Publications by authors named "Yanyan Ma"

135 Publications

Lack of association of FKBP5 SNPs and haplotypes with susceptibility and treatment response phenotypes in Han Chinese with major depressive disorder: A pilot case-control study (STROBE).

Medicine (Baltimore) 2021 Sep;100(36):e26983

University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.

Abstract: The identification of single-nucleotide polymorphisms (SNPs) in genes putatively related to pathophysiological processes in major depressive disorder (MDD) might improve both diagnosis and personalized treatment strategies eventually leading to more effective interventions. Considering the important role of the glucocorticoid receptor and the related FK506 binding protein 51 (FKBP51) in the pathophysiology of MDD, we aimed to investigate putative associations between variants of FKBP5, the coding gene of FKBP51, with antidepressant treatment resistance and MDD susceptibility.Nine common SNPs of the FKBP5 gene prioritized based on location and, putative or known functions were genotyped in Han Chinese population, including MDD patients with or without antidepressant-treatment resistance and healthy controls. Associations of FKBP5 SNPs with MDD susceptibility and treatment response were examined in the whole group of MDD patients, as well as in subgroups stratified by antidepressant treatment resistance, compared with healthy controls.In total, 181 Han Chinese patients with MDD and 80 healthy controls were recruited. No significant SNP or haplotype associations were observed in the whole patient group. There were nominal significant differences both for the haplotype block with SNPs in strong LD (r2 > 0.8, P = .040) and haplotype block with SNPs in moderate LD (r2 > 0.1, P = .017) between the haplotype distributions of patients with antidepressant treatment resistance (n = 81) and healthy controls, but both significances did not survive multiple testing correction. Furthermore, no specific haplotype could be observed causing a significant difference in any combination between all comparisons.No associations were observed of FKBP5 variants with MDD or antidepressant treatment response. The lack of associations might be due to the relatively small sample size of this study (power ranged from 0.100 to 0.752). A follow-up study will need larger, better phenotyped, and more homogeneous samples to draw a definitive conclusion regarding the involvement of this gene in MDD.
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http://dx.doi.org/10.1097/MD.0000000000026983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428740PMC
September 2021

Effect of Eccentric Calcification of an Aortic Valve on the Implant Depth of a Venus-A Prosthesis During Transcatheter Aortic Valve Replacement: A Retrospective Study.

Front Physiol 2021 6;12:718065. Epub 2021 Aug 6.

Department of Cardiovascular Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China.

Object: Our goal was to assess the implant depth of a Venus-A prosthesis during transcatheter aortic valve replacement (TAVR) when the areas of eccentric calcification were distributed in different sections of the aortic valve.

Methods: A total of 53 patients with eccentric calcification of the aortic valve who underwent TAVR with a Venus-A prosthesis from January 2018 to November 2019 were retrospectively analyzed. The patients were divided into three groups (A, B, and C) according to the location of the eccentric calcification, which was determined by preprocedural computerized tomography angiography (CTA) images. The prosthesis release process and position were evaluated by contrast aortography during TAVR, and the differences in valve implant depths were compared among the three groups. The effects of different aortic root structures and procedural strategies on prosthesis implant depth were analyzed.

Results: Eleven patients had eccentric calcification in region A; 19 patients, in region B; and 23 patients, in region C. The patients with eccentric calcification in region B had a higher risk of prosthesis migration (10.5% upward and 21.1% downward), and the position of the prosthesis after TAVR in group B was the deepest among the three groups. When eccentric calcification was located in region A or C, the prosthesis was released at the standard position with more stability, and the location of the prosthesis was less deep after TAVR (region A: 4.12 ± 3.4 mm; region B: 10.2 ± 5.3 mm; region C: 8.4 ± 4.0 mm; region A vs. region B, = 0.0004; region C vs. region B; and = 0.0360). In addition, the left ventricular outflow tract (LVOT) ( = 0.0213) and aortic root angulation ( = 0.0263) also had a significant effect on implant depth in the aortic root structure of the patients. The prosthesis size was 28.3 ± 2.4 in the deep implant group and 26.4 ± 2.0 in the appropriate implant group ( = 0.0068).

Conclusion: The implant depth of the Venus-A prosthesis is closely related to the distribution of eccentric calcification in the aortic valve during TAVR. Surgeons should adjust the surgical strategy according to aortic root morphology to prevent prosthesis migration.
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http://dx.doi.org/10.3389/fphys.2021.718065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378511PMC
August 2021

The associations of CNR1 SNPs and haplotypes with vulnerability and treatment response phenotypes in Han Chinese with major depressive disorder: A case-control association study.

Mol Genet Genomic Med 2021 Aug 6:e1752. Epub 2021 Aug 6.

Tianjin Mental Health Institute, Tianjin Anding Hospital, Tianjin, China.

Background: Understanding how genetic polymorphisms are associated with the pathophysiology of major depressive disorder (MDD) may aid in diagnosis and the development of personalized treatment strategies. CNR1 is the gene coding Cannabinoid type 1 receptor which is highly involved in emotional processing and in regulating neurotransmitter releases. We aimed to investigate the associations of CNR1 single-nucleotide polymorphisms (SNPs) with MDD susceptibility and treatment response.

Methods: The study reported data on 181 Han Chinese with MDD and 80 healthy controls. The associations of CNR1 genetic polymorphisms with MDD susceptibility and treatment response were examined, wherein the MDD patients were subgrouped further by responding to antidepressant treatment, compared with healthy controls separately.

