Publications by authors named "Fan Yang"

4,397 Publications

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Enhanced β-carotene production by overexpressing the DID2 gene, a subunit of ESCRT complex, in engineered Yarrowia lipolytica.

Biotechnol Lett 2021 Jun 23. Epub 2021 Jun 23.

Engineering Research Center of High-Valued Utilization of Fruit Resources in Western China, Ministry of Education, Shaanxi Normal University, 620 West Changan Avenue, Changan, Xian, 710119, People's Republic of China.

Objective: β-Carotene has been widely used in the food and feed industry and has significant commercial value. This study aimed to increase the β-carotene production in engineered Yarrowia lipolytica by optimizing the host metabolic network. The DID2 gene, a subunit of the endosomal sorting complex required for transport (ESCRT), was integrated into a β-carotene producing strain.

Results: The β-carotene production was increased by 260%, and the biomass increased by 10% for engineered Y. lipolytica. Meanwhile, DID2 elevated the mRNA level and protein level of the genes in the β-carotene synthesis pathway, then increased precursors (FPP, Lycopene) utilization. DID2 also increased the mRNA level of the genes in the glucose pathway, pentose phosphate pathway, and tricarboxylic acid cycle and promoted glucose utilization and cofactors consumption.

Conclusion: The ESCRT protein complex subunit, DID2, improved β-carotene production in engineered Y. lipolytica and beneficial to glucose utilization and cofactors consumption. This study provided new finding of the DID2 gene's function and it mostly could be used for many other natural product productions.
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http://dx.doi.org/10.1007/s10529-021-03150-wDOI Listing
June 2021

Yes-associated protein regulates the hepatoprotective effect of vitamin D receptor activation through promoting adaptive bile duct remodeling in cholestatic mice.

J Pathol 2021 Jun 22. Epub 2021 Jun 22.

Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China.

Mounting clinical evidence has revealed that vitamin D receptor (VDR) is associated with cholestatic liver injury, although the functions of VDR in this condition remain largely unexplored. Here, we investigated the effects of VDR activation on bile duct ligation (BDL) mice, and the underlying mechanisms were further investigated. A low-calcemic VDR agonist, paricalcitol (PAL, 200 ng/kg), was intraperitoneally injected into BDL mice every other day for 5 days or 28 days. Liver histology, liver function indicators, cholangiocyte proliferation, fibrosis scores and inflammation were evaluated. Mice treated with PAL were rescued from the decreased survival rate induced by BDL and liver damage was reduced. Mechanistically, PAL promoted cholangiocyte proliferation, which was likely conducive to proliferating bile duct maturation and increased branching of bile ducts. PAL treatment also increased the expression of Yes-associated protein (YAP) and its target protein epithelial cell adhesion molecule (EpCam) and decreased the level of inactive cytoplasmic phosphorylated YAP. YAP knockdown abrogated PAL-induced primary bile duct epithelial cell proliferation, confirmed with YAP inhibitor administration. In addition, BDL-induced liver fibrosis and inflammatory cell infiltration were reduced by PAL treatment at both day 5 and day 28 post-BDL. In conclusion, VDR activation mitigates cholestatic liver injury by promoting adaptive bile duct remodeling through cholangiocytic YAP upregulation. Because PAL is an approved clinical drug, it may be useful for treatment of cholestatic liver disease. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5750DOI Listing
June 2021

The efficacy and deficiency of contemporary treatment for spinal cord arteriovenous shunts.

Brain 2021 Jun 22. Epub 2021 Jun 22.

Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.

Contemporary treatments for spinal cord arteriovenous shunts are only based on clinicians' treatment experiences and expertise due to its rarity. We reviewed the clinical course of the largest multi-cantered cohort to evaluate the efficacy and deficiency of contemporary interventional treatments for spinal cord arteriovenous shunts. The clinical features, treatment results and clinical outcomes of 463 spinal cord arteriovenous shunts patients were retrospectively assessed. The main outcome was the neurological deterioration that was evaluated based on the modified Aminoff and Logue scale. According to post-treatment DSA, complete obliteration was defined as disappearance of the intradural lesion, whereas partial obliteration was defined as any residual intradural lesion remaining visible and was further categorized as shunt-reduction obliteration (the nidus or shunt points was reduced) or palliative obliteration (only obliterated aneurysms or feeders). Cure rate was 40.6% for whole cohort, 58.5% after microsurgery, and 26.4% after embolization. The curative resection was associated with non-metameric lesions, lesions with a maximum diameter < 3 cm and lesions without anterior sulcal artery supply. The curative embolization was associated with fistula-type lesions, non-metameric lesions, and main drainage diameter < 1.5 mm. Permanent treatment-related neurological deficits rate was 11.2% for the whole cohort, 16.1% after microsurgery, and 5.6% after embolization. The pre-treatment clinical deterioration rate was 32.5%/year, which decreased to 9.3%/year after clinical interventions. After partial treatment, the long-term acute and gradual deterioration rate were 5.3%/year and 3.6%/year, respectively. The acute deteriorations were associated with metameric lesions, craniocervical lesions, lesions with a maximum diameter ≥2 cm and residual aneurysm. Residual aneurysm was the only predictor of acute deterioration for non-metameric spinal cord arteriovenous shunts. The gradual deteriorations were associated with palliative obliteration, absence of pre-treatment acute deterioration and intact main drainage. Although clinical risks of spinal cord arteriovenous shunts were reduced after clinical interventions, contemporary treatments for spinal cord arteriovenous shunt remains associated with considerable risks and incomplete efficacy. Individualized treatment plans should be adopted according to the angioarchitectural features and major clinical risks of specific lesions. There is a higher opportunity for complete obliteration for lesions with simple angioarchitecture. However, regarding most of spinal cord arteriovenous shunts with complex vascular anatomy, partial treatment is the only choice. For these patients, palliative obliteration targeting the aneurysms is recommended for reducing hemorrhagic risk, whereas shunt-reduction obliteration is necessary for non-haemorrhagic myelopathy. Contemporary treatment is ineffective in reducing hemorrhagic risk of incurable metameric spinal cord arteriovenous shunts.
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http://dx.doi.org/10.1093/brain/awab237DOI Listing
June 2021

Pyrolysis temperature-dependent carbon retention and stability of biochar with participation of calcium: Implications to carbon sequestration.

