Publications by authors named "Yifei Lu"

68 Publications

Physiological functions and therapeutic applications of neutral sphingomyelinase and acid sphingomyelinase.

Biomed Pharmacother 2021 Jul 3;139:111610. Epub 2021 May 3.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address:

Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can regulate cell growth and apoptosis. Increasing evidence shows that NSM and ASM play key roles in many processes, such as apoptosis, immune function and inflammation. Therefore, NSM and ASM have broad prospects in clinical treatments, especially in cancer, cardiovascular diseases (such as atherosclerosis), nervous system diseases (such as Alzheimer's disease), respiratory diseases (such as chronic obstructive pulmonary disease) and the phenotype of dwarfisms in adolescents, playing a complex regulatory role. This review focuses on the physiological functions of NSM and ASM and summarizes their roles in certain diseases and their potential applications in therapy.
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http://dx.doi.org/10.1016/j.biopha.2021.111610DOI Listing
July 2021

Phage Endolysin LysP108 Showed Promising Antibacterial Potential Against Methicillin-resistant .

Front Cell Infect Microbiol 2021 15;11:668430. Epub 2021 Apr 15.

Department of Microbiology, College of Basic Medical Science, Army Medical University, Chongqing, China.

As a potential antibacterial agent, endolysin can directly lyse Gram-positive bacteria from the outside and does not lead to drug resistance. Considering that XN108 is the first reported methicillin-resistant (MRSA) strain in mainland China with a vancomycin MIC that exceeds 8 µg mL, we conducted a systematic study on its phage-encoded endolysin LysP108. Standard plate counting method revealed that LysP108 could lyse and with damaged outer membrane, resulting in a significant reduction in the number of live bacteria. Scanning electron microscopy results showed that cells could be lysed directly from the outside by LysP108. Live/dead bacteria staining results indicated that LysP108 possessed strong bactericidal ability, with an anti-bacterial rate of approximately 90%. Crystal violet staining results implied that LysP108 could also inhibit and destroy bacterial biofilms. animal experiments suggested that the area of subcutaneous abscess of mice infected with MRSA was significantly reduced after the combined injection of LysP108 and vancomycin in comparison with monotherapy. The synergistic antibacterial effects of LysP108 and vancomycin were confirmed. Therefore, the present data strongly support the idea that endolysin LysP108 exhibits promising antibacterial potential to be used as a candidate for the treatment of infections caused by MRSA.
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http://dx.doi.org/10.3389/fcimb.2021.668430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082462PMC
April 2021

Phase-Matching Quantum Key Distribution with Discrete Phase Randomization.

Entropy (Basel) 2021 Apr 23;23(5). Epub 2021 Apr 23.

Henan Key Laboratory of Quantum Information and Cryptography, SSF IEU, Zhengzhou 450001, China.

The twin-field quantum key distribution (TF-QKD) protocol and its variations have been proposed to overcome the linear Pirandola-Laurenza-Ottaviani-Banchi (PLOB) bound. One variation called phase-matching QKD (PM-QKD) protocol employs discrete phase randomization and the phase post-compensation technique to improve the key rate quadratically. However, the discrete phase randomization opens a loophole to threaten the actual security. In this paper, we first introduce the unambiguous state discrimination (USD) measurement and the photon-number-splitting (PNS) attack against PM-QKD with imperfect phase randomization. Then, we prove the rigorous security of decoy state PM-QKD with discrete phase randomization. Simulation results show that, considering the intrinsic bit error rate and sifting factor, there is an optimal discrete phase randomization value to guarantee security and performance. Furthermore, as the number of discrete phase randomization increases, the key rate of adopting vacuum and one decoy state approaches infinite decoy states, the key rate between discrete phase randomization and continuous phase randomization is almost the same.
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http://dx.doi.org/10.3390/e23050508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146613PMC
April 2021

Construction of heparin-based hydrogel incorporated with Cu5.4O ultrasmall nanozymes for wound healing and inflammation inhibition.

Bioact Mater 2021 Oct 9;6(10):3109-3124. Epub 2021 Mar 9.

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China.

Excessive production of inflammatory chemokines and reactive oxygen species (ROS) can cause a feedback cycle of inflammation response that has a negative effect on cutaneous wound healing. The use of wound-dressing materials that simultaneously absorb chemokines and scavenge ROS constitutes a novel 'weeding and uprooting' treatment strategy for inflammatory conditions. In the present study, a composite hydrogel comprising an amine-functionalized star-shaped polyethylene glycol (starPEG) and heparin for chemokine sequestration as well as CuO ultrasmall nanozymes for ROS scavenging ([email protected]) was developed. The material effectively adsorbs the inflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, decreasing the migratory activity of macrophages and neutrophils. Furthermore, it scavenges the ROS in wound fluids to mitigate oxidative stress, and the sustained release of CuO promotes angiogenesis. In acute wounds and impaired-healing wounds (diabetic wounds), [email protected] hydrogels outperform the standard-of-care product Promogram® in terms of inflammation reduction, increased epidermis regeneration, vascularization, and wound closure.
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http://dx.doi.org/10.1016/j.bioactmat.2021.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960791PMC
October 2021

Role and clinical significance of TGF‑β1 and TGF‑βR1 in malignant tumors (Review).