Results: The CNR1 SNPs rs806367 and rs6454674 and haplotype C-T-T-C of rs806366, rs806367, rs806368, and rs806370 were associated with increased susceptibility for MDD and antidepressant treatment resistance, but the association was not detected in other SNPs or the haplotype block of rs806368 and rs806370.

Conclusion: The CNR1 is a promising candidate for the genetic association study of MDD. Larger and well-characterized samples are required to confirm the genetic association of CNR1 with MDD because of the limitations such as relatively small sample size and lack of information for correcting confounding factors.
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http://dx.doi.org/10.1002/mgg3.1752DOI Listing
August 2021

Thermal-triggered packing of lipophilic NIR dye IR780 in hepatitis B core at critical ionic strength and cargo-host ratio for improved stability and enhanced cancer phototherapy.

Biomaterials 2021 09 21;276:121035. Epub 2021 Jul 21.

State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China. Electronic address:

Virus-like particles (VLPs) holding internal cavity with diameter from tens up to one hundred nanometers are attractive platform for drug delivery. Nevertheless, the packing of drugs in the nanocage mainly relies on complicated disassembly-reassembly process. In this study, hepatitis B core protein (HBc) VLPs which can withstand temperature up to 90 °C was employed as carrier to load a lipophilic near infrared dye IR780. It was found that an attaching-dis-atching-diffusing process was involved for the entering of IR780 in the cavity of HBc. The first two steps were associated with the electrostatic interactions between oppositely charged HBc and IR780, which was critically manipulated by ionic strength and HBc/IR780 mass ratio at which they were mixed; while the diffusion of IR780 across the shell of HBc showed a temperature-dependent manner that can be triggered by thermal induced pore-opening of the HBc capsid. At optimized condition, about 1055 IR780 molecules were encapsulated in each HBc by simply mixing them for 10 min at 60 °C. Compared with free IR780, the HBc-IR780 particles showed significantly improved aqueous and photostability, as well as enhanced photothermal and photodynamic performance for cancer therapy. This study provides a novel drug loading strategy and nanomemedicine for cancer phototherapies.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121035DOI Listing
September 2021

Protein Phosphatase 4 Promotes Hepatocyte Lipoapoptosis by Regulating RAC1/MLK3/JNK Pathway.

Oxid Med Cell Longev 2021 15;2021:5550498. Epub 2021 Jun 15.

The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.

Lipotoxicity-induced apoptosis, also referred to as lipoapoptosis, is one of the important initial factors promoting the progression from hepatosteatosis to nonalcoholic steatohepatitis (NASH). Saturated free fatty acids (SFAs), which are increased significantly in NASH, are directly hepatotoxic which induce hepatocyte lipoapoptosis. Previously, we reported that protein phosphatase 4 (PP4) was a novel regulator of hepatic insulin resistance and lipid metabolism, but its role in hepatic lipoapoptosis remains unexplored. In this study, we found out that PP4 was upregulated in the livers of western diet-fed-induced NASH mice and SFA-treated murine primary hepatocytes and HepG2 cells. In addition, we found for the first time that suppression of PP4 decreased SFA-induced JNK activation and expression of key modulators of hepatocyte lipoapoptosis including p53-upregulated modulator of apoptosis (PUMA) and Bcl-2-interacting mediator (Bim) and reduced hepatocyte lipoapoptosis level as well both in vitro and in vivo. Further study revealed that PP4 induced JNK activation and lipoapoptosis-related protein expression by regulating the RAC1/MLK3 pathway instead of the PERK/CHOP pathway. The effects of palmitate-treated and PP4-induced lipoapoptosis pathway activation were largely abolished by RAC1 inhibition. Moreover, we identified that PP4 interacted with RAC1 and regulated GTPase activity of RAC1. In conclusion, these results demonstrated that PP4 was a novel regulator of hepatocyte lipoapoptosis and mediated hepatocyte lipoapoptosis by regulating the RAC1/MLK3/JNK signaling pathway. Our finding provided new insights into the mechanisms of this process.
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http://dx.doi.org/10.1155/2021/5550498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221892PMC
June 2021

Application of three-dimensional transesophageal echocardiography in preoperative evaluation of transcatheter aortic valve replacement.

BMC Cardiovasc Disord 2021 06 28;21(1):315. Epub 2021 Jun 28.

Department of Cardiovascular Surgery, Xijing Hospital, Air Force Medical University, 127. Changle West Rd, Xi'an, 710032, China.

Background: Our goal was to determine the accuracy of 3-dimensional transesophageal echocardiography (3D-TEE) compared with that of computed tomography (CT) in the preoperative evaluation for transcatheter aortic valve replacement (TAVR) when the errors caused by inconsistent software and method have been eliminated and the representativeness of the sample has been improved. We also investigated the influence of aortic root calcification on the accuracy of 3D-TEE in aortic annulus evaluations.

Methods: Part I: 45 of 233 patients who underwent TAVR in the department of cardiovascular surgery at the Xijing hospital from January 2016 to August 2019 were studied retrospectively. Materialise Mimics software and the multiplanar reconstruction method were used for evaluation, based on 3D-TEE and CT. The annulus area-derived diameter, the annulus perimeter-derived diameter (Dp), the annulus mean diameter, the left ventricular outflow tract Dp diameter, the sinotubular junction (STJ) diameter-Dp, and the aortic sinus diameter were compared and analyzed. Part II: 31 of 233 patients whose 3D-TEE and CT data were well preserved and in the required format were included. HU450 and HU850 were used as indicators to measure the severity of calcification. The Spearman rank correlation and Linear regression were used to analyze the correlation between aortic root calcification and the accuracy of 3D-TEE in aortic annulus measurement.