Environ Pollut 2021 Jun 9;287:117566. Epub 2021 Jun 9.

School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China; China-UK Low Carbon College, Shanghai Jiao Tong University, Shanghai, 201306, China.

Converting biomass waste into biochar by slow pyrolysis with subsequent soil amendment is a prospective approach with multiple environmental benefits including soil contamination remediation, soil amelioration and carbon sequestration. This study selected cow manure as precursor to produce biochar under 300 °C, 400 °C, 500 °C and 600 °C, and a remarkable promotion of carbon (C) retention in biochar by incorporation of exogenous Ca was achieved at all investigated pyrolysis temperatures. The C retention was elevated from 49.2 to 68.3% of pristine biochars to 66.1-79.7% of Ca-composite biochars. It was interesting that extent of this improvement increased gradually with rising of pyrolysis temperature, i.e., doping Ca in biomass promoted pyrolytic C retention in biochar by 16.6%, 23.4%, 29.1% and 31.1% for 300 °C, 400 °C, 500 °C and 600 °C, respectively. Thermogravimetric-mass spectrometer (TG-MS) and X-ray photoelectron spectroscopy (XPS) showed that Ca catalyzed thermal-chemical reactions and simultaneously suppressed the release of small organic molecular substances (C-C) via physical blocking (CaO, CaCO, and CaClOH) and chemical bonding (CO and OC-O). The catalyzation mainly occurred at 200-400 °C, while the suppression was more prominent at higher temperatures. Raman spectra and 2D FTIR analysis on biochar microstructure showed that presence of Ca had negative influence on carbon aromatization and thus weakened biochar's stability, while increasing pyrolysis temperature enhanced the stability of carbon structure. Finally, with integrating "C retention" during pyrolysis and "C stability" in biochar, the maximum C sequestration (56.3%) was achieved at 600 °C with the participation of Ca. The study highlights the importance of both Ca and pyrolysis temperature in enhancing biochar's capacity of sequestrating C.
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http://dx.doi.org/10.1016/j.envpol.2021.117566DOI Listing
June 2021

Potential Gene Association Studies of Chemotherapy-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis.

Front Cardiovasc Med 2021 4;8:651269. Epub 2021 Jun 4.

Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

Chemotherapy is widely used in the treatment of cancer patients, but the cardiotoxicity induced by chemotherapy is still a major concern to most clinicians. Currently, genetic methods have been used to detect patients with high risk of chemotherapy-induced cardiotoxicity (CIC), and our study evaluated the correlation between genomic variants and CIC. The systematic literature search was performed in the PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), China Biology Medicine disc (CBMdisc), the Embase database, China National Knowledge Internet (CNKI) and Wanfang database from inception until June 2020. Forty-one studies were identified that examined the relationship between genetic variations and CIC. And these studies examined 88 different genes and 154 single nucleotide polymorphisms (SNPs). Our study indicated 6 variants obviously associated with the increased risk for CIC, including CYBA rs4673 (pooled odds ratio, 1.93; 95% CI, 1.13-3.30), RAC2 rs13058338 (2.05; 1.11-3.78), CYP3A5 rs776746 (2.15; 1.00-4.62) ABCC1 rs45511401 (1.46; 1.05-2.01), ABCC2 rs8187710 (2.19; 1.38-3.48), and HER2-Ile655Val rs1136201 (2.48; 1.53-4.02). Although further studies are required to validate the diagnostic and prognostic roles of these 6 variants in predicting CIC, our study emphasizes the promising benefits of pharmacogenomic screening before chemotherapy to minimize the CIC.
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http://dx.doi.org/10.3389/fcvm.2021.651269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213036PMC
June 2021

Candidate Gene Analysis for Nitrogen Absorption and Utilization in Japonica Rice at the Seedling Stage Based on a Genome-Wide Association Study.

Front Plant Sci 2021 4;12:670861. Epub 2021 Jun 4.

Key Laboratory of Germplasm Enhancement, Physiology and Ecology of Food Crops in Cold Region, Ministry of Education, Northeast Agricultural University, Harbin, China.

Over-application of nitrogen (N) fertilizer in fields has had a negative impact on both environment and human health. Domesticated rice varieties with high N use efficiency (NUE) reduce fertilizer requirements, enabling sustainable agriculture. Genome-wide association study (GWAS) analysis of N absorption and utilization traits under low and high N conditions was performed to obtain 12 quantitative trait loci (QTLs) based on genotypic data including 151,202 single-nucleotide polymorphisms (SNPs) developed by re-sequencing 267 japonica rice varieties. Eighteen candidate genes were obtained by integrating GWAS and transcriptome analyses; among them, the functions of , , and genes in N transport and assimilation have been identified, and OsJAZ12 and OsJAZ13 also play important roles in rice adaptation to abiotic stresses. A NUE-related candidate gene, , was identified by quantitative real-time PCR (qRT-PCR) analyses. encodes a NAC transcription factor and has been shown to be a positive regulator of the drought stress response in rice. Overexpression of significantly increased rice NUE and grain yield under deficient N conditions, but the difference was not significant under sufficient N conditions. NUE and grain yield significantly decreased under both N supply conditions in the mutant. This study provides crucial insights into the genetic basis of N absorption and utilization in rice, and a NUE-related gene, , was cloned to provide important resources for rice breeding with high NUE and grain yield.
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http://dx.doi.org/10.3389/fpls.2021.670861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212024PMC
June 2021

Structural insights into the recognition of histone H3Q5 serotonylation by WDR5.