Int J Mol Med 2021 04 19;47(4). Epub 2021 Feb 19.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China.

The appearance and growth of malignant tumors is a complicated process that is regulated by a number of genes. In recent years, studies have revealed that the transforming growth factor‑β (TGF‑β) signaling pathway serves an important role in cell cycle regulation, growth and development, differentiation, extracellular matrix synthesis and immune response. Notably, two members of the TGF‑β signaling pathway, TGF‑β1 and TGF‑β receptor 1 (TGF‑βR1), are highly expressed in a variety of tumors, such as breast cancer, colon cancer, gastric cancer and hepatocellular carcinoma. Moreover, an increasing number of studies have demonstrated that TGF‑β1 and TGF‑βR1 promote proliferation, migration and epithelial‑mesenchymal transition of tumor cells by activating other signaling pathways, signaling molecules or microRNAs (miRs), such as the NF‑κB signaling pathway and miR‑133b. In addition, some inhibitors targeting TGF‑β1 and TGF‑βR1 have exhibited positive effects in experiments. The present review discusses the association between TGF‑β1 or TGF‑βR1 and tumors, and the development of some inhibitors, hoping to provide more approaches to help identify novel tumor markers to restrain and cure tumors.
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http://dx.doi.org/10.3892/ijmm.2021.4888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895515PMC
April 2021

Low Liver Enzymes and Risk of Dementia: The Atherosclerosis Risk in Communities (ARIC) Study.

J Alzheimers Dis 2021 ;79(4):1775-1784

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia.

Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia.

Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996-1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association.

Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08-1.65). The corresponding HR was 1.22 (0.99-1.51) for AST.

Conclusion: Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia.
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http://dx.doi.org/10.3233/JAD-201241DOI Listing
January 2021

Research progress in the role and mechanism of Cadherin-11 in different diseases.

J Cancer 2021 1;12(4):1190-1199. Epub 2021 Jan 1.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Cadherin is an important cell-cell adhesion molecule, which mediates intercellular adhesion through calcium dependent affinity interaction. Cadherin-11 (CDH11, OB-cadherin) is a member of cadherin family, and its gene is situated on chromosome 16q22.1. Increasing lines of researches have proved that CDH11 plays important roles in the occurrence and development of a lot of diseases, such as tumors, arthritis and so on. CDH11 often leads to promoter methylation inactivation, which can induce cancer cell apoptosis, suppress cell motility and invasion, and can inhibit cancer through Wnt/β-catenin, AKT/Rho A and NF-κB signaling pathways. This review focused on the current knowledge of CDH11, including its function and mechanism in different diseases. In this article, we aimed to have a more comprehensive and in-depth understanding of CDH11 and to provide new ideas for the treatment of some diseases.
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http://dx.doi.org/10.7150/jca.52720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797656PMC
January 2021

Targeted Metabolomics Identifies Differential Serum and Liver Amino Acids Biomarkers in Rats with Alcoholic Liver Disease.

J Nutr Sci Vitaminol (Tokyo) 2020 ;66(6):536-544

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine.

To investigate changes in serum and hepatic levels of amino acids in ALD and to provide novel evidence and approaches for the prevention and treatment of ALD. Twenty specific pathogen-free SD male rats were devided into two groups, ten for the control group, and ten for the model group. Serum biochemical markers, including alanine aminotransferase, aspartate aminotransferase, laminin and hyaluronidase were measured. Histological analysis of liver tissues was performed. Serum and liver amino acids levels were quantitatively determined by ultra-high-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-TQMS)-based targeted metabolomics. Compared with the normal group, ALD rats showed an obvious increase in the levels of β-alanine, alanine, serine, ornithine, tyrosine and the tyrosine ratio, while there was a decrease in arginine levels, the BTR ratio and Fischer's ratio in serum. Additionally, ALD rats exhibited a significant increase in the levels of cysteine and putrescine, while there was a decrease in sarcosine, β-alanine, serine, proline, valine, threonine, ornithine, lysine, histidine, tyrosine, symmetric dimethylarginine, methionine, isoleucine and methionine-sulfoxide levels in liver tissues compared with the normal group. The serum and liver amino acids showed significant changes in ALD rats and can be considered as potential specific diagnostic biomarkers for ALD.
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http://dx.doi.org/10.3177/jnsv.66.536DOI Listing
January 2020

Integrative transcriptomics and metabolomics explore the mechanism of kaempferol on improving nonalcoholic steatohepatitis.

