Publications by authors named "Qiang Fu"

1,758 Publications

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Comparative analysis of the miRNA-mRNA regulation networks in turbot (Scophthalmus maximus L.) following Vibrio anguillarum infection.

Dev Comp Immunol 2021 Jun 12:104164. Epub 2021 Jun 12.

School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China. Electronic address:

MicroRNAs could not only regulate posttranscriptional silencing of target genes in eukaryotic organisms, but also have positive effect on their target genes as well. These microRNAs have been reported to be involved in intestine mucosal immune responses to pathogen infection in teleost. Therefore, we constructed the immune-related miRNA-mRNA networks in turbot intestine following V. anguillarum infection. In our results, 1,550 differentially expressed (DE) genes and 167 DE miRNAs were identified. 113 DE miRNAs targeting 89 DE mRNAs related to immune response were used to construct miRNA-mRNA interaction networks. Functional analysis showed that target genes were associated with synthesis and degradation of ketone bodies, mucin type O-Glycan biosynthesis, homologous recombination, biotin metabolism, and intestinal immune network for IgA production that were equivalent to the function of IgT and IgM in fish intestine. Finally, 10 differentially expressed miRNAs and 7 differentially expressed mRNAs were selected for validating the accuracy of high-throughput sequencing results by qRT-PCR. The results of this study will provide valuable information for the elucidation of the regulation mechanisms of miRNA-mRNA interactions involved in disease resistance in teleost intestine mucosal immune system.
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http://dx.doi.org/10.1016/j.dci.2021.104164DOI Listing
June 2021

Effect of iron addition on mAb productivity and oxidative stress in Chinese hamster ovary culture.

Biotechnol Prog 2021 Jun 9:e3181. Epub 2021 Jun 9.

Department of Chemical Engineering, University of Massachusetts Lowell, Lowell, Massachusetts, USA.

Trace metals play a critical role in the development of culture media used for the production of therapeutic proteins. Iron has been shown to enhance the productivity of monoclonal antibodies during Chinese hamster ovary (CHO) cell culture. However, the redox activity and pro-oxidant behavior of iron may also contribute toward the production of reactive oxygen species (ROS). In this work, we aim to clarify the influence of trace iron by examining the relationship between iron supplementation to culture media, mAb productivity and glycosylation, and oxidative stress interplay within the cell. Specifically, we assessed the impacts of iron supplementation on (a) mAb production and glycosylation; (b) mitochondria-generated free hydroxyl radicals (ROS); (c) the cells ability to store energy during oxidative phosphorylation; and (d) mitochondrial iron concentration. Upon the increase of iron at inoculation, CHO cells maintained a capacity to rebound from iron-induced viability lapses during exponential growth phase and improved mAb productivity and increased mAb galactosylation. Fluorescent labeling of the mitochondrial hydroxyl radical showed enhanced environments of oxidative stress upon iron supplementation. Additional labeling of active mitochondria indicated that, despite the enhanced production of ROS in the mitochondria, mitochondrial membrane potential was minimally impacted. By replicating iron treatments during seed train passaging, the CHO cells were observed to adapt to the shock of iron supplementation prior to inoculation. Results from these experiments demonstrate that CHO cells have the capacity to adapt to enhanced environments of oxidative stress and improve mAb productivity and mAb galactosylation with minimal perturbations to cell culture.
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http://dx.doi.org/10.1002/btpr.3181DOI Listing
June 2021

Berbamine inhibits Japanese Encephalitis virus (JEV) infection by compromising TPRMLs-mediated endolysosomal trafficking of Low-density lipoprotein receptor (LDLR).

Emerg Microbes Infect 2021 Jun 8:1-43. Epub 2021 Jun 8.

City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.

Japanese encephalitis virus (JEV), a member of the genus, is an important pathogen that causes human and animal infectious diseases in Asia. So far, no effective antiviral agents are available to treat JEV infection. Here, we found that LDLR is a host factor required for JEV entry. Berbamine significantly decreases the level of LDLR at the plasma membrane by inducing the secretion of LDLR via extracellular vesicles (EVs), thereby inhibiting JEV infection. Mechanistically, berbamine blocks TRPMLs (Ca permeable non-selective cation channels in endosomes and lysosomes) to compromise the endolysosomal trafficking of LDLR. This leads to the increased secretion of LDLR via EVs and the concomitant decrease in its level at the plasma membrane, thereby rendering cells resistant to JEV infection. Berbamine also protects mice from the lethal challenge of JEV. In summary, these results indicate that berbamine is an effective anti-JEV agent by preventing JEV entry.
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http://dx.doi.org/10.1080/22221751.2021.1941276DOI Listing
June 2021

Unique structure of active platinum-bismuth site for oxidation of carbon monoxide.

Nat Commun 2021 Jun 7;12(1):3342. Epub 2021 Jun 7.

Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China.

