Publications by authors named "Xuan Liu"

975 Publications

Pyruvate kinase isoform M2 impairs cognition in systemic lupus erythematosus by promoting microglial synaptic pruning via the β-catenin signaling pathway.

J Neuroinflammation 2021 Oct 13;18(1):229. Epub 2021 Oct 13.

The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.

Background: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe complication, which involves pathological damage to the brain and cognitive function. However, its exact mechanism of action still remains unclear. In this study, we explored the role of microglia in the cognitive dysfunction of NPSLE mice. We also analyzed and compared the metabolites in the hippocampal tissues of the lupus model and control mice.

Methods: MRL/MpJ-Fas (MRL/lpr) female mice were used as the NPSLE mouse model. Metabolomics was used to assess hippocampal glycolysis levels. Glucose, lactic acid, IL-6, and IL-1β of the hippocampus were detected by ELISA. Based on the glycolysis pathway, we found that pyruvate kinase isoform M2 (PKM2) in the hippocampus was significantly increased. Thus, the expression of PKM2 was detected by qRT-PCR and Western blotting, and the localization of PKM2 in microglia (IBA-1) or neurons (NeuN) was assessed by immunofluorescence staining. Flow cytometry was used to detect the number and phenotype of microglia; the changes in microglial phagocytosis and the β-catenin signaling pathway were detected in BV2 cells overexpressing PKM2. For in vivo experiments, MRL/lpr mice were treated with AAV9-shPKM2. After 2 months, Morris water maze and conditional fear tests were applied to investigate the cognitive ability of mice; H&E and immunofluorescence staining were used to evaluate brain damage; flow cytometry was used to detect the phenotype and function of microglia; neuronal synapse damage was monitored by qRT-PCR, Western blotting, and immunofluorescence staining.

Results: Glycolysis was elevated in the hippocampus of MRL/lpr lupus mice, accompanied by increased glucose consumption and lactate production. Furthermore, the activation of PKM2 in hippocampal microglia was observed in lupus mice. Cell experiments showed that PKM2 facilitated microglial activation and over-activated microglial phagocytosis via the β-catenin signaling pathway. In vivo, AAV9-shPKM2-treated mice showed decreased microglial activation and reduced neuronal synapses loss by blocking the β-catenin signaling pathway. Furthermore, the cognitive impairment and brain damage of MRL/lpr mice were significantly relieved after microglial PKM2 inhibition.

Conclusion: These data indicate that microglial PKM2 have potential to become a novel therapeutic target for treating lupus encephalopathy.
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http://dx.doi.org/10.1186/s12974-021-02279-9DOI Listing
October 2021

Behavioral innovation promotes alien bird invasions.

Innovation (N Y) 2021 Nov 11;2(4):100167. Epub 2021 Sep 11.

Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang, Beijing 100101, China.

Behavioral innovation is believed to represent the ability of species to adapt to novel environments and to thus affect the observed establishment success of alien species in a new range. However, the relative importance of behavioral innovation in explaining alien species establishment among key event-, location-, and species-level factors remains poorly evaluated. In addition, the effects of technical innovation in food searching and handling techniques and consumer innovation in the use of new foods on establishment success are not clear. Here, based on a global dataset including information on 247 species across 9,899 successful and 2,370 failed introduction events spanning 199 countries or regions worldwide, we show that the behavioral innovation rate is a key factor facilitating alien bird establishment success after considering propagule pressure, climate matching, historical invasional meltdown, and life-history traits. Furthermore, we find that technical innovation is more influential than consumer innovation in explaining establishment success. Our results contribute to a deeper understanding of the effect of behavioral innovation on the establishment success of alien species in new ranges and may help predict the response of both native and alien species to accelerating global change during the Anthropocene.
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http://dx.doi.org/10.1016/j.xinn.2021.100167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488305PMC
November 2021

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives.

Beilstein J Org Chem 2021 22;17:2462-2476. Epub 2021 Sep 22.

Key Laboratory for Green Chemistry of Jiangxi Province, Key Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China.

Great progress has been made in the tandem annulation of enynes in the past few years. This review only presents the corresponding reactions of 1,3-enyne structural motifs to provide the functionalized pyridine and pyrrole derivatives. The functionalization reactions cover iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, alkylation, selenylation, sulfenylation, amidation, esterification, and hydroxylation. We also briefly introduce the applications of the products and the reaction mechanisms for the synthesis of corresponding N-heterocycles.
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http://dx.doi.org/10.3762/bjoc.17.163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474070PMC
September 2021

Sub-15-fs X-ray pump and X-ray probe experiment for the study of ultrafast magnetization dynamics in ferromagnetic alloys.

Opt Express 2021 Sep;29(20):32388-32403

In this paper, we present a new setup for the measurement of element-specific ultrafast magnetization dynamics in ferromagnetic thin films with a sub-15-fs time resolution. Our experiment relies on a split and delay approach which allows us to fully exploit the shortest X-rays pulses delivered by X-ray Free Electrons Lasers (close to the attosecond range), in an X-ray pump - X-ray probe geometry. The setup performance is demonstrated by measuring the ultrafast elemental response of Ni and Fe during demagnetization of ferromagnetic Ni and NiFe (Permalloy) samples upon resonant excitation at the corresponding absorption edges. The transient demagnetization process is measured in both reflection and transmission geometry using, respectively, the transverse magneto-optical Kerr effect (T-MOKE) and the Faraday effect as probing mechanisms.
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http://dx.doi.org/10.1364/OE.430828DOI Listing
September 2021

Safety and efficacy of grazoprevir/elbasvir in the treatment of acute hepatitis C in hemodialysis patients.