Food Funct 2020 Nov;11(11):10058-10069

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Kaempferol has been confirmed to be effective in improving metabolic diseases such as diabetes and obesity. However, its effect and mechanism in nonalcoholic steatohepatitis (NASH) are unclear. We aim to confirm whether kaempferol could improve NASH and find the corresponding differential genes and metabolites. Transcriptomics combined with metabolomics was used to investigate the alterations in genes and metabolites expression after kaempferol treatment in mice with high-fat-diet-induced NASH. The results showed that kaempferol reduced the level of alanine transaminase (ALT), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) in serum and triglyceride (TG), lipid droplets, and inflammatory cell infiltration in liver. Further, 277 differentially expressed genes (DEGs) were identified through liver transcriptomics and the five most obvious DEGs were found to be CYP2b9, Cyp4a12b, Mup17, Mup7, and Mup16, which revealed that HFD induced fatty acid degradation, ribosome, and glyoxylic acid and dicarboxylic acid metabolism. Nine serum metabolites (methylcysteine, l-tryptophan, adrenic acid, d-2-hydroxyglutaric acid, tartaric acid, p-cresol sulfate, l-alanine, l-tryosine, and glutaconic acid) and 3 liver differential metabolites (gallic acid, γ-lindenic acid, and l-phenylalanine) were also identified, while the pathways were mainly involved in phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. Integrating transcriptomics and metabolomics analyses indicated that kaempferol possesses the ability to improve NASH associated with energy metabolism, lipid metabolism, oxidative stress, and inflammation-related pathways. This study provides a powerful means of multiomics data integration and reveals the potent therapy and biomarkers for kaempferol.
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http://dx.doi.org/10.1039/d0fo02123gDOI Listing
November 2020

Simplified blood pressure measurement approaches and implications for hypertension screening: the Atherosclerosis Risk in Communities study.

J Hypertens 2021 Mar;39(3):447-452

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore.

Objectives: Averaging multiple blood pressure (BP) measurements is recommended for hypertension (HTN) screening but can be impractical, especially in resource-constrained settings. We aimed to explore the implications of fewer BP measurements on BP classification and subsequent cardiovascular disease (CVD) risk.

Methods: We studied 8905 middle-aged participants without diagnosed HTN and quantified misclassified HTN (≥140/90 mmHg) by simplified BP approaches (e.g. single 1st BP, single 2nd BP, mainly 1st but 2nd BP if 1st was in a certain range) vs. the reference standard of the average of 2nd and 3rd BP. We also assessed CVD risk related to HTN status.

Results: There were 823 participants classified as HTN by the standard approach. With single 1st BP, 2.8% of non-HTN were overidentified as HTN, and 18.3% of HTN were identified as not having HTN. The corresponding estimates with single 2nd BP were 2.1 and 6.4%. Similar estimates were seen when 2nd BP was used if 1st BP at least 130/80 (1.9 and 8.1%), with only 27.8% requiring 2nd BP. Two thousand, one hundred and seventy-eight CVD cases were documented in this population over 30 years. HTN by either the standard approach or any of the simplified approaches conferred higher CVD risk vs. consistent no HTN by both approaches.

Conclusion: In those without diagnosed HTN, a simplified BP measurement approach using the 2nd BP only when the 1st BP is at least 130/80 could reduce the total number of BP measurements by more than 50%, identify HTN with limited misclassification (2-8%), and predict CVD risks reasonably well.
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http://dx.doi.org/10.1097/HJH.0000000000002682DOI Listing
March 2021

Efficacy of High-Dose Vitamin D Supplementation as an Adjuvant Treatment on Pneumonia: Systematic Review and a Meta-Analysis of Randomized Controlled Studies.

Nutr Clin Pract 2021 Apr 9;36(2):368-384. Epub 2020 Oct 9.

Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, P. R. China.

The purpose of this meta-analysis was to summarize randomized controlled trial (RCT) evidence and evaluate the efficacy and safety of vitamin D (VD) supplementation as an adjunct to antibiotics for the treatment of pneumonia. Data sources published from the inception dates up to January 2020 were searched. RCTs of VD supplementation of any duration, age, and dosing regimen type were eligible for inclusion if data on pneumonia were collected. Thirteen studies (4786 randomized participants) fulfilled eligibility criteria. VD supplementation significantly increased levels of serum 25(OH)D (mean difference = 15.97; 95% CI, 7.49-24.44; P = .002) and reduced incidence of repeat episodes of pneumonia (risk ratio [RR] = 0.68; 95% CI, 0.50-0.93; P = .02). Subgroup analysis revealed VD supplementation had more reducing effects on repeat episodes of pneumonia among participants in trials in which the population were children (RR = 0.66; 95% CI, 0.48-0.90), duration <3 months (RR = 0.55; 95% CI, 0.33-0.91), or dose of VD <300,000 IU (RR = 0.51; 95% CI, 0.29-0.89). Although our results suggested that VD supplementation had a positive effect on recovery rate of pneumonia (RR = 1.28; 95% CI, 0.94-1.74; I = 13%), there was no statistical difference (P = .12). High-dose VD intervention may have an effect on reducing the incidence rate of repeat episodes of pneumonia by enhancing immune efficacy, although more population studies are needed to support that VD supplementation has therapeutic effects on pneumonia itself.
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http://dx.doi.org/10.1002/ncp.10585DOI Listing
April 2021

Bone marrow mesenchymal stem cells-derived exosomes for penetrating and targeted chemotherapy of pancreatic cancer.