As the technology development, the future advanced combustion engines must be designed to perform at a low temperature. Thus, it is a great challenge to synthesize high active and stable catalysts to resolve exhaust below 100 °C. Here, we report that bismuth as a dopant is added to form platinum-bismuth cluster on silica for CO oxidation. The highly reducible oxygen species provided by surface metal-oxide (M-O) interface could be activated by CO at low temperature (~50 °C) with a high CO production rate of 487 μmol·g·s at 110 °C. Experiment data combined with density functional calculation (DFT) results demonstrate that Pt cluster with surface Pt-O-Bi structure is the active site for CO oxidation via providing moderate CO adsorption and activating CO molecules with electron transformation between platinum atom and carbon monoxide. These findings provide a unique and general approach towards design of potential excellent performance catalysts for redox reaction.
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http://dx.doi.org/10.1038/s41467-021-23696-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184822PMC
June 2021

Graphene-Reinforced Zn-Ni Alloy Composite Coating on Iron Substrates by Pulsed Reverse Electrodeposition and Its High Corrosion Resistance.

ACS Omega 2021 Jun 17;6(21):13728-13741. Epub 2021 May 17.

School of Physics and Technology, and MOE Key Laboratory of Artificial Micro- and Nano-structures, Wuhan University, Wuhan 430072, China.

In this paper, a novel kind of graphene (Gr)-reinforced Zn-Ni alloy composite coating is successfully prepared on an iron substrate by pulsed reverse electrodeposition. Hydrophilic graphene oxide (GO) is directly added to the electrolyte and reduced to Gr during coating. The experimental results reveal that (1) there is an optimal adding amount (about 0.4 g/L) of GO in the electrolyte for achieving the highest mechanical properties and corrosion resistance; (2) the composite coating shows grain refinement and a dense microstructure due to heterogeneous nucleation sites provided from the Gr sheets during electrodeposition; and (3) compared to the regular Zn-Ni coating, the composite coating exhibits many enhancements, including hardness increase by 2.3 times, elastic modulus increase by 39%, and corrosion rate decrease from 37.66 to 1.30 mils/annum. This process has advantages such as being simple, effective, well repeatable, economical, and supporting large-scale production and is expected to be widely applied in electronics, automobiles, marine engineering, and military industries.
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http://dx.doi.org/10.1021/acsomega.1c00977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173559PMC
June 2021

The CC and CXC chemokine receptors in turbot (Scophthalmus maximus L.) and their response to Aeromonas salmonicida infection.

Dev Comp Immunol 2021 Jun 1;123:104155. Epub 2021 Jun 1.

School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China. Electronic address:

Chemokines are crucial regulators of cell mobilization for development, homeostasis, and immunity. Chemokines signal through binding to chemokine receptors, a superfamily of seven-transmembrane domain G-coupled receptors. In the present study, eleven CC chemokine receptors (CCRs) and seven CXC chemokine receptors (CXCRs) were identified from turbot genome. Phylogenetic and syntenic analyses were performed to annotate these genes, indicating the closest relationship between the turbot chemokine receptors and their counterparts of Japanese flounders (Paralichthys olivaceus). Evolutionary analyses revealed that the tandem duplications of CCR8 and CXCR3, the whole genome duplications of CCR6, CCR9, CCR12, and CXCR4, and the teleost-specific CCR12 led to the expansion of turbot chemokine receptors. In addition, turbot chemokine receptors were ubiquitously expressed in nine examined healthy tissues, with high expression levels observed in spleen, gill, and head kidney. Moreover, most turbot chemokine receptors were significantly differentially expressed in spleen and gill after Aeromonas salmonicida infection, and exhibited general down-regulations at early time points and then gradually up-regulated. Finally, protein-protein interaction network (PPI) analyses indicated that chemokine receptors interacted with a few immune-related genes such as interleukins, Grk genes, CD genes, etc. These results should be valuable for comparative immunological studies and provide insights for further functional characterization of chemokine receptors in turbots.
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http://dx.doi.org/10.1016/j.dci.2021.104155DOI Listing
June 2021

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication.

Pharmaceutics 2021 May 18;13(5). Epub 2021 May 18.

Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.

Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFR. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling.
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http://dx.doi.org/10.3390/pharmaceutics13050747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158526PMC
May 2021

Identification and characterization of a C-type lectin in turbot (Scophthalmus maximus) which functioning as a pattern recognition receptor that binds and agglutinates various bacteria.

Fish Shellfish Immunol 2021 May 29;115:104-111. Epub 2021 May 29.

School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, Shandong Province, 266109, China. Electronic address:

C-type lectins (CTLs) are important pathogen pattern recognition receptors that recognize carbohydrate structures. In present study, a C-type lectin domain family 4 member E-like gene from turbot, which tentatively named SmCLEC4E-like (SmCLEC4EL), was identified, and the expressional and functional analyses were performed. In our results, SmCLEC4EL showed conserved synteny with CLEC4E-like genes from several fish species in genome, and possessed a typical type II transmembrane CTL architecture: an N-terminal intracellular region, a transmembrane domain and a C-terminal extracellular region which contained a predicted carbohydrate recognition domain (CRD). In addition, SmCLEC4EL exhibited the highest expression level in spleen in healthy fish, and showed significantly induced expression in mucosal tissues, intestine and skin, under bacteria challenge. Finally, the recombinant SmCLEC4EL protein combined with LPS, PGN, LTA and five different kinds of bacteria in a dose-dependent manner, and agglutinated these bacteria strains in the presence of calcium. These findings collectively demonstrated that SmCLEC4EL, a calcium-dependent CTL, could function as a pattern recognition receptor in pathogen recognition and participate in host anti-bacteria immunity.
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http://dx.doi.org/10.1016/j.fsi.2021.05.020DOI Listing
May 2021

Ultrapermeable Composite Membranes Enhanced Via Doping with Amorphous MOF Nanosheets.