Results: The measurement results based on 3D-TEE were significantly lower than those obtained using CT (P < 0.05), except for the STJ diameter-Dp in diastole (P = 0.11). The correlation coefficient of the two groups was 0.699-0.954 (P < 0.01), which also indicated a significant correlation between the two groups. A Bland-Altman plot showed that the ordinate values were mostly within the 95% consistency limit; the consistency of the two groups was good. By establishing the linear regression equation, the two groups can be inferred from each other. The Spearman rank correlation analysis and the Linear regression analysis showed that the influence of aortic calcification on the accuracy of the 3D-TEE annulus evaluation was limited.

Conclusions: Although an evaluation based on 3D-TEE underestimated the results, we can deduce CT results from 3D-TEE because the two methods exhibit considerable correlation and consistency.

Trial Registration: Name: Surgery and Transcatheter Intervention for Structural Heart Diseases. Number: NCT02917980. URL: https://clinicaltrials.gov/ct2/results?term=NCT02917980 .
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http://dx.doi.org/10.1186/s12872-021-02101-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237423PMC
June 2021

Pyruvate dehydrogenase deficiency disease detected by the enzyme activity of peripheral leukocytes.

Mol Genet Genomic Med 2021 Aug 22;9(8):e1728. Epub 2021 Jun 22.

ChinovoLaboratory, Beijing, P. R. China.

Background: Pyruvate dehydrogenase complex (PDHC) deficiency is a common neurodegenerative disease associated with abnormal mitochondrial energy metabolism. The diagnosis of PDHC is difficult because of the lack of a rapid, accurate, and cost-effective clinical diagnostic method.

Methods: A 4-year-old boy was preliminarily diagnosed with putative Leigh syndrome based on the clinical presentation. PDHC activity in peripheral blood leukocytes and a corresponding gene analysis were subsequently undertaken. Sodium pyruvate 1- C was used for the analysis of PDHC activity in peripheral leukocytes. The genes encoding PDHC were then scanned for mutations.

Results: The results showed that the corresponding PDHC activity was dramatically decreased to 10.5 nmol/h/mg protein as compared with that of healthy controls (124.6 ± 7.1 nmol/h/mg). The ratio of PDHC to citrate synthase was 2.1% (control: 425.3 ± 27.1). The mutation analysis led to the identification of a missense mutation, NM_000284.4:g214C>T, in exon 3 of PDHC.

Conclusion: The peripheral blood leukocyte PDHC activity assay may provide a practical enzymatic diagnostic method for PDHC-related mitochondrial diseases.
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http://dx.doi.org/10.1002/mgg3.1728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404224PMC
August 2021

Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer.

Front Oncol 2021 2;11:647559. Epub 2021 Jun 2.

Department of Scientific Research Office, Affiliated Hospital of Qinghai University, Xining, China.

Lactate has been observed to fuel TCA cycle and is associated with cancer progression in human lung cancer, the leading cause of cancer deaths worldwide, but the effect of lactate on lung cancer metabolism is rarely reported. In this study, disordered metabolism in non-small cell lung cancer was demonstrated by increased G6PD and SDHA protein levels immunofluorescence, and up-regulated lactate dehydrogenase was found to be associated with poor prognosis. Then flow cytometry and Seahorse XFe analyzer were utilized to detect the effect of lactate on glycolysis and mitochondrial function in non-small cell lung cancer cells. The results show that in non-small cell lung cancer cells lactate attenuates glucose uptake and glycolysis while maintaining mitochondrial homeostasis as indicated by improved mitochondrial membrane potential. Further exploration found that mRNA levels of glycolytic enzymes (, ) and TCA cycle enzymes (, ) are respectively down-regulated and up-regulated by lactate, and increased histone lactylation was observed in promoters of and chromatin immunoprecipitation assay. Taken together, the above results indicate that lactate modulates cellular metabolism at least in part through histone lactylation-mediated gene expression in non-small cell lung cancer.
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http://dx.doi.org/10.3389/fonc.2021.647559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208031PMC
June 2021

Three-dimensional printing for heart diseases: clinical application review.

Biodes Manuf 2021 Apr 30:1-13. Epub 2021 Apr 30.

Department of Cardiovascular Surgery, Xijing Hospital, Airforce Medical University, Xi'an, 710032 China.

Heart diseases remain the top threat to human health, and the treatment of heart diseases changes with each passing day. Convincing evidence shows that three-dimensional (3D) printing allows for a more precise understanding of the complex anatomy associated with various heart diseases. In addition, 3D-printed models of cardiac diseases may serve as effective educational tools and for hands-on simulation of surgical interventions. We introduce examples of the clinical applications of different types of 3D printing based on specific cases and clinical application scenarios of 3D printing in treating heart diseases. We also discuss the limitations and clinically unmet needs of 3D printing in this context.
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http://dx.doi.org/10.1007/s42242-021-00125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085656PMC
April 2021

Generation of an induced pluripotent stem cell line SDQLCHi026-A from a hereditary tyrosinemia type I patient carrying compound heterozygote mutations in FAH gene.

Stem Cell Res 2021 05 9;53:102331. Epub 2021 Apr 9.