Acta Pharm Sin B 2020 Aug 28;10(8):1563-1575. Epub 2019 Nov 28.

Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancy, with an only 6% 5-year relative survival rate. The dismal therapeutic effect is attributed to the chemotherapy resistance and unique pathophysiology with abundant inflammatory cytokines and abnormal hyperplasia of extracellular matrix (ECM). Based on the theory that bone marrow mesenchymal stem cells (BM-MSCs) can influence the tumorous microenvironment and malignant growth of PDAC, we employed exosomes (Exos) derived from BM-MSCs as PDAC-homing vehicles to surpass the restrictions of pathological ECM and increase the accumulation of therapeutics in tumor site. To overcome chemoresistance of PDAC, paclitaxel (PTX) and gemcitabine monophosphate (GEMP)-an intermediate product of gemcitabine metabolism-were loaded in/on the purified Exos. In this work, the Exo delivery platform showed superiorities in homing and penetrating abilities, which were performed on tumor spheroids and PDAC orthotopic models. Meanwhile, the favorable anti-tumor efficacy and , plus relatively mild systemic toxicity, was found. Loading GEMP and PTX, benefitting from the naturally PDAC selectivity, the Exo platform we constructed performs combined functions on excellent penetrating, anti-matrix and overcoming chemoresistance (Scheme 1). Worth expectantly, the Exo platform may provide a prospective approach for targeted therapies of PDAC.
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http://dx.doi.org/10.1016/j.apsb.2019.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488356PMC
August 2020

The impact of ATP-binding cassette transporters on metabolic diseases.

Nutr Metab (Lond) 2020 3;17:61. Epub 2020 Aug 3.

Center of Chinese Medical Therapy and Systems Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Cailun Road 1200, Shanghai, 201203 China.

Currently, many people worldwide suffer from metabolic diseases caused by heredity and external factors, such as diet. One of the symptoms of metabolic diseases is abnormal lipid metabolism. ATP binding cassette (ABC) transporters are one of the largest transport protein superfamilies that exist in nearly all living organisms and are mainly located on lipid-processing cells. ABC transporters have been confirmed to be closely related to the pathogenesis of diseases such as metabolic diseases, cancer and Alzheimer's disease based on their transport abilities. Notably, the capability to transport lipids makes ABC transporters critical in metabolic diseases. In addition, gene polymorphism in ABC transporters has been reported to be a risk factor for metabolic diseases, and it has been reported that relevant miRNAs have significant roles in regulating ABC transporters. In this review, we integrate recent studies to examine the roles of ABC transporters in metabolic diseases and aim to build a network with ABC transporters as the core, linking their transport abilities with metabolic and other diseases.
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http://dx.doi.org/10.1186/s12986-020-00478-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398066PMC
August 2020

A two-membrane electrodialytic carbonate eluent generator for ion chromatography.

J Chromatogr A 2020 Jul 20;1622:461095. Epub 2020 Apr 20.

Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong RD, Shanghai 200237, China. Electronic address:

A two-membrane electrodialytic carbonate eluent generator (EDG) for ion chromatography (IC) is described. It is in a sandwich-like configuration, in which the central eluent channel is spatially isolated from two outer regenerant channels by stacked cation exchange membranes (CEMs) and anion exchange membranes (AEMs). A platinum screen electrode is placed in each of two outer regenerant channels. The electrode at the CEMs side is set as an anode with respect to the electrode at the AEMs side being cathode. Potassium carbonate and/or bicarbonate solution is pumped into the regenerant channel as feed solution. The electromigration of carbonate and/or bicarbonate and potassium from feed solution respectively through AEMs and CEMs will form a gas-free eluent. With this configuration, ion transport behavior through AEMs was explored. The device demonstrated good reproducibility, as indicated by the relative standard deviation of retention time of less than 0.08%.
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http://dx.doi.org/10.1016/j.chroma.2020.461095DOI Listing
July 2020

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases.

J Cancer 2020 15;11(12):3519-3535. Epub 2020 Mar 15.

Center of Chinese Medical Therapy and Systems Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.
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http://dx.doi.org/10.7150/jca.41841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150451PMC
March 2020

Kynurenine-3-monooxygenase: A new direction for the treatment in different diseases.

Food Sci Nutr 2020 Feb 20;8(2):711-719. Epub 2020 Jan 20.

Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai China.