ACS Cent Sci 2021 Apr 25;7(4):671-680. Epub 2021 Mar 25.

Department of Chemical Engineering, The University of Melbourne, Parkville, VIC 3010, Australia.

Thin-film composite (TFC) polymeric membranes have attracted increasing interest to meet the demands of industrial gas separation. However, the development of high-performance TFC membranes within their current configuration faces two key challenges: (i) the thickness-dependent gas permeability of polymeric materials (mainly poly(dimethylsiloxane) (PDMS)) and (ii) the geometric restriction effect due to the limited pore accessibility of the underlying porous substrate. Here we demonstrate that the incorporation of trace amounts (∼1.8 wt %) of amorphous metal-organic framework (MOF) nanosheets into the gutter layer of TFC assemblies can simultaneously address these two limitations by the creation of rapid, transmembrane gas diffusion pathways. The resultant PDMS&MOF membrane displayed excellent CO permeance of 10450 GPU and CO/N selectivity of 9.1. Leveraging this strategy, we successfully fabricate a novel TFC membrane, consisting of a PDMS&MOF gutter and an ultrathin (∼54 nm) poly(ethylene glycol) top selective layer via surface-initiated atom transfer radical polymerization. The complete TFC membrane exhibits excellent processability and remarkable CO/N separation performance (1990 GPU with a CO/N ideal selectivity of 39). This study reveals a strategy for the design and fabrication of a new TFC membrane system with unprecedented gas-separation performance.
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http://dx.doi.org/10.1021/acscentsci.0c01711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155479PMC
April 2021

Stromal Score-Based Gene Signature: A Prognostic Prediction Model for Colon Cancer.

Front Genet 2021 12;12:655855. Epub 2021 May 12.

Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background: Growing evidence has revealed the crucial roles of stromal cells in the microenvironment of various malignant tumors. However, efficient prognostic signatures based on stromal characteristics in colon cancer have not been well-established yet. The present study aimed to construct a stromal score-based multigene prognostic prediction model for colon cancer.

Methods: Stromal scores were calculated based on the expression profiles of a colon cancer cohort from TCGA database applying the ESTIMATE algorithm. Linear models were used to identify differentially expressed genes between low-score and high-score groups by limma R package. Univariate, LASSO, and multivariate Cox regression models were used successively to select the prognostic gene signature. Two independent datasets from GEO were used as external validation cohorts.

Results: Low stromal score was demonstrated to be a favorable factor to the overall survival of colon cancer patients in TCGA cohort ( = 0.0046). Three hundred and seven stromal score-related differentially expressed genes were identified. Through univariate, LASSO, and multivariate Cox regression analyses, a gene signature consisting of LEP, NOG, and SYT3 was recognized to build a prognostic prediction model. Based on the predictive values estimated by the established integrated model, patients were divided into two groups with significantly different overall survival outcomes ( < 0.0001). Time-dependent Receiver operating characteristic curve analyses suggested the satisfactory predictive efficacy for the 5-year overall survival of the model (AUC value = 0.733). A nomogram with great predictive performance combining the multigene prediction model and clinicopathological factors was developed. The established model was validated in an external cohort (AUC value = 0.728). In another independent cohort, the model was verified to be of significant prognostic value for different subgroups, which was demonstrated to be especially accurate for young patients (AUC value = 0.763).

Conclusion: The well-established model based on stromal score-related gene signature might serve as a promising tool for the prognostic prediction of colon cancer.
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http://dx.doi.org/10.3389/fgene.2021.655855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150004PMC
May 2021

Characterization of toll-like receptor 1 (TLR1) in turbot (Scophthalmus maximus L.).

Fish Shellfish Immunol 2021 May 27;115:27-34. Epub 2021 May 27.

School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China. Electronic address:

TLRs are the first and best-characterized pattern recognition receptors conserved across all the species. Different from mammals, the TLRs in teleost fishes are very diversified due to various evolutionary mechanisms. Here, we characterized one TLR1 gene in turbot, with a 2,415 bp open reading frame (ORF), that encoding 804 amino acid residues, and have the highest similarity and identity both to Paralichthys olivaceus with 88.9% and 79.9%. In phylogenetic analysis, it was firstly clustered with P. olivaceus, and then clustered with Takifugu rubripes. TLR1 was widely expressed in all the examined healthy tissues with the highest expression level in spleen, followed by head-kidney. In addition, it was significantly regulated in gill, skin and intestine following Edwardsiella tarda and Vibrio anguillarum challenge with different expression patterns. In in vitro stimulation with pathogen-associated molecular patterns, TLR1 showed significantly strong and elevated responses to LPS, but only responded to LTA and Poly(I:C) at the highest evaluated concentration, while no response was detected using PGN stimulation. Moreover, in subcellular localization analysis, TLR1 was distributed in the cytoplasm, membrane and nucleus. Taken together, TLR1 played vital roles for host immune response to bacterial infection, only with strong binding ability to LPS and involved in the production of inflammatory cytokines. However, the specific ligand for TLR1 and its functional association with other TLRs should be further characterized in fish species.
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http://dx.doi.org/10.1016/j.fsi.2021.05.018DOI Listing
May 2021

Structural basis for zinc-induced activation of a zinc uptake transcriptional regulator.