Sci Adv 2021 Jun 18;7(25). Epub 2021 Jun 18.

Hefei National Laboratory for Physical Sciences at Microscale, the first affiliated hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, CAS Center for Excellence in Biomacromolecules, and School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China.

Serotonylation of histone H3Q5 (H3Q5ser) is a recently identified posttranslational modification of histones that acts as a permissive marker for gene activation in synergy with H3K4me3 during neuronal cell differentiation. However, any proteins that specifically recognize H3Q5ser remain unknown. Here, we found that WDR5 interacts with the N-terminal tail of histone H3 and functions as a "reader" for H3Q5ser. Crystal structures of WDR5 in complex with H3Q5ser and H3K4me3Q5ser peptides revealed that the serotonyl group is accommodated in a shallow surface pocket of WDR5. Experiments in neuroblastoma cells demonstrate that H3K4me3 modification is hampered upon disruption of WDR5-H3Q5ser interaction. WDR5 colocalizes with H3Q5ser in the promoter regions of cancer-promoting genes in neuroblastoma cells, where it promotes gene transcription to induce cell proliferation. Thus, beyond revealing a previously unknown mechanism through which WDR5 reads H3Q5ser to activate transcription, our study suggests that this WDR5-H3Q5ser-mediated epigenetic regulation apparently promotes tumorigenesis.
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http://dx.doi.org/10.1126/sciadv.abf4291DOI Listing
June 2021

Superionic Conductivity in Ceria-Based Heterostructure Composites for Low-Temperature Solid Oxide Fuel Cells.

Nanomicro Lett 2020 Aug 29;12(1):178. Epub 2020 Aug 29.

Jiangsu Provincial Key Laboratory of Solar Energy Science and Technology/Energy Storage Research Center, School of Energy and Environment, Southeast University, Nanjing, 210096, People's Republic of China.

Ceria-based heterostructure composite (CHC) has become a new stream to develop advanced low-temperature (300-600 °C) solid oxide fuel cells (LTSOFCs) with excellent power outputs at 1000 mW cm level. The state-of-the-art ceria-carbonate or ceria-semiconductor heterostructure composites have made the CHC systems significantly contribute to both fundamental and applied science researches of LTSOFCs; however, a deep scientific understanding to achieve excellent fuel cell performance and high superionic conduction is still missing, which may hinder its wide application and commercialization. This review aims to establish a new fundamental strategy for superionic conduction of the CHC materials and relevant LTSOFCs. This involves energy band and built-in-field assisting superionic conduction, highlighting coupling effect among the ionic transfer, band structure and alignment impact. Furthermore, theories of ceria-carbonate, e.g., space charge and multi-ion conduction, as well as new scientific understanding are discussed and presented for functional CHC materials.
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http://dx.doi.org/10.1007/s40820-020-00518-xDOI Listing
August 2020

Impact of Concomitant Impairments of the Left and Right Ventricular Myocardial Strain on the Prognoses of Patients With ST-Elevation Myocardial Infarction.

Front Cardiovasc Med 2021 31;8:659364. Epub 2021 May 31.

Department of Cardiology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.

The impact of concomitant impairments of left and right ventricular (LV and RV) strain on the long-term prognosis of acute ST-elevation myocardial infarction (STEMI) is not clear. We analyzed CMR images and followed up 420 first STEMI patients from the EARLY Assessment of MYOcardial Tissue Characteristics by CMR in STEMI (EARLY-MYO-CMR) registry (NCT03768453). These patients received timely primary percutaneous coronary intervention (PCI) within 12 h and CMR examination within 1 week (median, 5 days; range, 2-7 days) after infarction. Global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) of both ventricles were measured based on CMR cine images. Conventional CMR indexes were also assessed. Primary clinical outcome was composite major adverse cardiac and cerebrovascular events (MACCEs) including cardiovascular death, re-infarction, re-hospitalization for heart failure and stroke. In addition, CMR data from 40 people without apparent heart disease were used as control group. Compared to controls, both LV and RV strains were remarkably reduced in STEMI patients. During follow-up (median: 52 months, interquartile range: 29-68 months), 80 patients experienced major adverse cardiac and cerebrovascular events (MACCEs) including cardiovascular death, re-infarction, heart failure, and stroke. LV-GCS > -11.20% was an independent predictor of MACCEs ( < 0.001). RV-GRS was the only RV strain index that could effectively predict the risk of MACCEs (AUC = 0.604, 95% CI [0.533, 0.674], = 0.004). Patient with RV-GRS ≤ 38.79% experienced more MACCEs than those with preserved RV-GRS (log rank < 0.001). Moreover, patients with the concomitant decrease of LV-GCS and RV-GRS were more likely to experience MACCEs than patients with decreased LV-GCS alone (log rank = 0.010). RV-GRS was incremental to LV-GCS for the predictive power of MACCEs (continuous NRI: 0.327; 95% CI: 0.095-0.558; = 0.006). Finally, tobacco use ( = 0.003), right coronary artery involvement ( = 0.002), and LV-GCS > -11.20% ( = 0.012) was correlated with lower RV-GRS. The concomitant decrease of LV and RV strain is associated with a worse long-term prognosis than impaired LV strain alone. Combination assessment of both LV and RV strain indexes could improve risk stratification of patients with STEMI. ClinicalTrials.gov, NCT03768453. Registered 7 December 2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03768453.
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http://dx.doi.org/10.3389/fcvm.2021.659364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200389PMC
May 2021

N, P-Codoped Carbon Film Derived from Phosphazenes and Its Printing Integration with a Polymer Carpet "Molecular Welding" for Flexible Electronics.

ACS Appl Mater Interfaces 2021 Jun 15. Epub 2021 Jun 15.