Kynurenine-3-monooxygenase (KMO) is an enzyme that relies on nicotinamide adenine dinucleotide phosphate (NADP), a key site in the kynurenine pathway (KP), which has great effects on neurological diseases, cancer, and peripheral inflammation. This review mainly pay attention to the research of KMO mechanism for the treatment of different diseases, and hopes to provide assistance for clinical and drug use. KMO controlling the chief division of the KP, which directly controls downstream product quinolinic acid (QUIN) and indirectly controls kynurenic acid (KYNA), plays an important role in many diseases, especially neurological diseases.
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http://dx.doi.org/10.1002/fsn3.1418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020307PMC
February 2020

rhBMP‑7 suppresses TGF‑β1‑induced endothelial to mesenchymal transition in circulating endothelial cells by regulating Smad5.

Mol Med Rep 2020 Jan 21;21(1):478-484. Epub 2019 Nov 21.

Department of Cardiology, Taizhou Hospital, Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China.

Endothelial to mesenchymal transition (EndMT) has been confirmed to participate in several cardiovascular diseases. In addition, EndMT of circulating endothelial cells (CECs) contributes to the pathology of musculoskeletal injury. However, little is known about the molecular mechanism of CECs undergoing EndMT. In the present study, human CECs were isolated and identified using anti‑CD146‑coupled magnetic beads. CECs were exposed to transforming growth factor (TGF)‑β1 or TGF‑β1 + recombinant human bone morphogenetic protein 7 (rhBMP‑7) or TGF‑β1 + rhBMP‑7 + Smad5 antagonist Jun activation domain‑binding protein 1. Vascular endothelial (VE)‑cadherin and vimentin expression were detected by immunofluorescence staining in TGF‑β1‑treated CECs. The expression levels of von Willebrand factor (vWF), E‑selectin, VE‑cadherin, vimentin, fibronectin, α smooth muscle actin (α‑SMA) and Smad2/3 were detected by reverse transcription‑quantitative PCR or western blot analysis. It was identified that rhBMP‑7 attenuated TGF‑β1‑induced endothelial cell injury. TGF‑β1 could induce the EndMT process in CECs, as confirmed by the co‑expression of VE‑cadherin and vimentin. TGF‑β1 significantly reduced the expression of VE‑cadherin, and induced the expression of vimentin, fibronectin and α‑SMA. rhBMP‑7 reversed the effects of TGF‑β1 on the expression of these genes. Additionally, Smad5 antagonist reversed the effects of rhBMP‑7 on TGF‑β1‑induced EndMT, and upregulated rhBMP‑7‑inhibited Smad2/3 expression. In conclusion, TGF‑β1 could induce EndMT in CECs and rhBMP‑7 may suppress this process by regulating Smad5.
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http://dx.doi.org/10.3892/mmr.2019.10842DOI Listing
January 2020

Multi-label classification of retinal lesions in diabetic retinopathy for automatic analysis of fundus fluorescein angiography based on deep learning.

Graefes Arch Clin Exp Ophthalmol 2020 Apr 14;258(4):779-785. Epub 2020 Jan 14.

Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China.

Purpose: To automatically detect and classify the lesions of diabetic retinopathy (DR) in fundus fluorescein angiography (FFA) images using deep learning algorithm through comparing 3 convolutional neural networks (CNNs).

Methods: A total of 4067 FFA images from Eye Center at the Second Affiliated Hospital of Zhejiang University School of Medicine were annotated with 4 kinds of lesions of DR, including non-perfusion regions (NP), microaneurysms, leakages, and laser scars. Three CNNs including DenseNet, ResNet50, and VGG16 were trained to achieve multi-label classification, which means the algorithms could identify 4 retinal lesions above at the same time.

Results: The area under the curve (AUC) of DenseNet reached 0.8703, 0.9435, 0.9647, and 0.9653 for detecting NP, microaneurysms, leakages, and laser scars, respectively. For ResNet50, AUC was 0.8140 for NP, 0.9097 for microaneurysms, 0.9585 for leakages, and 0.9115 for laser scars. And for VGG16, AUC was 0.7125 for NP, 0.5569 for microaneurysms, 0.9177 for leakages, and 0.8537 for laser scars.

Conclusions: Experimental results demonstrate that DenseNet is a suitable model to automatically detect and distinguish retinal lesions in the FFA images with multi-label classification, which lies the foundation of automatic analysis for FFA images and comprehensive diagnosis and treatment decision-making for DR.
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http://dx.doi.org/10.1007/s00417-019-04575-wDOI Listing
April 2020

Physiology and proteomic analysis reveals root, stem and leaf responses to potassium deficiency stress in alligator weed.

Sci Rep 2019 11 22;9(1):17366. Epub 2019 Nov 22.

College of Agronomy, Sichuan Agricultural University, Chengdu, 611130, China.

