five known endometriosis risk loci. SMR analyses identified potential target genes pleiotropically or causally associated with reproductive traits and diseases including endometriosis. However, without taking account of genetic variants, a direct comparison between women with and without endometriosis showed no significant difference in endometrial gene expression.

Large Scale Data: The eQTL dataset generated in this study is available at http://reproductivegenomics.com.au/shiny/endo_eqtl_rna/. Additional datasets supporting the conclusions of this article are included within the article and the supplementary information files, or are available on reasonable request.

Limitations, Reasons For Caution: Data are derived from fresh tissue samples and expression levels are an average of expression from different cell types within the endometrium. Subtle cell-specifc expression changes may not be detected and differences in cell composition between samples and across the menstrual cycle will contribute to sample variability. Power to detect tissue specific eQTLs and differences between women with and without endometriosis was limited by the sample size in this study. The statistical approaches used in this study identify the likely gene targets for specific genetic risk factors, but not the functional mechanism by which changes in gene expression may influence disease risk.

Wider Implications Of The Findings: Our results identify novel genetic variants that regulate gene expression in endometrium and the majority of these are shared across tissues. This allows analysis with large publicly available datasets to identify targets for female reproductive traits and diseases. Much larger studies will be required to identify genetic regulation of gene expression that will be specific to endometrium.

Study Funding/competing Interest(s): This work was supported by the National Health and Medical Research Council (NHMRC) under project grants GNT1026033, GNT1049472, GNT1046880, GNT1050208, GNT1105321, GNT1083405 and GNT1107258. G.W.M is supported by a NHMRC Fellowship (GNT1078399). J.Y is supported by an ARC Fellowship (FT180100186). There are no competing interests.
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http://dx.doi.org/10.1093/humrep/dez279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048713PMC
February 2020

Diminished 25-OH vitamin D levels and vitamin D receptor variants are associated with susceptibility to type 2 diabetes with coronary artery diseases.

J Clin Lab Anal 2020 Apr 3;34(4):e23137. Epub 2019 Dec 3.

Department of Peripheral Vascular Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Background: Role of plasma vitamin D and genetic variants of its receptor (VDR) in susceptibility to different diseases has been documented. Various studies in different populations have been highlighted strong associations with diabetes and cardiovascular diseases. Vitamin D deficiency has been linked with the development of type 2 diabetes (T2D) and the onset of coronary artery diseases (CAD). However, the role of vitamin D in predisposition to CAD in patients with T2D is ill-defined.

Materials And Methods: We enrolled 674 Chinese T2D patients, and based on clinical phenotype, patients were further categorized into patients with (n = 138) or without coronary artery disease (n = 536). Five hundred twenty-one healthy subjects from similar geographical areas, free from diabetic or coronary disorders, were enrolled as controls. Serum levels of 25-OH vitamin D were quantified by ELISA. Common VDR (FokI, TaqI, BsmI, and ApaI) polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results: Patients with T2D displayed lower levels of 25-OH vitamin D compared with healthy controls. Furthermore, T2D patients with CAD clinical phenotype had the lowest levels of vitamin D. Prevalence of FokI and TaqI mutants was significantly higher in diabetic patients when compared to controls. Interestingly, Tt genotype was more frequent in the artery disease group in comparison with T2D patients without heart involvement. Combined analysis of VDR polymorphisms and serum levels of vitamin D revealed a significant role in predisposition to T2D with or without CAD.

Conclusions: Lower vitamin D levels and variants of VDR polymorphisms (FokI and TaqI) are associated with susceptibility to T2D and clinical manifestation.
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http://dx.doi.org/10.1002/jcla.23137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171300PMC
April 2020

A resource-efficient tool for mixed model association analysis of large-scale data.

Nat Genet 2019 12 25;51(12):1749-1755. Epub 2019 Nov 25.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test statistics and hence to spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we develop an MLM-based tool (fastGWA) that controls for population stratification by principal components and for relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrate by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then apply fastGWA to 2,173 traits on array-genotyped and imputed samples from 456,422 individuals and to 2,048 traits on whole-exome-sequenced samples from 46,191 individuals in the UKB.
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http://dx.doi.org/10.1038/s41588-019-0530-8DOI Listing
December 2019

Cortical thickness lateralization and its relation to language abilities in children.

Dev Cogn Neurosci 2019 10 22;39:100704. Epub 2019 Aug 22.

Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

The humans' brain asymmetry is observed in the early stages of life and known to change further with age. The developmental trajectory of such an asymmetry has been observed for language, as one of the most lateralized cognitive functions. However, it remains unclear how these age-related changes in structural asymmetry are related to changes in language performance. We collected longitudinal structural magnetic resonance imaging data of children from 5 to 6 years to investigate structural asymmetry development and its linkage to the improvement of language comprehension abilities. Our results showed substantial changes of language performance across time, which were associated with changes of cortical thickness asymmetry in the triangular part of the inferior frontal gyrus (IFG), constituting a portion of Broca's area. This suggests that language improvement is influenced by larger cortical thinning in the left triangular IFG compared to the right. This asymmetry in children's brain at age 5 and 6 years was further associated with the language performance at 7 years. To our knowledge, this is the first longitudinal study to demonstrate that children's improvement in sentence comprehension seems to depend on structural asymmetry changes in the IFG, further highlighting its crucial role in language acquisition.
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http://dx.doi.org/10.1016/j.dcn.2019.100704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892251PMC
October 2019

High-Efficiency Rescue of Equine Infectious Anemia Virus from a CMV-Driven Infectious Clone.