Nucleic Acids Res 2021 Jun;49(11):6511-6528

State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Life Science and Technology, Guangxi Key Laboratory for Sugarcane Biology, Guangxi University, Nanning 530004, China.

The zinc uptake regulator (Zur) is a member of the Fur (ferric uptake regulator) family transcriptional regulators that plays important roles in zinc homeostasis and virulence of bacteria. Upon zinc perception, Zur binds to the promoters of zinc responsive genes and controls their transcription. However, the mechanism underlying zinc-mediated Zur activation remains unclear. Here we report a 2.2-Å crystal structure of apo Zur from the phytopathogen Xanthomonas campestris pv. campestris (XcZur), which reveals the molecular mechanism that XcZur exists in a closed inactive state before regulatory zinc binding. Subsequently, we present a 1.9-Å crystal structure of holo XcZur, which, by contrast, adopts an open state that has enough capacity to bind DNA. Structural comparison and hydrogen deuterium exchange mass spectrometry (HDX-MS) analyses uncover that binding of a zinc atom in the regulatory site, formed by the hinge region, the dimerization domain and the DNA binding domain, drives a closed-to-open conformational change that is essential for XcZur activation. Moreover, key residues responsible for DNA recognition are identified by site-directed mutagenesis. This work provides important insights into zinc-induced XcZur activation and valuable discussions on the mechanism of DNA recognition.
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http://dx.doi.org/10.1093/nar/gkab432DOI Listing
June 2021

Differential Recovery of Small Intestinal Segments after Partial-Body Irradiation in Non-Human Primates.

Radiat Res 2021 May 27. Epub 2021 May 27.

Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

In the event of a radiological attack or accident, it is more likely that the absorbed radiation dose will be heterogeneous, rather than uniformly distributed throughout the body. This type of uneven dose distribution is known as partial-body irradiation (PBI). Partial exposure of the vital organs, specifically the highly radiosensitive intestines, may cause death, if the injury is significant and the post-exposure recovery is considerably compromised. Here we investigated the recovery rate and extent of recovery from PBI-induced intestinal damage in large animals. Rhesus macaques (Macaca mulatta) were randomly divided into four groups: sham-irradiated (0 Gy), 8 Gy PBI, 11 Gy PBI and 14 Gy PBI. A single dose of ionizing radiation was delivered in the abdominal region using a uniform bilateral anteroposterior and posteroanterior technique. Irradiated animals were scheduled for euthanasia on days 10, 28 or 60 postirradiation, and sham-irradiated animals on day 60. Intestinal structural injuries were assessed via crypt depth, villus height, and mucosal surface length in the four different intestinal regions (duodenum, proximal jejunum, distal jejunum and ileum) using H&E staining. Higher radiation doses corresponded with more injury at 10 days post-PBI, and faster recovery. However, at 60 days post-PBI, damage was still evident in all regions of the intestine. The proximal and distal ends (duodenum and ileum, respectively) sustained less damage and recovered more fully than the jejunum.
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http://dx.doi.org/10.1667/RADE-20-00272.1DOI Listing
May 2021

Dual-atom Pt heterogeneous catalyst with excellent catalytic performances for the selective hydrogenation and epoxidation.

Nat Commun 2021 May 26;12(1):3181. Epub 2021 May 26.

Department of Chemistry, Tsinghua University, Beijing, China.

Atomically monodispersed heterogeneous catalysts with uniform active sites and high atom utilization efficiency are ideal heterogeneous catalytic materials. Designing such type of catalysts, however, remains a formidable challenge. Herein, using a wet-chemical method, we successfully achieved a mesoporous graphitic carbon nitride (mpg-CN) supported dual-atom Pt catalyst, which exhibited excellent catalytic performance for the highly selective hydrogenation of nitrobenzene to aniline. The conversion of ˃99% is significantly superior to the corresponding values of mpg-CN-supported single Pt atoms and ultra-small Pt nanoparticles (~2 nm). First-principles calculations revealed that the excellent and unique catalytic performance of the Pt species originates from the facile H dissociation induced by the diatomic characteristics of Pt and the easy desorption of the aniline product. The produced Pt/mpg-CN samples are versatile and can be applied in catalyzing other important reactions, such as the selective hydrogenation of benzaldehyde and the epoxidation of styrene.
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http://dx.doi.org/10.1038/s41467-021-23517-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155026PMC
May 2021

Fully Organic Bulk Polymer with Metallic Thermal Conductivity and Tunable Thermal Pathways.

Adv Sci (Weinh) 2021 May 24:e2004821. Epub 2021 May 24.

College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, P. R. China.

Electrically insulating polymers are indispensable for electronic and energy applications, but their poor thermal conduction has increasingly become a bottleneck for high-performance devices. Highly drawn low-dimensional polymeric fibers and thin films can exhibit metallic conductivity. Extending this to bulk materials required by real world applications is prohibitive due to the additional interfacial thermal conduction barriers. It is demonstrated that highly aligned ultrahigh molecular weight polyethylene microfibers can be incorporated into a silicone matrix to yield a fully organic bulk polymer composite with a continuous vertical phonon pathway. This leads to a perpendicular thermal conductivity of 38.27 W m K , at par with metals and two orders of magnitude higher than other bulk organic polymers. Taking further advantage of the mechanical flexibility of the microfibers, the processing method offers the freedom to tailor heat transfer pathways in a macroscopic 3D space. The material/process opens up opportunities for efficient thermal management in high-performance devices.
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http://dx.doi.org/10.1002/advs.202004821DOI Listing
May 2021

Dual-scale categorization based deep learning to evaluate programmed cell death ligand 1 expression in non-small cell lung cancer.