Alligator weed is reported to have a strong ability to adapt to potassium deficiency stress. Proteomic changes in response to this stress are largely unknown in alligator weed seedlings. In this study, we performed physiological and comparative proteomics of alligator weed seedlings between normal growth (CK) and potassium deficiency (LK) stress using 2-DE techniques, including root, stem and leaf tissues. Seedling height, soluble sugar content, PGK activity and HO contents were significantly altered after 15 d of LK treatment. A total of 206 differentially expressed proteins (DEPs) were identified. There were 72 DEPs in the root, 79 in the stem, and 55 in the leaves. The proteomic results were verified using western blot and qRT-PCR assays. The most represented KEGG pathway was "Carbohydrate and energy metabolism" in the three samples. The "Protein degradation" pathway only existed in the stem and root, and the "Cell cycle" pathway only existed in the root. Protein-protein interaction analysis demonstrated that the interacting proteins detected were the most common in the stem, with 18 proteins. Our study highlights protein changes in alligator weed seedling under LK stress and provides new information on the comprehensive analysis of the protein network in plant potassium nutrition.
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http://dx.doi.org/10.1038/s41598-019-53916-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874644PMC
November 2019

Dandelion-Like Tailorable Nanoparticles for Tumor Microenvironment Modulation.

Adv Sci (Weinh) 2019 Nov 12;6(21):1901430. Epub 2019 Sep 12.

Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Medical Neurobiology Department of Pharmaceutics School of Pharmacy Fudan University Shanghai 201203 China.

Tumor-associated macrophages (TAMs) constitute over 50% of the number of cells within the tumor, playing a major role in tumor progression and invasion. Remodeling the tumor immune microenvironment by modulating TAM polarization has been emerging as a new and promising therapeutic strategy. However, the high interstitial fluid pressure and dense extracellular matrix lead to insufficient penetration of nanosized therapies. To overcome this dilemma, an acid-triggered size-changeable nanoparticle (aptamer/acid sensitive linker crosslinked DGL/zoledronic acid, i.e., [email protected](DGL-ZA) NPs) with effective tumor distribution, extravasation, and penetration is designed. Dendrigraft poly--lysines (DGLs) which can induce tumor autophagy as mimics of natural abnormal proteins are crosslinked via a mild-acid-responsive linker (1,6-bis(4-formylbenzoyloxy) hexane). Long circulation property and tumor penetration are achieved simultaneously by catching DGLs in neutral pH while releasing them in the tumor's pH, like dandelion seeds in midair. The macrophage conditioning agent zoledronic acid (ZA) is loaded on DGLs by the charge attraction. A Tenascin-C targeting aptamer (GBI-10) is modified onto (DGL-ZA) NPs for a tumor-homing effect. [email protected](DGL-ZA) NPs show both enhanced penetration in in vitro 3D triple negative breast cancer spheroids and in vivo tumor tissues. Effective macrophage regulation, enhanced tumor autophagy, and excellent in vivo antitumor efficacy are achieved, suggesting this tactic as a significant antitumor strategy.
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http://dx.doi.org/10.1002/advs.201901430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839635PMC
November 2019

Physical Activity and Subsequent Risk of Hospitalization With Peripheral Artery Disease and Critical Limb Ischemia in the ARIC Study.

J Am Heart Assoc 2019 11 23;8(21):e013534. Epub 2019 Oct 23.

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD.

Background Whether physical activity is a determinant of peripheral artery disease (PAD) remains unclear. We therefore assessed the association of physical activity (amount and intensity) with subsequent risk of hospitalization with PAD and its severe form, critical limb ischemia, in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results We included 12 513 participants free of cardiovascular disease at baseline (1987-1989), with a mean age of 53.9 years, 55.3% women, and 25.0% black. Physical activity was assessed using a modified Baecke questionnaire and categorized into poor (no moderate [3 to <6 metabolic equivalents] or vigorous [≥6 metabolic equivalents] exercise), intermediate (1-74 min/wk vigorous or 1-149 min/wk moderate plus vigorous exercise), and recommended (≥75 min/wk vigorous or ≥150 min/wk moderate plus vigorous exercise). We also modeled moderate and vigorous exercise individually. All analyses applied Cox regression models. Intermediate and recommended exercise were seen in 24.7% and 38.1%, respectively. During a median follow-up of 25.4 years, 434 incident hospitalizations with PAD (166 critical limb ischemia) were documented. Recommended versus poor activity was associated with a lower demographically adjusted PAD risk (hazard ratio, 0.68; 95% CI, 0.54-0.85) but attenuated after accounting for lifestyle factors (hazard ratio, 0.84; 95% CI, 0.66-1.05). When analyzing moderate and vigorous exercise separately, vigorous exercise was robustly related to lower risk of hospitalization with PAD, and critical limb ischemia in particular (hazard ratio, 0.72; 95% CI, 0.54-0.97 per 200 metabolic equivalents*min/wk increment in the most extended model). Conclusions Higher amount and intensity of physical activity were related to lower risks of hospitalization with PAD and critical limb ischemia, further highlighting the importance of engaging in physical activity for vascular health.
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http://dx.doi.org/10.1161/JAHA.119.013534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898846PMC
November 2019

Recent progress regarding kaempferol for the treatment of various diseases.

Exp Ther Med 2019 Oct 13;18(4):2759-2776. Epub 2019 Aug 13.

Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China.