State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029, P. R. China.

Although high-performance graphene-based micro/nano flexible electronic devices have shown promising applications in numerous fields, there are still many problems in converting graphene into practical applications. Heteroatom-doped graphene materials are of huge importance because heteroatom doping can significantly change the electronic structure and introduce the active site, which benefits the integration with a promising substrate and achieves nondestructive transfer of carbon materials. Herein, we analyze in detail the pyrolysis gas composition of heteroatom-enriched phosphazenes with different structures and prepare a series of high-quality N, P-codoped carbon-based films from phosphazene solid sources on a low-cost glass substrate by a convenient one-step method. The N, P-codoped carbon film shows reflectivity, good conductivity, and transparency. In addition, with the help of "molecular welding", we achieve nondestructive transfer of a conductive carbon-based film from a glass substrate to promising layer-polyimide (PI) and prepare a flexible free-standing carbon/PI hybrid film with an excellent binding interface. The flexible conductive hybrid film shows excellent durability under an extremely low temperature environment and superior bending stability after 800 bending cycles. The results suggest that a phosphazene precursor is an amazing choice for constructing high-quality heteroatom-doped conductive carbon films. Besides, this work provides a promising way for nondestructive transfer of the conductive carbon-based films and large-scale preparation of large-area patterned conductive thin films.
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http://dx.doi.org/10.1021/acsami.1c04010DOI Listing
June 2021

miR-141-5p suppresses vascular smooth muscle cell inflammation, proliferation, and migration via inhibiting the HMGB1/NF-κB pathway.

J Biochem Mol Toxicol 2021 Jun 14:e22828. Epub 2021 Jun 14.

Department of Pharmacy, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.

MicroRNAs (miRNAs) have been identified as significant modulators in the pathogenesis of atherosclerosis (AS). Additionally, the dysregulation of vascular smooth muscle cells (VSMCs) is a crucial biological event during AS. Our study aimed to explore the functional roles and molecular mechanisms of miR-141-5p in VSMCs dysfunction. C57BL/6 mice were used to establish AS animal model. Human VSMCs were treated by oxidized low-density lipoprotein (ox-LDL) to establish AS cell model. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to probe miR-141-5p and high-mobility group box 1 (HMGB1) mRNA expressions in VSMCs or plasma samples of the mice. Inflammatory cytokines were detected by enzyme-linked immunosorbent assay kits. Cell counting kit-8 and bromodeoxyuridine assays were performed to evaluate cell proliferation. Cell migration and apoptosis were detected with Transwell assay and flow cytometry analysis, respectively. The target gene of miR-141-5p was predicted with the TargetScan database, and the interaction between miR-141-5p and HMGB1/nuclear factor-κB (NF-κB) was further validated by dual-luciferase reporter assay, qRT-PCR, and Western blot analysis. miR-141-5p was found to be decreased in the plasma of patients and mice model with AS. Its expression was also downregulated in VSMCs treated by ox-LDL. miR-141-5p overexpression inhibited the inflammation, proliferation, migration of VSMCs, and promoted the apoptosis of VSMCs. HMGB1 was identified as a direct target of miR-141-5p, and miR-141-5p could repress the activity of HMGB1/NF-κB signaling. HMGB1 restoration reversed the effects of miR-141-5p, and NF-κB inhibitor JSH-23 showed similar effects with miR-141-5p mimics. miR-141-5p inhibits VSMCs' dysfunction by targeting the HMGB1/NF-κB pathway, which probably functions as a protective factor during the development of AS.
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http://dx.doi.org/10.1002/jbt.22828DOI Listing
June 2021

How kindness can be contagious in healthcare.

Nat Med 2021 Jun 14. Epub 2021 Jun 14.

School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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http://dx.doi.org/10.1038/s41591-021-01401-xDOI Listing
June 2021

Porcine Epidemic Diarrhea Virus Membrane Protein Interacted with IRF7 to Inhibit Type I IFN Production during Viral Infection.

J Immunol 2021 Jun 14. Epub 2021 Jun 14.

State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; and

Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic porcine enteropathogenic coronavirus causing severe enteritis and lethal watery diarrhea in piglets. PEDV infection suppresses the synthesis of type I IFN, and multiple viral proteins of PEDV have been shown to target the adaptors of innate immune pathways to inhibit type I IFN production. In this study, we identified PEDV membrane (M) protein as a new antagonist of type I IFN production in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells and determined the antagonistic mechanism used by M protein to target IFN regulatory factor 7 (IRF7), an important regulator of type I IFN production. IRF7 is phosphorylated and activated by TBK1 and IKKε in response to viral infection. We found that PEDV M protein interacted with the inhibitory domain of IRF7 and significantly suppressed TBK1/IKKε-induced IRF7 phosphorylation and dimerization of IRF7, leading to the decreased expression of type I IFN, although it did not affect the interaction between TBK1/IKKε and IRF7. As expected, overexpression of M protein significantly increased PEDV replication in porcine cells. The M proteins of both epidemic PEDV strains and vaccine strain showed similar antagonistic effect on type I IFN production, and the 1-55 region of M protein was essential for disruption of IRF7 function by interacting with IRF7. Taken together, our data identified a new, to our knowledge, IFN antagonist of PEDV, as well as a novel, to our knowledge, antagonistic mechanism evolved by PEDV to inhibit type I IFN production.
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http://dx.doi.org/10.4049/jimmunol.2001186DOI Listing
June 2021

The Expression of Semaphorin 7A in Human Periapical Lesions.

J Endod 2021 Jun 11. Epub 2021 Jun 11.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China. Electronic address:

Introduction: Semaphorin7A (SEMA7A) is a membrane bound or secretory protein exerting multiple functions in the regulation of inflammation, neural degradation, and cancer progression. Human periapical lesions are chronic and infectious diseases mainly caused by bacteria. However, the involvement of SEMA7A in human periapical lesions is still unclear. This study aimed to explore the expression of SEMA7A in human Periapical lesions accompanied by the potential association of SEMA7A with matrix metalloproteinase (MMP) 1 and MMP3 during the progression of apical periodontitis.