Medicine (Baltimore) 2021 May;100(20):e25994

Oncology Department, Changhai Hospital of Shanghai, Shanghai, China.

Abstract: In precision oncology, immune check point blockade therapy has quickly emerged as novel strategy by its efficacy, where programmed death ligand 1 (PD-L1) expression is used as a clinically validated predictive biomarker of response for the therapy. Automating pathological image analysis and accelerating pathology evaluation is becoming an unmet need. Artificial Intelligence and deep learning tools in digital pathology have been studied in order to evaluate PD-L1 expression in PD-L1 immunohistochemistry image. We proposed a Dual-scale Categorization (DSC)-based deep learning method that employed 2 VGG16 neural networks, 1 network for 1 scale, to critically evaluate PD-L1 expression. The DSC-based deep learning method was tested in a cohort of 110 patients diagnosed as non-small cell lung cancer. This method showed a concordance of 88% with pathologist, which was higher than concordance of 83% of 1-scale categorization-based method. Our results show that the DSCbased method can empower the deep learning application in digital pathology and facilitate computer-aided diagnosis.
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http://dx.doi.org/10.1097/MD.0000000000025994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137090PMC
May 2021

Collagenase-loaded pH-sensitive nanocarriers efficiently remodeled tumor stroma matrixes and improved the enrichment of nanomedicines.

Nanoscale 2021 May;13(20):9402-9414

College of Polymer Science and Engineering, Sichuan University, Chengdu 610041, China.

The dense extracellular matrix (ECM) in tumor tissue severely hinders the penetration and enrichment of antitumor nanomedicines, which could significantly affect their efficiency. In this study, we used pH-sensitive nanocarriers loaded with collagenase (Col) to remold the tumor microenvironment (TME). Furthermore, we combined the collagenase delivery system with a nanomedicine to improve its penetration and enrichment in the tumor, thereby improving efficacy. We synthesized acetalated dextran (Ace-DEX) with an ideal pH-sensitivity as the carrier material of collagenase. Under mild preparation conditions, collagenase was loaded into Ace-DEX nanoparticles (NPs) with a high loading capacity (>4%) and remained highly active (>90%). Col-carrying NPs (Col-NPs) significantly reduced the tumor collagen content by 15.1%. Pretreatment with Col-NPs increased the accumulation of doxorubicin (DOX)-loaded liposome (DOX-Lipo) in the tumor by 2.8-fold. There were no safety concerns as the Col-NP showed no significant toxicity and reduced Col-induced damage to healthy tissues. Additionally, the number of circulating tumor cells remained unchanged after Col-NP treatment, suggesting no increased risk of tumor metastasis. Because the Col-NP acts essentially independent of the subsequent treatment, it has considerable potential for enhancing many existing delivery systems and drugs for cancer treatment. It may also be used for treating other collagen-related diseases.
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http://dx.doi.org/10.1039/d1nr00950hDOI Listing
May 2021

Boosting Selective Nitrogen Reduction via Geometric Coordination Engineering on Single-Tungsten-Atom Catalysts.

Adv Mater 2021 May 16:e2100429. Epub 2021 May 16.

Key Laboratory of Colloid and Interface Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, State Key Laboratory of Crystal Materials, Shandong University, Jinan, 250100, P. R. China.

Atomic interface regulation that can efficiently optimize the performance of single-atom catalysts (SACs) is a worthwhile research topic. The challenge lies in deeply understanding the structure-properties correlation based on control of the coordination chemistry of individual atoms. Herein, a new kind of W SACs with oxygen and nitrogen coordination (W-NO/NC) and a high metal loading over 10 wt% is facilely prepared by introducing an oxygen-bridged [WO ] tetrahedron. The local structure and coordination environment of the W SACs are confirmed by high-angle annular dark-field scanning transmission electron microscopy, X-ray photoelectron spectroscopy, and extended X-ray absorption fine structure. The catalyst shows excellent selectivity and activity for the electrochemical nitrogen reduction reaction (NRR). Density functional theory calculation reveals that unique electronic structures of the N and O dual-coordinated W sites optimize the binding energy of the NRR intermediate, resulting in facilitating the electrocatalytic NRR. This work opens an avenue toward exploring the correlation between coordination structure and properties.
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http://dx.doi.org/10.1002/adma.202100429DOI Listing
May 2021

Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies.

Oncoimmunology 2021 Apr 26;10(1):1909296. Epub 2021 Apr 26.

Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. : We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. : Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. : The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients.
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http://dx.doi.org/10.1080/2162402X.2021.1909296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078693PMC
April 2021

Amphiphilic Core Cross-Linked Star Polymers for the Delivery of Hydrophilic Drugs from Hydrophobic Matrices.

Biomacromolecules 2021 Jun 13;22(6):2554-2562. Epub 2021 May 13.

Department of Biomedical Engineering, University of Melbourne, Parkville, 3010 VIC, Australia.