Kaempferol, also known as kaempferol-3 or kaempferide, is a flavonoid compound that naturally occurs in tea, as well as numerous common vegetables and fruits, including beans, broccoli, cabbage, gooseberries, grapes, kale, strawberries, tomatoes, citrus fruits, brussel sprouts, apples and grapefruit. The present review mainly summarizes the application of kaempferol in treating diseases and the underlying mechanisms that are currently being studied. Due to its anti-inflammatory properties, it may be used to treat numerous acute and chronic inflammation-induced diseases, including intervertebral disc degeneration and colitis, as well as post-menopausal bone loss and acute lung injury. In addition, it has beneficial effects against cancer, liver injury, obesity and diabetes, inhibits vascular endothelial inflammation, protects the cranial nerve and heart function, and may be used for treating fibroproliferative disorders, including hypertrophic scar.
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http://dx.doi.org/10.3892/etm.2019.7886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755486PMC
October 2019

Excess Body Weight and the Risk of Liver Cancer: Systematic Review and a Meta-Analysis of Cohort Studies.

Nutr Cancer 2020 23;72(7):1085-1097. Epub 2019 Sep 23.

Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Southeast University, Nanjing, P.R. China.

To update and expand the previous meta-analysis including all prospective studies on the issue of the associations between overweight, obesity, and liver cancer risk. We also performed a meta-regression to investigate a potential nonlinear and/or linear association between body mass index (BMI) and liver cancer risk. Literature search was conducted in four libraries from the beginning of indexing for each database to 1st September, 2018. The summary risk estimate was statistically significant on the association between overweight and the risk of liver cancer incidence (relative ratio [RR] = 1.19). The RRs were significantly stronger in people with known liver disease with overweight than in the general population with overweight (RR = 1.50 vs. RR = 1.10;  = .02). The meta-analysis showed an increase by 87% on the risk of liver cancer incidence in obesity categories, relative to categories of normal BMI (RR = 1.87,  < .01). Moreover, the results showed that, overweight was associated with 9% increased and obesity with 66% increased for risk of liver cancer mortality. In linear model, the relative risks of liver cancer were 1.32 for continuous BMI per 5 kg/m increase. This meta-analysis supports the hypothesis that overweight, obesity may significantly increase liver cancer risk.
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http://dx.doi.org/10.1080/01635581.2019.1664602DOI Listing
May 2021

GLUT1-mediated effective anti-miRNA21 pompon for cancer therapy.

Acta Pharm Sin B 2019 Jul 28;9(4):832-842. Epub 2019 Jan 28.

Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.

Oncogenic microRNAs are essential components in regulating the gene expression of cancer cells. Especially miR21, which is a major player involved of tumor initiation, progression, invasion and metastasis in several cancers. The delivery of anti-miR21 sequences has significant potential for cancer treatment. Nevertheless, since anti-miR21 sequences are extremely unstable and they need to obtain certain concentration to function, it is intensely difficult to build an effective delivery system for them. The purpose of this work is to construct a self-assembled glutathione (GSH)-responsive system with tumor accumulation capacity for effective anti-miR21 delivery and cancer therapy. A novel drug delivery nanosphere carrying millions of anti-miR21 sequences was developed through the rolling circle transcription (RCT) method. GSH-responsive cationic polymer polyethyleneimine (pOEI) was synthesized to protect the nanosphere from degradation by Dicer or other RNase in normal cells and optimize the pompon-like nanoparticle to suitable size. Dehydroascorbic acid (DHA), a targeting molecule, which is a substrate of glucose transporter 1 (GLUT 1) and highly expressed on malignant tumor cells, was connected to pOEI through PEG, and then the polymer was used for contracting a RNA nanospheres into nanopompons. The anti-miR21 nanopompons showed its potential for effective cancer therapy.
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http://dx.doi.org/10.1016/j.apsb.2019.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663942PMC
July 2019

2017 ACC/AHA blood pressure classification and incident peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) Study.

Eur J Prev Cardiol 2020 01 30;27(1):51-59. Epub 2019 Jul 30.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.

Aims: The aim of this study was to evaluate the associations of blood pressure categorization based on the 2017 American College of Cardiology and American Heart Association guideline with the risk of peripheral artery disease (PAD).

Methods: Among 13,113 middle-aged participants, we investigated the associations of 2017 blood pressure categories (systolic <120 and diastolic <80 mmHg (normal if no anti-hypertensive medications; reference), 120-129 and <80 (elevated), 130-139 and/or 80-89 (stage 1 hypertension), and ≥140 and/or ≥90 (stage 2 hypertension)) with incident PAD (hospitalizations with a diagnosis or leg revascularization) using Cox regression models. Analyses were separately conducted in individuals with and without anti-hypertensive medications.