Methods: Samples of periapical lesions and healthy controls were collected. Total RNA and protein were extracted respectively for quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Additionally, six healthy samples and twenty-seven periapical lesion samples were fixed, dehydrated, and embedded for further histologic and immunochemical analysis. The expression of SEMA7A was quantified by average integrated optical density (AIOD). Immunofluorescence analysis was conducted to explore the co-localization of SEMA7A/MMP1 and SEMA7A/MMP3.

Results: Compared with healthy controls, the mRNA and protein expression of SEMA7A was markedly upregulated in periapical lesions. Stronger expression of MMP1, MMP3, and inflammatory cytokines was exhibited in periapical lesions than in healthy groups. Increasing expression of SEMA7A can be observed in both the periapical granuloma group and the radicular cyst group compared with the normal group (P < 0.01). Immunofluorescence results showed the co-localization of SEMA7A with both MMP1 and MMP3 in vascular vessels and extracellular matrix.

Conclusions: SEMA7A was upregulated in periapical periodontitis and might be involved in the tissue destruction and infiltration of immune cells in periapical lesions.
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http://dx.doi.org/10.1016/j.joen.2021.06.005DOI Listing
June 2021

Assessment of Liver Function for Evaluation of Short- and Long-Term Outcomes in Type B Aortic Dissection Patients Undergoing Thoracic Endovascular Aortic Repair.

Front Cardiovasc Med 2021 12;8:643127. Epub 2021 May 12.

Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

Patients with decreased liver function suffer from poor outcomes when undergoing procedures. We aimed to explore the impact of liver fibrosis identified by aspartate transaminase-to-platelet ratio index (APRI) and poor liver functional reserve assessed by a model of end-stage liver disease (MELD) and albumin-bilirubin(ALBI) score on the prognosis of patients with type B aortic dissection (TBAD) undergoing thoracic endovascular aortic repair (TEVAR). A retrospective analysis of a prospectively maintained database from 2010 to 2017 was performed. APRI > 0.5 was used to identify those with significant liver fibrosis. Logistic and Cox regression analyses were performed to investigate the association between liver fibrosis, MELD, and ALBI with adverse events. TEVAR was performed on 812 TBAD patients including 35 with liver fibrosis and 777 without. Twenty-four (3.0%) patients deceased during hospitalization and 69 (8.8%) patients died after a median 48.2 months follow-up. Multivariable analysis revealed that liver fibrosis, MELD, and ALBI were independently associated with in-hospital [fibrosis: odds ratio (OR) 23.73, 95% confidence interval (CI) 8.89-63.33, < 0.001; MELD: OR 1.08, 95% CI 1.03-1.14, = 0.003; ALBI: OR 4.45; 95% CI 1.56-12.67, = 0.005] and follow-up mortality [fibrosis: hazard ratio (HR) 4.69, 95% CI 1.93-11.42, = 0.001; MELD: HR 1.07, 95% CI 1.04-1.10, < 0.001; ALBI: HR 2.88, 95% CI 1.53-5.43, = 0.001]. The association was further corroborated by a subgroup analysis. Liver fibrosis and poor liver functional reserve could significantly increase the morbidity and mortality after TEVAR. APRI, MELD, and ALBI should be calculated and routinely used for preoperative risk stratification. Strict preoperative preparation and elaborate postoperative care are necessary to improve these patients' prognosis.
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http://dx.doi.org/10.3389/fcvm.2021.643127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190657PMC
May 2021

Comparison of indoor and outdoor oxidative potential of PM: pollution levels, temporal patterns, and key constituents.

Environ Int 2021 Jun 9;155:106684. Epub 2021 Jun 9.

School of Energy and Environment, Southeast University, Nanjing, China; Engineering Research Center of Building Equipment, Energy, and Environment, Ministry of Education, Nanjing, China.

Oxidative potential (OP) of PM is an emerging health indicator representing its ability to induce oxidative stress and cause adverse health effects. We examined pollution levels, temporal variations, and key constituents of PM OP by DTT assay in both indoor and outdoor environments in Nanjing, China, for over one year. Outdoor OP (mass-normalized OP characterizes toxicity) and OP (volume-based OP characterizes overall oxidative burden) in Nanjing were at a medium level compared to results reported for twenty-seven cities. Although PM mass concentration consistently decreased during outdoor-to-indoor transport, OP varied by a factor of up to 2 in either direction, indicating a change of PM's ability to disrupt oxidative-reductive balance. Temporally, both outdoor and indoor OP exhibited a significant seasonality pattern (P < 0.01) as autumn > summer > spring > winter. Outdoor and indoor daytime-nighttime OP and OP are fluctuating within two-fold range. In addition, the change in water-soluble Fe had the highest correlation coefficient (P < 0.05) with ΔOP (ΔOP = OP-OP) among constituents measured here. Our results suggest that development of mitigation strategies take indoor PM's OP into account, instead of outdoors only, since they differ.
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http://dx.doi.org/10.1016/j.envint.2021.106684DOI Listing
June 2021

Knockdown of circ_0075503 suppresses cell migration and invasion by regulating miR-15a-5p and KLF12 in endometriosis.

Mol Cell Biochem 2021 Jun 11. Epub 2021 Jun 11.

Department of Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, No. 1 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, Guangdong, China.