Pediatric Research Institute, Qilu Children's Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, China. Electronic address:

Here we describe the generation of induced pluripotent stem cells (iPSCs) from a patient diagnosed as hereditary tyrosinemia type I (HT1) caused by FAH gene mutation. Induced pluripotent stem cells (iPSCs) were developed using non-integrating episomal vectors containing OCT4, SOX2, KLF4, BCL-XL and MYC. The established iPSC line (SDQLCHi026-A) displayed pluripotent cell morphology, high expression levels of pluripotency markers, differentiation potential in vitro, normal karyotype, and remaining the original FAH gene mutation.
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http://dx.doi.org/10.1016/j.scr.2021.102331DOI Listing
May 2021

Generation of two induced pluripotent stem cell lines from patients with X-linked Alport syndrome.

Stem Cell Res 2021 05 17;53:102343. Epub 2021 Apr 17.

Department of Nephrology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address:

Mutations in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome (XLAS). In this study, we generated two human induced pluripotent stem cell (iPSC) lines from two male patients carrying mutation c.796C > T (p.R266X) in COL4A5 gene. The two iPSC lines retain the original mutation, possess normal karyotypes, express pluripotency markers and bear differentiation potential.
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http://dx.doi.org/10.1016/j.scr.2021.102343DOI Listing
May 2021

Generation of an induced pluripotent stem cell line SDUBMSi005-A from a patient with double primary gastric and colon carcinoma.

Stem Cell Res 2021 05 27;53:102253. Epub 2021 Feb 27.

Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address:

It has been reported that mutations in CDH1 gene are associated with genetic susceptibility to colon, stomach, breast and prostate cancers. Here, an induced pluripotent stem cell (iPSC) line from a patient with double primary gastric and colon carcinoma carrying germline mutation (c. 1679C > G) in CDH1 gene was generated. The iPSC line had normal karyotype, expressed pluripotent markers and had ability to generate three germ layers.
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http://dx.doi.org/10.1016/j.scr.2021.102253DOI Listing
May 2021

Generation and characterization of an integration-free iPSC line SDUBMSi006-A from a patient with Alport syndrome caused by COL4A3 gene mutations.

Stem Cell Res 2021 04 11;52:102237. Epub 2021 Feb 11.

Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address:

Alport syndrome (AS) is a hereditary kidney disease caused by mutations in COL4A3, COL4A4, or COL4A5 genes. Here we report the generation of an induced pluripotent stem cell line (iPSC) from an AS patient carrying compound heterozygote mutations (c.4243G > C and c.4216G > A) in COL4A3 gene using non-integrative reprogramming technology. The established iPSC line demonstrates hESC morphology, expresses pluripotency markers, has normal karyotype, and is capable of differentiating into all three germ layers in vitro.
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http://dx.doi.org/10.1016/j.scr.2021.102237DOI Listing
April 2021

Dual-Emissive Probe for Reversible Visualization of ΔΨ Revealing Voltage Heterogeneity in a Single Mitochondrion.

Anal Chem 2021 02 10;93(7):3493-3501. Epub 2021 Feb 10.

Institute of Fluorescent Probes for Biological Imaging, School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Jinan 250022, Shandong, People's Republic of China.

Mitochondrial membrane potential (ΔΨ) is a fundamentally important parameter in eukaryotic cells playing central roles in various vital biological processes. Precise visualization of ΔΨ depends on the robust ratiometric fluorescent probes. In this work, a new dual-emissive fluorescent probe has been fabricated for ratiometric visualization of ΔΨ. The unique probe can form near-infrared emissive aggregates (∼670 nm) in mitochondria with high ΔΨ, which turned to green-emitting monomers (530 nm) with loss of ΔΨ. The reversible changes of ΔΨ can be clearly observed, and the ultralarge emission shift (∼140 nm) is greatly favorable for the clear observation of voltage distribution under a super-resolution microscope. With the robust probe, the heterogenous voltage distribution in a single mitochondrion has been revealed for the first time, which can facilitate the in-depth understanding of fine structures in mitochondria. The cell damages induced by various reagents were successfully visualized using the innovative probe, demonstrating its pronounced potential for biological research.
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http://dx.doi.org/10.1021/acs.analchem.0c04819DOI Listing
February 2021

Establishment of patient-specific induced pluripotent stem cell line SDUBMSi009-A from a patient with X-linked Lowe syndrome.

Stem Cell Res 2021 03 13;51:102171. Epub 2021 Jan 13.

Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address:

X-linked Lowe syndrome is a multisystem disorder showing major abnormalities in the eyes, kidneys and central nervous system. OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, is associated with Lowe syndrome when mutated. Here we report the establishment of SDUBMSi009-A, an induced pluripotent stem cell line derived from patient carrying splicing variant (c. 940-11G>A) of OCRL gene by non-integrative reprogramming technology. The iPSC line showed strong pluripotent characteristics, including expressing pluripotent markers and potential to differentiate into the three germ layers. In the meanwhile, the iPSC line kept a normal male karyotype.
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http://dx.doi.org/10.1016/j.scr.2021.102171DOI Listing
March 2021

Generation and characterization of an induced pluripotent stem cell line SDQLCHi018-A from a congenital myasthenic syndrome patient carrying compound heterozygote mutations in RAPSN gene.

Stem Cell Res 2021 03 8;51:102160. Epub 2021 Jan 8.

Pediatric Research Institute, Qilu Children's Hospital of Shandong University, Jinan, Shandong 250022, China.

Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS). In this study, we generated an induced pluripotent stem cell line (iPSC) derived from a 14-day-old male CMS patient carrying compound heterozygote mutations (c.532-2A > G and c.264C > A/p.Asn88Lys) in RAPSN gene. The established iPSC line harboring the original mutations, possessing a normal karyotype, is able to differentiate into all three germ layers in vitro and expresses pluripotency markers.
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http://dx.doi.org/10.1016/j.scr.2021.102160DOI Listing
March 2021

Novel compound heterozygous variants in the GFPT1 gene leading to rare limb-girdle congenital myasthenic syndrome with rimmed vacuoles.

Neurol Sci 2021 Aug 13;42(8):3485-3490. Epub 2021 Jan 13.

Department of Neurology, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.

Background:  Congenital myasthenic syndrome (CMS) is a heterogeneous group of rare disorders with impaired neuromuscular transmission caused by genetic defects, which is characterized by fatigable muscle weakness.

Case Presentation:  Herein, we report a case of limb-girdle CMS (LG-CMS) in a 15-year-old Chinese girl with limb weakness and mild ptosis. The patient presented with well-defined clinical manifestations, muscle imaging, and electrophysiological features associated with CMS. On muscle biopsy, in addition to tubular aggregates identified, an extremely unusual pathological change of rimmed vacuoles in muscle fibers was observed. Whole-exome sequencing disclosed two novel heterozygous variants (c.14 T>A and c.581 T>C) in the human glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene, leading to the substitutions of phenylalanine to tyrosine (p.F5Y) and serine (p.F194S), respectively. Both variants were predicted to be likely pathogenic by SIFT, Polyphen-2, and Mutation Taster. Treatments with pyridostigmine bromide and albuterol produced a dramatic improvement.

Conclusions:  Collectively, molecular genetic analysis and muscle biopsy play crucial roles in the diagnosis of GFPT1-related LG-CMS with rimmed vacuoles (a rare phenotype of CMS) and have important implications for treatment decision.
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http://dx.doi.org/10.1007/s10072-020-05021-0DOI Listing
August 2021

Efficient Screening of Glycan-Specific Aptamers Using a Glycosylated Peptide as a Scaffold.

Anal Chem 2021 01 10;93(2):956-963. Epub 2020 Dec 10.

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

Abnormal glycan structures are valuable biomarkers for disease states; the development of glycan-specific binders is thereby significantly important. However, the structural homology and weak immunogenicity of glycans pose major hurdles in the evolution of antibodies, while the poor availability of complex glycans also has extremely hindered the selection of anti-glycan aptamers. Herein, we present a new approach to efficiently screen aptamers toward specific glycans with a complex structure, using a glycosylated peptide as a scaffold. In this method, using peptide-imprinted magnetic nanoparticles (MNPs) as a versatile platform, a glycopeptide tryptically digested from a native glycoprotein was selectively entrapped for positive selection, while a nonglycosylated analogue with an identical peptide sequence was synthesized for negative selection. Alternating positive and negative selection steps were carried out to guide the directed evolution of glycan-binding aptamers. As proof of the principle, the biantennary digalactosylated disialylated -glycan A2G2S2, against which there have been no antibodies and lectins so far, was employed as the target. With the glycoprotein transferrin as a source of target glycan, two satisfied anti-A2G2S2 aptamers were selected within seven rounds. Since A2G2S2 is upregulated in cancerous liver cells, carboxyfluorescein (FAM)-labeled aptamers were prepared as fluorescent imaging reagents, and successful differentiation of cancerous liver cells over normal liver cells was achieved, which demonstrated the application feasibility of the selected aptamers. This approach obviated a tedious glycan preparation process and allowed favorable expose of the intrinsic flexible conformation of natural glycans. Therefore, it holds great promise for developing glycan-specific aptamers for challenging applications such as cancer targeting.
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http://dx.doi.org/10.1021/acs.analchem.0c03675DOI Listing
January 2021

Parasite Circulating Cell-free DNA in the Blood of Alveolar Echinococcosis Patients as a Diagnostic and Treatment-Status Indicator.

Clin Infect Dis 2021 07;73(1):e246-e251

Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China, National Engineering Research Center for Beijing Biochip Technology, Beijing, China, CapitalBio Corporation, Beijing, China.

Background: Alveolar echinococcosis (AE) is a serious parasitic disease caused by the larvae of Echinococcus multilocularis. It is the less common but substantially more deadly of the 2 major echinococcosis diseases that can occur globally but are concentrated in central Asia.

Methods: We analyzed parasite circulating cell-free DNA (cfDNA) in 149 plasma samples using a DNA sequencing-based method (105 AE, 16 cystic echinococcosis, 4 liver cancer, 4 gallstones, and 20 healthy volunteers). After identifying the Echinococcus-specific cfDNA (Em-cfDNA) sequences in the samples, we determined whether Em-cfDNA could be used for AE diagnosis and as a potential indicator of the effectiveness of surgical treatment. We also examined potential associations between Em-cfDNA levels and clinical features of AE patients.

Results: Our work demonstrates that varying reads of Em-cfDNA were detectable in the plasma of 100% of preoperative AE patients and that all of the non-AE patients and healthy volunteers were negative. Em-cfDNA has good sensitivity and specificity for the diagnosis of AE. We also found that Em-cfDNA levels apparently have reference value for evaluating the therapeutic efficacy of surgery interventions for AE lesions. Finally, our analysis revealed that Em-cfDNA levels can reflect meaningful information about lesion size in preoperative AE patients.