The delivery of hydrophilic drugs from hydrophobic polymers is a long-standing challenge in the biomaterials field due to the limited solubility of the therapeutic agent within the polymer matrix. In this work, we develop a drug delivery mechanism that enables the impregnation and subsequent elution of hydrophilic drugs from a hydrophobic polymer material. This was achieved by synthesizing core cross-linked star polymer amphiphiles with hydrophilic cores and hydrophobic coronas. While significant work has been done to create nanocarriers for hydrophilic drugs, this work is distinct from previous work in that it designs amphiphilic and core cross-linked particles for controlled release from hydrophobic matrices. Ultraviolet-mediated atom transfer radical polymerization was used to synthesize the poly(ethylene glycol) (PEG)-based hydrophilic cores of the star polymers, and hydrophobic coronas of poly(caprolactone) (PCL) were then built onto the stars using ring-opening polymerization. We illustrated the cytocompatibility of PCL loaded with these star polymers through human endothelial cell adhesion and proliferation for up to 7 days, with star loadings of up to 40 wt %. We demonstrated successful loading of the hydrophilic drug heparin into the star polymer core, achieving a loading efficiency and content of 50 and 5%, respectively. Finally, the heparin-loaded star polymers were incorporated into a PCL matrix and sustained release of heparin was illustrated for over 40 days. These results support the use of core cross-linked star polymer amphiphiles for the delivery of hydrophilic drugs from hydrophobic polymer matrices. These materials were developed for application as drug-eluting and biodegradable coronary artery stents, but this flexible drug delivery platform could have impact in a broad range of medical applications.
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http://dx.doi.org/10.1021/acs.biomac.1c00296DOI Listing
June 2021

The perioperative application of continuous cerebral autoregulation monitoring for cerebral protection in elderly patients.

Ann Palliat Med 2021 Apr;10(4):4582-4592

Department of Anesthesiology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.

Background: The majority of surgical patients aged 65 years and over are accompanied with underlying conditions, making them susceptible to perioperative cerebral complications. Here, we investigated the clinical value of continuous cerebral autoregulation (CA) monitoring in protecting against cerebral dysfunction in elderly patients undergoing surgery.

Methods: This study enrolled 40 elderly patients (aged ≥65 years) and 40 middle-aged patients (aged 45 to 64 years) selected to undergo robotic-assisted laparoscopic radical prostatectomy. Cerebral oxygenation was assessed by regional cerebral oxygen saturation (rScO2) using near-infrared spectroscopy (NIRS). CA function was estimated using the cerebral oximetry index (COX), which is the rolling correlation between rScO2 and the mean arterial pressure (MAP). With the patient in the Trendelenburg position, the rScO2, MAP, calculated COX, HR, end-tidal CO2, and sevoflurane concentrations were continuously recorded. Standardized anesthesia was administered to all patients (sevoflurane, propofol, remifentanil, and rocuronium). Postoperative delirium (POD) was screened for daily using the Confusion Assessment Method (CAM). The primary outcome was the difference in periods of CA dysfunction between the elderly and middle-aged groups. Secondary outcomes included the incidence of POD and the optimal MAP range in the 2 groups.

Results: Taking positive COX values (cutoff ≥0.3) to reflect periods of CA dysfunction, we found that the cumulative duration of CA dysfunction in the Trendelenburg position was longer in elderly patients than in middle-aged patients [ratio of cumulative time of CA dysfunction: middle-aged group, 32.8% (26.3%, 43.1%) vs. elderly group, 42.2% (33.1%, 51.2%)] (P<0.01), which showed that CA function was less efficient in elderly patients. Three patients (7.5%) in the elderly group and 1 patient (2.5%) in the middle-aged group screened positive for POD on at least 1 day during their hospital stay. Additionally, using the COX-based method, we estimated the optimal MAP targets in the middle-aged and elderly groups to be (67.8±8.9, 116.4±10.5) and (71.2±12.5, 111.3±8.9) mmHg, respectively.

Conclusions: The brains of patients ≥65 years are more vulnerable to systemic insult compared with those of middle-aged patients. POD may be associated with CA dysfunction. NIRS-derived COX can be used to identify the optimal MAP range.
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http://dx.doi.org/10.21037/apm-21-707DOI Listing
April 2021

Mitochondrial dysfunction: A potential target for Alzheimer's disease intervention and treatment.

Drug Discov Today 2021 May 5. Epub 2021 May 5.

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address:

Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder which manifests as a progressive decline in cognitive function. Mitochondrial dysfunction plays a critical role in the early stages of AD, and advances the progression of this age-related neurodegenerative disorder. Therefore, it can be a potential target for interventions to treat AD. Several therapeutic strategies to target mitochondrial dysfunction have gained significant attention in the preclinical stage, but the clinical trials performed to date have shown little progress. Thus, we discuss the mechanisms and strategies of different therapeutic agents for targeting mitochondrial dysfunction in AD. We hope that this review will inspire and guide the development of efficient AD drugs in the future.
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http://dx.doi.org/10.1016/j.drudis.2021.04.025DOI Listing
May 2021

Metal-organic framework grafted with melamine for the selective recognition and miniaturized solid phase extraction of aristolochic acid Ⅰ from traditional Chinese medicine.

J Chromatogr A 2021 Jun 20;1647:462155. Epub 2021 Apr 20.