Endometriosis is an estrogen-dependent disease. Several researches have reported the dysregulated circular RNAs (circRNAs) in endometriosis, whereas the functions of circRNAs are largely unknown. This study aims to explore the role and mechanism of circ_0075503 in migration and invasion of eutopic endometrial stromal cells. 30 paired ectopic and eutopic endometrium tissues were collected from patients with endometriosis. And primary endometrial stromal cells (ESCs) were stimulated with estradiol (E2) to establish the in vitro cellular model of endometriosis. The levels of circ_0075503, miR-15a-5p and Krüppel-like factor 12 (KLF12) were measured by quantitative reverse transcription polymerase chain reaction or western blot assays. Cell viability, migration and invasion were examined via 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide, transwell assay or western blot assays. The target relationship between miR-15a-5p and circ_0075503 or KLF12 was analyzed by dual-luciferase reporter assay and RNA Immunoprecipitation (RIP) assay. Circ_0075503 expression was elevated in ectopic endometrium and ectopic ESCs. Down-regulation of circ_0075503 suppressed E2-induced promotion of cell viability, migration and invasion in eutopic ESCs. Circ_0075503 could act as a sponge for miR-15a-5p, and KLF12 was targeted by miR-15a-5p. Inhibition of miR-15a-5p reversed the effects of circ_0075503 knockdown on E2-treated ESCs migration and invasion. Besides, miR-15a-5p repressed E2-induced promotion effects on cell migration and invasion via targeting KLF12. Circ_0075503 could regulate KLF12 expression by sponging miR-15a-5p. Knockdown of circ_0075503 inhibited E2-induced enhancement of cell migration and invasion in eutopic ESCs by regulating miR-15a-5p/KLF12 axis, indicating a novel target for the treatment of endometriosis.
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http://dx.doi.org/10.1007/s11010-021-04202-5DOI Listing
June 2021

NiCo alloy/C nanocomposites derived from a Ni-doped ZIF-67 for lightweight microwave absorbers.

Nanotechnology 2021 Jun 11. Epub 2021 Jun 11.

Shenzhen Technology University, No.3002, Lantian Road, Shenzhen, Guangdong, 518118, CHINA.

In this work, we prepared NiCo alloy/C with rhombic dodecahedron structure and superior microwave absorption performance by using ZIF-67 as the raw material. The rhombic dodecahedron NiCo alloy/C was with rough particles on the surface was photographed by field emission scanning electron microscopy (FESEM). By adjusting the doping amount of Ni and the temperature of pyrolysis, improved the impedance matching of NiCo alloy/C. Specifically, NiCo alloy/C exhibits a minimum reflection loss of -65.48 dB at 13.48 GHz, while the thickness is 1.63 mm. Defects introduced in the Ni doping process and the special rhombic dodecahedral structure can cause multiple loss mechanisms. Therefore, this NiCo alloy/C composite has the potential to be a potential microwave absorber material with lightweight and high microwave absorption properties.
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http://dx.doi.org/10.1088/1361-6528/ac0ac3DOI Listing
June 2021

SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury.

iScience 2021 May 29;24(5):102483. Epub 2021 Apr 29.

Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.

Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.
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http://dx.doi.org/10.1016/j.isci.2021.102483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169952PMC
May 2021

Chemical vapour deposition of Fe-N-C oxygen reduction catalysts with full utilization of dense Fe-N sites.

Nat Mater 2021 Jun 10. Epub 2021 Jun 10.

Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.

Replacing scarce and expensive platinum (Pt) with metal-nitrogen-carbon (M-N-C) catalysts for the oxygen reduction reaction in proton exchange membrane fuel cells has largely been impeded by the low oxygen reduction reaction activity of M-N-C due to low active site density and site utilization. Herein, we overcome these limits by implementing chemical vapour deposition to synthesize Fe-N-C by flowing iron chloride vapour over a Zn-N-C substrate at 750 °C, leading to high-temperature trans-metalation of Zn-N sites into Fe-N sites. Characterization by multiple techniques shows that all Fe-N sites formed via this approach are gas-phase and electrochemically accessible. As a result, the Fe-N-C catalyst has an active site density of 1.92 × 10 sites per gram with 100% site utilization. This catalyst delivers an unprecedented oxygen reduction reaction activity of 33 mA cm at 0.90 V (iR-corrected; i, current; R, resistance) in a H-O proton exchange membrane fuel cell at 1.0 bar and 80 °C.
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http://dx.doi.org/10.1038/s41563-021-01030-2DOI Listing
June 2021

Erratum for Zhu et al., "Foot-and-Mouth Disease Virus Viroporin 2B Antagonizes RIG-I-Mediated Antiviral Effects by Inhibition of Its Protein Expression".

J Virol 2021 Jun 10;95(13):e0054521. Epub 2021 Jun 10.

State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.

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http://dx.doi.org/10.1128/JVI.00545-21DOI Listing
June 2021

Lipid accumulation-induced hepatocyte senescence regulates the activation of hepatic stellate cells through the Nrf2-antioxidant response element pathway.

Exp Cell Res 2021 Jun 6;405(2):112689. Epub 2021 Jun 6.

Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Department of Gerontology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China; Research Center on Aging and Medicine, Fudan University, Shanghai, China. Electronic address:

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally. Elderly individuals are at a higher risk of developing NAFLD with severe clinical outcomes. Although NAFLD is closely related to liver aging, the role of hepatocyte senescence in the progression of NAFLD, especially in the development of fibrosis, is still unclear. The early stage of NAFLD is mainly characterized by lipid accumulation in hepatocytes, which could lead to severe oxidative stress, causing cellular senescence. In the present study, hepatocytes cultured in the presence of free fatty acids to induce lipid deposition were used as a hepatocyte senescence model in vitro. Senescent hepatocytes significantly increased the activation of co-cultured primary hepatic stellate cells (HSCs) and the expression of pro-fibrosis molecules. Moreover, the antioxidant regulator nuclear factor erythroid 2-related factor 2 (Nrf2) that was upregulated in senescent hepatocytes was found to be related to the activation of co-cultured HSCs. The Nrf2 agonist sulforaphane, which upregulated the transcriptional activity of the Nrf2-antioxidant response element (ARE) pathway, remarkably inhibited hepatocyte senescence and its activation effect on HSCs. However, the liver tissue obtained from non-alcoholic steatohepatitis (NASH) mice with Nrf2 knockdown showed decreased antioxidation and significant liver senescence and fibrosis. In conclusion, this study confirmed that lipid accumulation induces hepatocyte senescence, which leads to HSC activation and development of hepatic fibrosis. Increasing the activity of the Nrf2-ARE antioxidant pathway in senescent hepatocytes elicited the opposite effect, suggesting that targeting Nrf2 may prevent or delay the progression of aging-related liver fibrosis in NASH.
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http://dx.doi.org/10.1016/j.yexcr.2021.112689DOI Listing
June 2021

Autophagy modulates FSS-induced epithelial-mesenchymal transition in hepatocellular carcinoma cells.