Conclusions: We demonstrate that sequencing-based monitoring of Em-cfDNA can be used in the clinic as a powerful diagnostic indicator for AE. We also note that there is a strong potential for use of this liquid-biopsy method to monitor ongoing disease status in postintervention AE patients.
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http://dx.doi.org/10.1093/cid/ciaa1679DOI Listing
July 2021

Exosomes Derived from Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Inhibiting Pyroptosis.

Drug Des Devel Ther 2020 16;14:3765-3775. Epub 2020 Sep 16.

Department of Cardiovascular Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.

Objective: Mesenchymal stem cells (MSCs) show unique advantages in cardiomyocyte repairment. Exosomes derived from MSCs can enhance the viability of myocardial cells after ischemia/reperfusion (I/R) injury and regulate inflammation response. The study was designed to ascertain whether MSCs-exo protect the myocardium against I/R injury through inhibiting pyroptosis, and the underlying mechanisms.

Methods And Results: Experiments were carried out in H/R and I/R model. Cell viability was inhibited and NLRP3 and caspase1 protein levels were upregulated in H/R model. However, MSCs could inhibit cell apoptosis and pyroptosis in H/R model. Moreover, we used MSCs-exo to treated H/R model, and flow cytometric analysis results showed the inhibition function of MSCs-exo on cell apoptosis, and Western blot data suggested that NLRP3 and Caspase-1 expressions were downregulated in H/R model. Furthermore, exosomal miR-320b targeted NLRP3 protein, and MSCs-exo OE could inhibit NLRP3 expression and pyroptosis in H/R. In addition, the inhibition function of MSCs-exo on pyroptosis also was found in I/R model, and HE and Tunel staining also got similar results.

Conclusion: Exosomes derived from mesenchymal stem cells could protect the myocardium against ischemia/reperfusion injury through inhibiting pyroptosis.
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http://dx.doi.org/10.2147/DDDT.S239546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505733PMC
July 2021

High-concentration homocysteine inhibits mitochondrial respiration function and production of reactive oxygen species in neuron cells.

J Stroke Cerebrovasc Dis 2020 Oct 28;29(10):105109. Epub 2020 Jul 28.

Central Laboratory, Affiliated Hospital of Qinghai University, Tongren Road 29, Xining, Qinghai Province, China, 810000. Electronic address:

Objective: Homocysteine plays critical roles in cellular redox homeostasis, and hyperhomocysteinemia has been associated with multiple diseases, including neurological disorders involving reactive oxygen species-inducing and pro-inflammatory effects of homocysteine that are related to mitochondria. This study investigated the role of homocysteine in regulating mitochondria of neuron cell lines.

Methods: Neuron cells were pre-treated with homocysteine, and then flow cytometry was used to detect reactive oxygen species production and mitochondrial membrane potential, while Seahorse XFp Mito stress assay was used to comprehensively analyze mitochondrial function.

Results: The experimental results showed that high-concentration homocysteine diminished carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone-stimulated oxygen consumption rate and mitochondrial spare respiration capacity in a time- and concentration-dependent manner, and homocysteine also reduced reactive oxygen species in cultured neuron cell lines while no changes in mitochondrial membrane potential were observed.

Conclusion: These results indicate that homocysteine diminished mitochondrial respiration function in neuron cell lines mediated by its reactive oxygen species-reducing effects, which may underlie the association between hyperhomocysteinemia and human diseases.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105109DOI Listing
October 2020

Observation of the Elevation of Cholinesterase Activity in Brain Glioma by a Near-Infrared Emission Chemsensor.

Anal Chem 2020 10 10;92(19):13405-13410. Epub 2020 Sep 10.

Institute of Fluorescent Probes for Biological Imaging, School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Jinan, Shandong 250022, P. R. China.

The excessive expression of cholinesterases (ChEs) directly disturbs the metabolism of acetylcholine (ACh), causing disordering neurotransmission in the brain or even Alzheimer's disease and cancer. However, the variation of ChEs including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in brain glioma has not yet been investigated. Therefore, the development of a suitable method for in situ imaging ChEs in brain tissues to understand the physiological functions of ChEs in depth is very important. Herein, a new near-infrared emission fluorescent probe () for visualization of ChE activity was developed. exhibits ultrafast response to ChEs, low detection limit for AChE (0.127 U/mL) and BChE (0.0117 U/mL), and a large Stokes shift with near-infrared emission. Based on these excellent attributes, the was effectively utilized for imaging the fluctuations of ChE activity in the apoptosis cells and zebrafish. Notably, by utilizing the unique probe , we observed a significant enhancement of ChE activity in the tumor cells and brain glioma, for the first time. We believe that this interesting finding could provide a powerful guidance for tumor resection in the future.
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http://dx.doi.org/10.1021/acs.analchem.0c02770DOI Listing
October 2020

Five-year outcomes comparing percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass grafting in patients with left main coronary artery disease: A systematic review and meta-analysis.

Atherosclerosis 2020 09 4;308:50-56. Epub 2020 Jul 4.

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China. Electronic address:

Background And Aims: In patients with left main coronary artery disease (LMCAD), long-term outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) compared with coronary artery bypass grafting (CABG) remain controversial. We conducted a meta-analysis to compare the efficacy and safety of PCI with DES and CABG in LMCAD patients.