Results: During a median follow-up of 25.4 years, 466 incident PAD occurred (271 cases in 9858 participants without anti-hypertensive medications). In participants without anti-hypertensive medications, we observed significant hazard ratios of PAD in elevated blood pressure (1.80 (1.28-2.51)) and stage 2 hypertension (2.40 (1.72-3.34)), but not in stage 1 hypertension. Analyzing systolic and diastolic blood pressure separately, higher systolic blood pressure categories showed significant associations with incident PAD in a graded fashion whereas, for diastolic blood pressure, only ≥90 mmHg did. Generally similar patterns were seen among participants on anti-hypertensive medication, while they had higher risk of PAD than those without at each blood pressure category.

Conclusions: Systolic blood pressure, including the category of 130-139 mmHg, showed stronger associations with incident PAD than did diastolic blood pressure. Consequently, elevated blood pressure conferred similar or even greater risk of PAD than stage 1 hypertension, with implications on how to interpret new blood pressure categories in terms of leg vascular health.
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http://dx.doi.org/10.1177/2047487319865378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938694PMC
January 2020

A bipolar membrane-based cation electrolytic membrane suppressor for ion chromatography.

J Chromatogr A 2019 Oct 26;1603:422-425. Epub 2019 Jun 26.

Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address:

A bipolar membrane (BPM)-based cation electrolytic membrane suppressor (CEMS) for ion chromatography is described. It has a sandwiched configuration, similar to that of commercial CEMS, except that a BPM and an anion exchange membrane (AEM) are respectively used to isolate the central eluent channel from two outer regenerant chambers. The AEM side of BPM is facing the central channel, contactless with the cathode. The suppression hydroxide ions are generated by enhanced water splitting at the junction layer of BPM. The suppressor showed comparable performance to common one in terms of suppressed background conductivity (∼0.38 μS/cm) and very low noise level (∼0.6 nS/cm). Possible electrochemically induced reductive deamination of AEM when immersed into the alkaline solution at the cathode can be avoided.
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http://dx.doi.org/10.1016/j.chroma.2019.06.052DOI Listing
October 2019

Trained Macrophage Bioreactor for Penetrating Delivery of Fused Antitumor Protein.

ACS Appl Mater Interfaces 2019 Jul 19;11(26):23018-23025. Epub 2019 Jun 19.

Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy , Fudan University , Shanghai 201203 , China.

Macromolecular protein drugs are promising anti-neoplastic agents based on their precise tumor affinity and innocuousness to normal tissues. Although direct delivery of protein drugs remains impractical due to its short half-life in circulation, inefficiency in tumor accumulation, and poor penetrability in intratumoral distribution. Recently, biogenetic cell-based drug vectors have been widely reported for antitumor drug delivery. Macrophage is naturally independent with endogenous proteolysis, elimination of reticuloendothelial system, and immune surveillance. Meanwhile, its innate recruitment behaviors responsive to chronic inflammation signals make it a potential cellular vector for tumor targeting drug delivery. In this study, we develop a trained macrophage bioreactor for tumor homing and an in situ expression of fused antitumor protein. The recombinant tumor necrosis factor related apoptosis-inducing ligand is coded on a plasmid vector with penetrating domain on the C terminus, which improves the intratumoral distribution by facilitating protein dispersion in tumor tissue after in situ secretion. The combination of tumor-infiltrating macrophage bioreactor and multifunctional fused protein drug embodies a new effective tumor homing system for antitumor protein delivery.
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http://dx.doi.org/10.1021/acsami.9b06097DOI Listing
July 2019

Codelivery Nanosystem Targeting the Deep Microenvironment of Pancreatic Cancer.

Nano Lett 2019 06 14;19(6):3527-3534. Epub 2019 May 14.

Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Research Center on Aging and Medicine, Department of Pharmaceutics, School of Pharmacy , Fudan University , Shanghai 201203 , China.

Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive malignancies due to its unique microenvironment of which the cardinal histopathological feature is the remarkable desmoplasia of the stroma, taking up about 80% of the tumor mass. The desmoplastic stroma negatively affects drug diffusion and the infiltration of T cells, leading to an immunosuppressive microenvironment. However, this unique microenvironment can limit the physical spread of pancreatic cancer via a neighbor suppression effect. Here, a tumor central stroma targeting and microenvironment responsive strategy was applied to generate a nanoparticle coloading paclitaxel and phosphorylated gemcitabine. The designed nanoparticle disrupted the central stroma while preserving the external stroma, thereby promoting the antitumor effectiveness of chemotherapeutics. Additionally, the resulting nanoparticle can modulate the tumor immunosuppressive microenvironment by augmenting the number of cytotoxic T cells and restraining the percentage of T regulatory cells. The relatively intact external stroma can effectively maintain the neighbor suppression effect and prevent tumor metastasis. Combining stroma targeting with the delivery of stimuli-responsive polymeric nanoparticles embodies an effective tumor-tailored drug delivery system.
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http://dx.doi.org/10.1021/acs.nanolett.9b00374DOI Listing
June 2019

Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke.

Adv Mater 2019 May 8;31(21):e1808361. Epub 2019 Apr 8.

Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China.

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.
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http://dx.doi.org/10.1002/adma.201808361DOI Listing
May 2019