Mol Carcinog 2021 Jun 9. Epub 2021 Jun 9.

Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China.

Hepatocellular carcinoma is a highly fatal disease and threatens human health seriously. Fluid shear stress (FSS), which is caused by the leakage of plasma from abnormally permeable tumor blood vessels and insufficient lymphatic drainage, has been identified as contributing pathologically to cancer metastasis. Autophagy and epithelial-mesenchymal transition (EMT) are both reported to be involved in cancer cell migration and invasion, but little has been revealed about the interaction between autophagy and EMT under a tumor mechanical microenvironment. Here, we identified that exposure to 1.4 dyne/cm FSS could promote the formation of autophagosomes and significantly increase the expressions of autophagy-related markers of beclin1 and ATG7, and the ratio of LC3Ⅱ/Ⅰ in both of HepG2 and QGY-7703 cells. The FSS loading also elevated the levels of mesenchymal markers N-cadherin, Vimentin, Twist, Snail, and β-catenin, while the epithelial markers E-cadherin showed a decrease. Once the autophagy was blocked by 3-methyladenine (3-MA) or knocking ATG5 down, the occurrence of FSS-induced EMT was inhibited dramatically according to the expression and translocation of E-cadherin, N-cadherin, and β-catenin. Given the effect of EMT on cell migration, we observed that inhibition of autophagy could impede FSS-induced cell migration. Collectively, this study demonstrated that autophagy played a crucial role in FSS-induced EMT and cell migration in hepatocellular carcinoma.
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http://dx.doi.org/10.1002/mc.23327DOI Listing
June 2021

Identification of a nomogram based on an 8-lncRNA signature as a novel diagnostic biomarker for childhood acute lymphoblastic leukemia.

Aging (Albany NY) 2021 Jun 9;13(11):15548-15568. Epub 2021 Jun 9.

Medical Research Center, The Third People's Hospital of Chengdu, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China.

Childhood acute lymphoblastic leukemia (cALL) still represents a major cause of disease-related death in children. This study aimed to explore the prognostic value of long non-coding RNAs (lncRNAs) in cALL. We downloaded lncRNA expression profiles from the TARGET and GEO databases. Univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were applied to identify lncRNA-based signatures. We identified an eight-lncRNA signature (LINC00630, HDAC2-AS2, LINC01278, AL356599.1, AC114490.1, AL132639.3, FUT8.AS1, and TTC28.AS1), which separated the patients into two groups with significantly different overall survival rates. A nomogram based on the signature, BCR ABL1 status and white blood cell count at diagnosis was developed and showed good accuracy for predicting the 3-, 5- and 7-year survival probability of cALL patients. The C-index values of the nomogram in the training and internal validation set reached 0.8 (95% CI, 0.757 to 0.843) and 0.806 (95% CI, 0.728 to 0.884), respectively. The nomogram proposed in this study objectively and accurately predicted the prognosis of cALL. experiments suggested that LINC01278 promoted the proliferation of leukemic cells and inhibited leukemic cell apoptosis by targeting the inhibition of miR-500b-3p in cALL, and LINC01278 may be a biological target for the treatment of cALL in the future.
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http://dx.doi.org/10.18632/aging.203116DOI Listing
June 2021

Optical Flow Ratio for Assessing Stenting Result and Physiological Significance of Residual Disease.

EuroIntervention 2021 Jun 8. Epub 2021 Jun 8.

Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

Background: Optical flow ratio (OFR) is a novel method for fast computation of fractional flow reserve (FFR) from optical coherence tomography (OCT) images.

Aims: We aimed to evaluate the accuracy of OFR in predicting post-percutaneous coronary intervention (PCI) FFR and to evaluate the impact of stent expansion on within-stent OFR pressure drop (In-stent OFR).

Methods: Post-PCI OFR was computed in patients with both OCT and FFR interrogation immediately after PCI. Calculation of post-PCI OFR (called simulated residual OFR) from pre-PCI OCT pullbacks after elimination of the stenotic segment by virtual stenting was performed in a subgroup of patients who had pre-PCI OCT images. Stent underexpansion was quantified by the minimum expansion index (MEI) of the stented segment.

Results: A total of 125 paired comparisons between post-PCI OFR and FFR were obtained in 119 patients, among which simulated residual OFR was obtained in 64 vessels. Mean post-PCI FFR was 0.92 ± 0.05. Post-PCI OFR showed good correlation (r = 0.74, p<0.001) and agreement (mean difference = -0.01 ± 0.03, p = 0.051) with FFR. The accuracy in predicting post-PCI FFR≤0.90 was 84% for post-PCI OFR. Simulated residual OFR significantly correlated with post-PCI FFR (r = 0.42, p<0.001). MEI showed moderate correlation (r=-0.49, p<0.001) with In-stent OFR.

Conclusions: Post-PCI OFR showed good diagnostic concordance with post-PCI FFR. Simulated residual OFR significantly correlated with post-PCI FFR. Stent underexpansion significantly correlated with in-stent pressure drop.
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http://dx.doi.org/10.4244/EIJ-D-21-00185DOI Listing
June 2021

Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.