Methods: We comprehensively searched in Web of Science, EMBASE, PubMed, and Cochrane databases for eligible randomised controlled trials (RCTs) comparing the 5-year clinical outcomes between PCI with DES and CABG in LMCAD patients. Random-effect models were applied to analyse risk ratios (RRs) and hazard ratios (HRs) across studies, and I to assess heterogeneity.

Results: We screened 4 RCTs including 4394 patients distributed randomly into PCI (n = 2197) and CABG (n = 2197) groups. In comparison to CABG, PCI showed non-inferiority concerning a composite of death, myocardial infarction, and stroke (HR 1.22, 95% confident interval [CI] 0.84-1.75), death (HR 1.06, 95% CI 0.81-1.40) and stroke (HR 0.80, 95% CI 0.42-1.53). Regarding major adverse cardiac or cerebrovascular events (MACCE) rate, both strategies show clinical equipoise in patients with a low-to-intermediate Synergy Between PCI with TAXUS and Cardiac Surgery (SYNTAX) score (HR 1.20, 95% CI 0.85-1.70), while CABG had an advantage over PCI in those with a high SYNTAX score (HR 1.64, 95% CI 1.20-2.24).

Conclusions: CABG showed advantage over PCI with DES for LMCAD patients in MACCE. PCI and CABG showed equivalent 5-year clinical risk of a composite of all-cause mortality, myocardial infarction, and stroke, but the former had higher risk of repeat revascularization.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.06.024DOI Listing
September 2020

Epitope-Imprinted Magnetic Nanoparticles as a General Platform for Efficient Evolution of Protein-Binding Aptamers.

ACS Sens 2020 08 21;5(8):2537-2544. Epub 2020 Jul 21.

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

Aptamers are usually created by selection using a strategy termed systematic evolution of ligands by exponential enrichment (SELEX). Although numerous SELEX alternatives with improved selection efficiency have been developed, the overall success rate of SELEX at present is still not very ideal, which remains a great obstacle to aptamer-based research and application. In this study, an efficient and facile SELEX method was developed for screening of protein-binding aptamers, applying epitope-imprinted magnetic nanoparticles (MNPs) that exhibit highly favorable binding properties as a general affinity platform. As a proof of the principle, myoglobin (Mb) and β-microglobulin were employed as two target proteins. Two satisfied aptamers toward each target protein, with the dissociation constant at the 10 M level and cross-reactivity less than 16.5%, were selected within three rounds, taking only 1 day. A dual aptamer-based fluorescence sandwich assay was constructed using a pair of the selected aptamers. The resulting assay allowed for quantitatively detecting Mb in human serum and distinguishing acute myocardial infarction patients from healthy individuals. The epitope-imprinted MNP-based SELEX is straightforward and generally applicable for a wide range of target proteins, providing a promising aptamer selection tool for aptamer-based research and real-world applications.
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http://dx.doi.org/10.1021/acssensors.0c00846DOI Listing
August 2020

Interaction between delivery mode and maternal age in predicting overweight and obesity in 1,123 Chinese preschool children.

Ann Transl Med 2020 Apr;8(7):474

Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Pediatric overweight/obesity has escalated to epidemic proportions worldwide. In this study, we aimed to assess the association of delivery mode and maternal age, both individually and interactively, with the risk of being overweight or obese among Chinese preschool children.

Methods: We cross-sectionally recruited 1,123 preschool children from five kindergartens in Beijing. Data were collected by a pre-validated self-developed questionnaire. Overweight and obesity are defined according to the World Health Organization (WHO), International Obesity Task Force (IOTF), and China criteria, respectively.

Results: Cesarean delivery was significantly associated with pediatric overweight/obesity under the WHO [adjusted odds ratio (aOR), 95% confidence interval (CI): 1.60, 1.12-2.29], IOTF (1.77, 1.23-2.53), and China (1.43, 1.06-1.94) criteria, respectively. Maternal age <28 years reached statistical significance under both WHO (1.69, 1.09-2.61) and IOTF (1.69, 1.09-2.61) criteria in predicting pediatric overweight/obesity. The interaction between cesarean delivery and maternal age <28 years was remarkably significant under the WHO (2.26, 1.10-4.67), IOTF (2.92, 1.43-5.96), and China (2.36, 1.24-4.50) criteria.

Conclusions: Our findings indicate that the interaction between cesarean delivery and maternal age <28 years can remarkably increase the risk of overweight/obesity among Chinese preschool children.
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http://dx.doi.org/10.21037/atm.2020.03.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210148PMC
April 2020

The effect of gradually increased mandibular advancement on the efficacy of an oral appliance in the treatment of obstructive sleep apnea.

J Clin Sleep Med 2020 08;16(8):1369-1376

Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.

Study Objectives: To analyze the effect of gradual increments of mandibular advancement on the treatment efficacy of mandibular advancement devices and identify determinants of effective and target protrusion for OSA.

Methods: Patients were prospectively recruited. The mandible was titrated from 0 mm with a stepwise increment of 0.5 mm until the AHI was reduced to the lowest level. Rhinospirometry, rhinomanometry, and magnetic resonance imaging were used to observe the change of respiratory function and upper airway morphology.