Virol Sin 2019 12 2;34(6):725-728. Epub 2019 Aug 2.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of the Chinese Academy of Agricultural Sciences, Harbin, 150069, China.

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http://dx.doi.org/10.1007/s12250-019-00153-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888787PMC
December 2019

Association of insulin, C-peptide and blood lipid patterns in patients with impaired glucose regulation.

BMC Endocr Disord 2019 Jul 15;19(1):75. Epub 2019 Jul 15.

Department of Endocrinology, Ninth Hospital of Xi'an, No. 151 South Second Ring Road, Xi'an, Shaanxi, 710054, China.

Background: To investigate any associations between blood glucose (BG) and lipid levels in patients with different glucose tolerance statuses, including type 2 diabetes (T2DM) and impaired glucose regulation (IGR) cases as well as normal glucose tolerance (NGT) individuals.

Methods: A total of 354 participants were recruited to this study including 174 in the T2DM group, 112 in the IGR group and 68 in the NGT group. We compared BG, insulin and C-peptide (CP), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) serum levels during a 3 h oral glucose tolerance test (OGTT) in the 3 groups.

Results: Basic overall HbA1c serum concentration percentages were 5.52, 6.33 and 9.76% for the NTG, IGR and T2DM cases. During the OGTT, insulin secretion in the IGR group was almost double that of the T2DM group. CP levels were highest in the IGR patients and OGTT related BG concentrations were highest in the T2DM group followed by IGR, but in the IGR group hyperglycemia was less pronounced than in T2DM patients (P <  0.001). Compared to the NGT group, TC, TG and LDL-C serum concentrations were significantly higher (P ≤ 0.001) and HDL-C concentrations were significantly lower (P ≤ 0.001) in IGR and T2DM cases compared to the NTG group.

Conclusions: IGR led to similar unfavorable blood lipid patterns compared with T2DM patients and an imbalance of insulin and CP serum concentrations during an OGTT.
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http://dx.doi.org/10.1186/s12902-019-0400-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631747PMC
July 2019

OSCA: a tool for omic-data-based complex trait analysis.

Genome Biol 2019 05 28;20(1):107. Epub 2019 May 28.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.

The rapid increase of omic data has greatly facilitated the investigation of associations between omic profiles such as DNA methylation (DNAm) and complex traits in large cohorts. Here, we propose a mixed-linear-model-based method called MOMENT that tests for association between a DNAm probe and trait with all other distal probes fitted in multiple random-effect components to account for unobserved confounders. We demonstrate by simulations that MOMENT shows a lower false positive rate and more robustness than existing methods. MOMENT has been implemented in a versatile software package called OSCA together with a number of other implementations for omic-data-based analyses.
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http://dx.doi.org/10.1186/s13059-019-1718-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537380PMC
May 2019

Equine Influenza Virus in Asia: Phylogeographic Pattern and Molecular Features Reveal Circulation of an Autochthonous Lineage.

J Virol 2019 07 14;93(13). Epub 2019 Jun 14.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China

Equine influenza virus (EIV) causes severe acute respiratory disease in horses. Currently, the strains belonging to the H3N8 subtype are divided into two clades, Florida clade 1 (FC1) and Florida clade 2 (FC2), which emerged in 2002. Both FC1 and FC2 clades were reported in Asian and Middle East countries in the last decade. In this study, we described the evolution, epidemiology, and molecular characteristic of the EIV lineages, with focus on those detected in Asia from 2007 to 2017. The full genome phylogeny showed that FC1 and FC2 constituted separate and divergent lineages, without evidence of reassortment between the clades. While FC1 evolved as a single lineage, FC2 showed a divergent event around 2004 giving rise to two well-supported and coexisting sublineages, European and Asian. Furthermore, two different spread patterns of EIV in Asian countries were identified. The FC1 outbreaks were caused by independent introductions of EIV from the Americas, with the Asian isolates genetically similar to the contemporary American lineages. On the other hand, the FC2 strains detected in Asian mainland countries conformed to an autochthonous monophyletic group with a common ancestor dated in 2006 and showed evidence of an endemic circulation in a local host. Characteristic aminoacidic signature patterns were detected in all viral proteins in both Asian-FC1 and FC2 populations. Several changes were located at the top of the HA1 protein, inside or near antigenic sites. Further studies are needed to assess the potential impact of these antigenic changes in vaccination programs. The complex and continuous antigenic evolution of equine influenza viruses (EIVs) remains a major hurdle for vaccine development and the design of effective immunization programs. The present study provides a comprehensive analysis showing the EIV evolutionary dynamics, including the spread and circulation within the Asian continent and its relationship to global EIV populations over a 10-year period. Moreover, we provide a better understanding of EIV molecular evolution in Asian countries and its consequences on the antigenicity. The study underscores the association between the global horse movement and the circulation of EIV in this region. Understanding EIV evolution is imperative in order to mitigate the risk of outbreaks affecting the horse industry and to help with the selection of the viral strains to be included in the formulation of future vaccines.
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http://dx.doi.org/10.1128/JVI.00116-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580976PMC
July 2019
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