Nat Commun 2021 06 8;12(1):3424. Epub 2021 Jun 8.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
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http://dx.doi.org/10.1038/s41467-021-23832-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187342PMC
June 2021

An efficient alpha seeding method for optimized extreme learning machine-based feature selection algorithm.

Comput Biol Med 2021 May 23;134:104505. Epub 2021 May 23.

College of Information Engineering, Nanjing University of Finance and Economics, Nanjing, 210023, China.

Embedded feature selection algorithms, such as support vector machine based recursive feature elimination (SVM-RFE), have proven to be effective for many real applications. However, due to the model selection problem, SVM-RFE naturally suffers from a heavy computational burden as well as high computational complexity. To solve these issues, this paper proposes using an optimized extreme learning machine (OELM) model instead of SVM. This model, referred to as OELM-RFE provides an efficient active set solver for training the OELM algorithm. We also present an effective alpha seeding algorithm to efficiently solve successive quadratic programming (QP) problems inherent in OELM. One of the salient characteristics of OELM-RFE is that it has only one tuning parameter: the penalty constant C. Experimental results from work on benchmark datasets show that OELM-RFE tends to have higher prediction accuracy than SVM-RFE, and requires fewer model selection efforts. In addition, the alpha seeding method works better on more datasets.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104505DOI Listing
May 2021

Uncertainty Analysis in Intervention Impact on Health Inequality for Resource Allocation Decisions.

Med Decis Making 2021 Jun 8:272989X211009883. Epub 2021 Jun 8.

Centre for Health Economics, University of York, York, Yorkshire, UK.

Cost-effectiveness analysis, routinely used in health care to inform funding decisions, can be extended to consider impact on health inequality. Distributional cost-effectiveness analysis (DCEA) incorporates socioeconomic differences in model parameters to capture how an intervention would affect both overall population health and differences in health between population groups. In DCEA, uncertainty analysis can consider the decision uncertainty around on both impacts (i.e., the probability that an intervention will increase overall health and the probability that it will reduce inequality). Using an illustrative example assessing smoking cessation interventions (2 active interventions and a "no-intervention" arm), we demonstrate how the uncertainty analysis could be conducted in DCEA to inform policy recommendations. We perform value of information (VOI) analysis and analysis of covariance (ANCOVA) to identify what additional evidence would add most value to the level of confidence in the DCEA results. The analyses were conducted for both national and local authority-level decisions to explore whether the conclusions about decision uncertainty based on the national-level estimates could inform local policy. For the comparisons between active interventions and "no intervention," there was no uncertainty that providing the smoking cessation intervention would increase overall health but increase inequality. However, there was uncertainty in the direction of both impacts when comparing between the 2 active interventions. VOI and ANCOVA show that uncertainty in socioeconomic differences in intervention effectiveness and uptake contributes most to the uncertainty in the DCEA results. This suggests potential value of collecting additional evidence on intervention-related inequalities for this evaluation. We also found different levels of decision uncertainty between settings, implying that different types and levels of additional evidence are required for decisions in different localities.
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http://dx.doi.org/10.1177/0272989X211009883DOI Listing
June 2021

Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of and .

Theranostics 2021 8;11(14):6891-6904. Epub 2021 May 8.

Women's Hospital, and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Tanshinone, a type of diterpenes derived from , is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified and as two possible downstream genes of Tan I's effects on EZH2. Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested and as two potential therapeutic targets for myeloid malignant diseases.
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http://dx.doi.org/10.7150/thno.53170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171091PMC
May 2021

The Severity of CVB3-Induced Myocarditis Can Be Improved by Blocking the Orchestration of NLRP3 and Th17 in Balb/c Mice.

Mediators Inflamm 2021 12;2021:5551578. Epub 2021 May 12.

Internal Medicine-Cardiovascular Department, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi 545005, China.

Background: The functional characteristics of NLRP3 in the pathogenesis of coxsackievirus B3- (CVB3-) induced viral myocarditis (VMC) have not been fully elucidated, and the targeted therapeutic effect of NLRP3 or its related pathway in VMC has not been reported.

Method: In this work, the change patterns of NLRP3- and Th17-related factors were detected during the pathological process of CVB3-induced VMC in Balb/c mice. The correlation between NLRP3 and Th17 cells during the VMC process was analyzed by Spearman test. The coculture system of spleen CD4 T and bone marrow CD11c DC cells was set to explore the orchestration of NLRP3 and Th17 in the pathological development of VMC in vitro. Anti-IL-1 antibody or NLRP3 Balb/c were used to block the NLRP3 pathway indirectly and directly to analyze the NLRP3-targeting therapeutic value.

Results: The change patterns of NLRP3- and Th17-related molecules in the whole pathological process of mouse CVB3-induced VMC were described. Through Spearman correlation analysis, it was confirmed that there was a close correlation between NLRP3 and Th17 cells in the whole pathological process of VMC. And the interaction mode between NLRP3 and Th17 was preliminarily explored in the cell experiment in vitro. Under the intervention of an anti-IL-1 antibody or NLRP3 knockout, the survival rate of the intervention group was significantly improved, the degree of myocardial inflammation and fibrosis was significantly alleviated, and the content of myocardial IL-17 and spleen Th17 was also significantly decreased.

Conclusion: Our findings demonstrated a key role of the NLRP3 inflammasome and its close relationship with Th17 in the pathological progression of CVB3-induced VMC and suggested a possible positive feedback-like mutual regulation mechanism between the NLRP3 inflammasome and Th17 in vitro and in the early stage of CVB3 infection. Taking NLRP3 as a new starting point, it provides a new target and idea for the prevention and treatment of CVB3-induced VMC.
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http://dx.doi.org/10.1155/2021/5551578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139334PMC
May 2021