School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address:

Aristolochic acid Ⅰ is a nephrotoxic compound and exist in some traditional Chinese medicines at trace level. Up to now, specific enrichment of aristolochic acid Ⅰ remains important procedure and key problem in its analysis. In this study, melamine was proposed as the recognition unit and grafted on the surface of metal-organic framework to fabricate a specific material for aristolochic acid Ⅰ. This material was prepared by using a two-step strategy and the preparation process was optimized. The physical and chemical properties were investigated using scanning electron microscopy, Fourier-transfer infrared spectroscopy, X-ray diffraction and nitrogen adsorption-desorption techniques. Adsorption properties were evaluated by binding experiments. The melamine modified material exhibited a uniform morphology, high specific surface area (460.20 m g), high adsorption capacity (25.57 mg g), fast mass transfer rate and excellent selectivity. Further, a specific and sensitive method was established by using this material as adsorbent of mini-solid phase extraction. The limit of detection was as low as 0.02 μg mL. Therefore, melamine modified metal-organic framework is an ideal adsorbent for the recognition and enrichment of aristolochic acid Ⅰ.
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http://dx.doi.org/10.1016/j.chroma.2021.462155DOI Listing
June 2021

Proteomic and phosphoproteomic profiles of Sertoli cells in buffalo.

Theriogenology 2021 Aug 27;170:1-14. Epub 2021 Apr 27.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Animal Reproduction Institute, Guangxi University, Nanning, Guangxi, China. Electronic address:

Sertoli cells provide nutrients and support for germ cell differentiation and maintain a stable microenvironment for spermatogenesis. Comprehensive identification of Sertoli cellular proteins is important in understanding spermatogenesis. In this study, we performed an integrative analysis of the proteome and phosphoproteome to explore the role of Sertoli cells in spermatogenesis. A total of 2912 and 753 proteins were identified from the proteome and phosphoproteome in Sertoli cells, respectively; 438 proteins were common to the proteome and phosphoproteome. Data are available via ProteomeXchange with identifier PXD024984. In the proteome, ACTG1, ACTB, ACTA2, MYH9 were the most abundant proteins. Gene Ontology (GO) analysis indicated that most of the proteins were involved in the processes of localization, biosynthesis, gene expression, and transport. In addition, some of the proteins related to Sertoli cell functions were also enriched. In the phosphoproteome, most of the proteins were involved in gene expression and the RNA metabolic process; the pathways mainly involved the spliceosome, mitogen-activated protein kinase signaling pathway, focal adhesion, and tight junctions. The pleckstrin homology-like domain is the most highly enriched protein domain in phosphoproteins. Cyclin-dependent kinases and protein kinases C were found to be highly active kinases in the kinase-substrate network analysis. Ten proteins most closely related to network stability were found in the analysis of the network interactions of proteins identified jointly in the phosphoproteome and proteome. Through immunohistochemistry and immunofluorescence verification of vimentin, it was found that there were localization differences between phosphorylated and non-phosphorylated vimentin in testicular tissue. This study is the first in-depth proteomic and phosphoproteomic analysis of buffalo testicular Sertoli cells. The results provide insight into the role of Sertoli cells in spermatogenesis and provide clues for further study of male reproduction.
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http://dx.doi.org/10.1016/j.theriogenology.2021.04.013DOI Listing
August 2021

Postoperative Infection of Male Posterior Urethral Stenosis with Pelvic Fracture: A Retrospective Study from a Chinese Tertiary Teferral Center.

Urology 2021 Apr 30. Epub 2021 Apr 30.

Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital; Shanghai Oriental Institute for Urologic Reconstruction, Shanghai, 200233, China. Electronic address:

Objectives: To investigate the risk factors for postoperative infection, including systemic inflammatory response syndrome, sepsis and surgical site infection, after posterior urethral anastomosis for the treatment of male posterior urethral stenosis with pelvic fractures.

Methods: We retrospectively analyzed data from patients who underwent transperineal end-to-end anastomotic urethroplasty between January 2016 and December 2018. Descriptive statistics were used to analyze patient characteristics and perioperative features. Univariate analysis was performed to identify prognostic factors associated with postoperative infection. Multivariate analysis was used to identify independent risk factors for postoperative infection.

Results: Among 261 patients included in the analysis, 16.48% had SIRS, 3.83% had sepsis, and 8.05% had SSI. The primary results suggested that penile septum separation, inferior pubic resection, operating duration, preoperative urine culture result, preoperative waiting time, urethral stenosis length, and draining method were significant predictors of postoperative infections. Multivariate analysis revealed that more complex surgical procedures, operating duration and positive urine culture results were independent risk factors for SIRS and preoperative positive urine culture result was an independent risk factor for sepsis and SSI.

Conclusions: Positive preoperative urine culture was the main risk factor for postoperative infections. More complex surgical procedures, such as penile septum separation and inferior pubic resection, and longer operating duration were more likely to be associated with postoperative SIRS.
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http://dx.doi.org/10.1016/j.urology.2021.04.021DOI Listing
April 2021

Whole-genome resequencing of Osmanthus fragrans provides insights into flower color evolution.

Hortic Res 2021 May 1;8(1):98. Epub 2021 May 1.

Key Laboratory of Horticultural Plant Biology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China.