Results: Forty-two patients aged 41.5 ± 9.0 years participated. There was a dose-dependent relationship between mandibular protrusion and the AHI improvement rate, the success rate, and the normalization rate; the changing curves plateaued after approximately 70% of maximal mandibular protrusion was achieved. The correlation between AHI and mandibular protrusion became stronger as the severity of OSA increased. The target protrusion for patients with mild, moderate, and severe OSA was 3.5 ± 1.8 mm (38.6 ± 19.4% maximal mandibular protrusion), 5.8 ± 1.9 mm (62.9 ± 18.8% maximal mandibular protrusion), and 5.9 ± 2.2 mm (68.8 ± 15.6% maximal mandibular protrusion), respectively. Regression analysis revealed that the factors influencing effective and target protrusion included change of maximal lateral dimension of the total upper airway with mandibular advancement devices, mean lateral dimension of the oropharynx, and soft palate length. Further protrusion brought more lateral expansion of the velopharynx, whereas the change in nasal ventilation was not significant.

Conclusions: The dose-dependent effect of mandibular protrusion on reduction of AHI by mandibular advancement devices was nonlinear and became more pronounced with increased severity of OSA. The mandibular protrusion should be more personalized to each patient.

Clinical Trial Registration: Registry: Chinese Clinical Trial Registry; Name: Study of the Onset Point of Oral Appliance Treatment in Obstructive Sleep Apnea and Hypopnea Syndrome; URL: http://www.chictr.org.cn/showproj.aspx?proj=22291; Identifier: ChiCTR-IND-17013232.
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http://dx.doi.org/10.5664/jcsm.8556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446065PMC
August 2020

Convenient Construction of Orthogonal Dual Aptamer-Based Plasmonic Immunosandwich Assay for Probing Protein Disease Markers in Complex Samples and Living Animals.

ACS Sens 2020 05 23;5(5):1436-1444. Epub 2020 Apr 23.

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

Aptamers, because of their outstanding merits including simple synthesis and easy modification, have been widely used as antibody alternatives to construct novel immunosandwich assays. Dual aptamer-based sandwich assays exhibit multiple advantages over conventional immunosandwich assays and single aptamer-based sandwich assays. However, their construction is hampered by the limited knowledge of binding orthogonality of aptamers reported in the literature. Herein, we present a new strategy for conveniently constructing an orthogonal dual aptamer-based plasmonic immunosandwich assay (odA-PISA) for probing proteins in complex samples and living animals. An orthogonal aptamer pair was first efficiently selected from the aptamers reported in the literature by affinity capillary electrophoresis. Then, a target protein-capturing gold thin-layer-coated probe and silver nanoparticle-based Raman labeling nanotags were conveniently prepared with the selected aptamers and used to construct the assay. The double aptamers used ensured the specificity, whereas the plasmonic coupling effect between the target-capturing probe and the generated Raman nanotags significantly enhanced the Raman signal intensity, providing high sensitivity. As a proof of principle, alkaline phosphatase (ALP) was used as the target. The constructed odA-PISA exhibited high specificity and high sensitivity toward ALP, giving cross-reactivity ≤ 4.2% and the limit of detection of 3.8 pM (S/N = 4). The quantitative determination of ALP in human serum and probing ALP in tumor-bearing mice were achieved, showing the great application potential of the method. This strategy is widely applicable to other protein disease markers. Therefore, it opened a new access to the construction of sensitive dual aptamer-based sandwich assays for real-world applications, particularly disease diagnosis.
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http://dx.doi.org/10.1021/acssensors.0c00359DOI Listing
May 2020

Aurone Derivative Revealing the Metabolism of Lipid Droplets and Monitoring Oxidative Stress in Living Cells.

Anal Chem 2020 05 22;92(9):6631-6636. Epub 2020 Apr 22.

School of Materials Science and Engineering, Institute of Fluorescent Probes for Biological Imaging, University of Jinan, Jinan, Shandong 250022, China.

Lipid droplets (LDs) are closely connected to many physiological processes and abnormal LDs are related to many diseases. Herein, a family of two-photon fluorescence compounds based on the aurone skeleton were developed as efficient LDs imaging probes. They exhibit the obvious solvatochromism effect from blue to orange emission (∼140 nm shift) in various solvents. The robust probes possess low toxicity to living cells, high photobleaching resistance, and superior photostability and can light up LDs with high specificity. Furthermore, the probe DMMB (aurone skeleton with dimethylamino) was carefully applied in real-time monitoring of the morphological changes of LDs and the interactions between LDs and mitochondria under specific physiological conditions (e.g., starvation). We have observed for the first time the dynamic change between mitochondria and LDs when mitochondrial damage is caused by a large excess of HO in a short period of time.
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http://dx.doi.org/10.1021/acs.analchem.0c00456DOI Listing
May 2020

An integration-free iPSC line SDQLCHi025-A from a girl with multiminicore disease carrying compound heterozygote mutations in RYR1 gene.

Stem Cell Res 2020 05 20;45:101775. Epub 2020 Mar 20.

Pediatric Research Institute, Qilu Children's Hospital of Shandong University, Jinan, Shandong 250022, China. Electronic address:

Peripheral blood mononuclear cells for reprogramming in this work were donated by a girl with clinically and genetically diagnosed multiminicore disease harboring compound heterozygote mutations of RYR1 gene. Induced pluripotent stem cells (iPSCs) were obtained by non-integrating episomal vectors containing OCT4, SOX2, KLF4, BCL-XL and c-MYC. The iPSC line (SDQLCHi025-A) presented pluripotent cell morphology, high mRNA levels of pluripotency markers, differentiation potential in vitro, a normal karyotype, and carrying RYR1 gene mutations.
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http://dx.doi.org/10.1016/j.scr.2020.101775DOI Listing
May 2020
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