Osmanthus fragrans is a well-known ornamental plant that has been domesticated in China for 2500 years. More than 160 cultivars have been found during this long period of domestication, and they have subsequently been divided into four cultivar groups, including the Yingui, Jingui, Dangui, and Sijigui groups. These groups provide a set of materials to study genetic evolution and variability. Here, we constructed a reference genome of O. fragrans 'Liuyejingui' in the Jingui group and investigated its floral color traits and domestication history by resequencing a total of 122 samples, including 119 O. fragrans accessions and three other Osmanthus species, at an average sequencing depth of 15×. The population structure analysis showed that these 119 accessions formed an apparent regional cluster. The results of linkage disequilibrium (LD) decay analysis suggested that varieties with orange/red flower color in the Dangui group had undergone more artificial directional selection; these varieties had the highest LD values among the four groups, followed by the Sijigui, Jingui, and Yingui groups. Through a genome-wide association study, we further identified significant quantitative trait loci and genomic regions containing several genes, such as ethylene-responsive transcription factor 2 and Arabidopsis pseudoresponse regulator 2, that are positively associated with petal color. Moreover, we found a frameshift mutation with a 34-bp deletion in the first coding region of the carotenoid cleavage dioxygenase 4 gene. This frameshift mutation existed in at least one site on both alleles in all varieties of the Dangui group. The results from this study shed light on the genetic basis of domestication in woody plants, such as O. fragrans.
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http://dx.doi.org/10.1038/s41438-021-00531-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087690PMC
May 2021

Complement genes in black rockfish (Sebastods schlegelii): genome-wide identification, evolution and their potential functions in response to Vibrio anguillarum infection.

Fish Shellfish Immunol 2021 Jul 28;114:119-131. Epub 2021 Apr 28.

School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China. Electronic address:

As complex components of innate immune system, members of complement system play crucial roles during the process of defensing against pathogens. Black rockfish (Sebastes schlegelii) is one of the important aquaculture species in East Asian. However, studies of complement genes in black rockfish and its related immune activities are still lacking. Therefore, a total of 112 members of the complement genes were identified from the genome of black rockfish and were classified into five subgroups. According to their functional annotations, 30 genes belonged to pattern recognition, 6 genes belonged to proteases, 14 genes belonged to complement components, 36 genes belonged to receptors, and 26 genes belonged to regulators. It can be found that many complement genes evolved into multi-copies, especially in teleost, which may be influenced by whole-genome duplication or tandem duplication events. Complement genes were randomly distributed on 22 chromosomes. The number of introns of complement genes varied from 1 to 70. Results of the expression patterns of 10 randomly selected genes from 5 subtypes response to Vibrio anguillarum infection revealed that most of the members of the complement genes were induced in gill and skin. In contrast, most genes in intestine showed downregulation. This study systematically characterized and analyzed the complement genes in black rockfish and provided new insights into their functions responding to bacterial infection.
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http://dx.doi.org/10.1016/j.fsi.2021.04.020DOI Listing
July 2021

Oxidative Strong Metal-Support Interactions between Metals and Inert Boron Nitride.

J Phys Chem Lett 2021 May 26;12(17):4187-4194. Epub 2021 Apr 26.

State Key Laboratory of Catalysis, iChEM, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116023, China.

The strong metal-support interaction (SMSI) is one of the most important concepts in heterogeneous catalysis, which has been widely investigated between metals and active oxides triggered by reductive atmospheres. Here, we report the oxidative strong metal-support interaction (O-SMSI) effect between Pt nanoparticles (NPs) and inert hexagonal boron nitride (h-BN) sheets, in which Pt NPs are encapsulated by oxidized boron (BO) overlayers derived from the h-BN support under oxidative conditions. De-encapsulation of Pt NPs has been achieved by washing in water, and the residual ultrathin BO overlayers work synergistically with surface Pt sites for enhancing CO oxidation reaction. The O-SMSI effect is also present in other h-BN-supported metal catalysts such as Au, Rh, Ru, and Ir within different oxidative atmospheres including O and CO, which is determined by metal-boron interaction and O affinity of metals.
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http://dx.doi.org/10.1021/acs.jpclett.1c00934DOI Listing
May 2021

Unsaturated fatty acid-tuned assembly of photosensitizers for enhanced photodynamic therapy via lipid peroxidation.

J Control Release 2021 Jun 22;334:213-223. Epub 2021 Apr 22.

Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China. Electronic address:

Photodynamic therapy (PDT) destroys tumor cells mainly through singlet oxygen (O) generated by light-irradiated photosensitizers (PSs). However, the fleeting half-life of O greatly impairs PDT efficacy. Herein, we propose an unreported unsaturated fatty acid (UFA)-assisted PS co-assembly strategy to address this problem. Three UFAs, namely, oleic acid (OA), linoleic acid (LA) and linolenic acid (LNA), are capable of co-assembling with 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (TAPP) into uniform nanoparticles. Under irradiation, TAPP produces O, which directly attacks tumor cells and simultaneously oxidizes UFAs to generate lipid hydroperoxides with sustained damage. Interestingly, the unsaturation degree of UFAs is not only related to their peroxidation rate but also has a remarkable impact on the intracellular TAPP release characteristic of the nanoparticles (NPs). The TAPP-LA NPs could release the cargo rapidly and produce the highest lipid peroxidation and reactive oxygen species levels upon irradiation. Such a unique finding sheds new light on UFA-based combination applications for enhanced photodynamic efficacy by boosting lipid peroxidation.
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http://dx.doi.org/10.1016/j.jconrel.2021.04.022DOI Listing
June 2021