J Med Virol 2021 Oct 2. Epub 2021 Oct 2.

Laboratory Department, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210000, China.

Treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents (DAAs) in hemodialysis patients requires extensive consideration. At present, studies regarding DAAs for acute HCV infection in such patients are limited. The present study aims to evaluate the efficacy and safety of grazoprevir (GZR) plus elbasvir (EBR) treatment in acute hepatitis C (AHC) patients undergoing hemodialysis. Patients undergoing hemodialysis who had a nosocomial acute HCV infection were enrolled. All patients received GZR 100 mg/EBR 50 mg once daily for 12 weeks and were followed up for 12 weeks. Serum alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and HCV RNA levels were monitored during treatment and follow-up periods. Sustained virologic response (SVR) at 12 weeks after treatment cessation and treatment emergent adverse events (AEs) were assessed. A total of 68 AHC patients were enrolled. All patients were infected with HCV genotype 1b and achieved SVR12. Decreasing ALT, AST, and TBIL were observed over time in the first four weeks and became steady thereafter. Forty-eight (70.59%) patients reported at least one AEs. The most common AEs were fatigue, headache, and nausea. Two AHC patients discontinued treatment due to serious but drug-unrelated AEs. In conclusion, GZR/EBR has a high efficacy and safety profile in hemodialysis-dependent patients with genotype 1b AHC. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jmv.27374DOI Listing
October 2021

Bile acid metabolism dysregulation associates with cancer cachexia: roles of liver and gut microbiome.

J Cachexia Sarcopenia Muscle 2021 Sep 28. Epub 2021 Sep 28.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.

Background: Cancer cachexia is a multifactorial metabolic syndrome in which bile acid (BA) metabolism might be involved. The aim of the present study was to clarify the contribution of liver and gut microbiota to BA metabolism disturbance in cancer cachexia and to check the possibility of targeting BA metabolism using agents such as tauroursodeoxycholic acid (TUDCA) for cancer cachexia therapy.

Methods: The BA profiles in liver, intestine, and serum of mice with cancer cachexia induced by inoculation of colon C26 tumour cells were analysed using metabolomics methods and compared with that of control mice. Proteomic analysis of liver protein expression profile and 16S rRNA gene sequencing analysis of gut microbiota composition in cancer cachexia mice were conducted. Expression levels of genes related to farnesoid X receptor (FXR) signalling pathway in the intestine and liver tissues were analysed using RT-PCR analysis. The BA profiles in serum of clinical colon cancer patients with or without cachexia were also analysed and compared with that of healthy volunteers. The effects of TUDCA in treating cancer cachexia mice were observed.

Results: In the liver of cancer cachexia mice, expression of BA synthesis enzymes was inhibited while the amount of total BAs increased (P < 0.05). The ratios of conjugated BAs/un-conjugated BAs significantly increased in cancer cachexia mice liver (P < 0.01). Gut microbiota dysbiosis such as decrease in Lachnospiraceae and increase in Enterobacteriaceae was observed in the intestine of cancer cachexia mice, and microbial metabolism of BAs was reduced. Increase in expression of FGF15 in intestine (P < 0.01) suggested the activation of FXR signalling pathway which might contribute to the regulation of BA synthesis enzymes, transporters, and metabolic enzymes. Increase in the BA conjugation was observed in the serum of cancer cachexia mice. Results of clinical patients showed changes in BA metabolism, especially the increase in BA conjugation, and also suggested compensatory mechanism in BA metabolism regulation. Oral administration of 50 mg/kg TUDCA could significantly ameliorate the decrease in body weight (P < 0.001), muscle loss (P < 0.001), and atrophy of heart and liver (P < 0.05) in cancer cachexia mice without influence on tumour growth.

Conclusions: Bile acid metabolism dysregulation such as decrease in BA synthesis, increase in BA conjugation, and decrease in BA microbial metabolism was involved in development of cancer cachexia in mice. Targeting BA metabolism using agents such as TUDCA might be helpful for cancer cachexia therapy.
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http://dx.doi.org/10.1002/jcsm.12798DOI Listing
September 2021

Near-infrared manipulation of multiple neuronal populations via trichromatic upconversion.

Nat Commun 2021 09 27;12(1):5662. Epub 2021 Sep 27.

Department of Chemistry, Institutes of Brain Science, State Key Laboratory of Molecular Engineering of Polymers, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, P. R. China.

Using multi-color visible lights for independent optogenetic manipulation of multiple neuronal populations offers the ability for sophisticated brain functions and behavior dissection. To mitigate invasive fiber insertion, infrared light excitable upconversion nanoparticles (UCNPs) with deep tissue penetration have been implemented in optogenetics. However, due to the chromatic crosstalk induced by the multiple emission peaks, conventional UCNPs or their mixture cannot independently activate multiple targeted neuronal populations. Here, we report NIR multi-color optogenetics by the well-designed trichromatic UCNPs with excitation-specific luminescence. The blue, green and red color emissions can be separately tuned by switching excitation wavelength to match respective spectral profiles of optogenetic proteins ChR2, C1V1 and ChrimsonR, which enables selective activation of three distinct neuronal populations. Such stimulation with tunable intensity can not only activate distinct neuronal populations selectively, but also achieve transcranial selective modulation of the motion behavior of awake-mice, which opens up a possibility of multi-color upconversion optogenetics.
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http://dx.doi.org/10.1038/s41467-021-25993-7DOI Listing
September 2021

The Impact of Consequences Awareness of Public Environment on Medicine Return Behavior: A Moderated Chain Mediation Model.

Int J Environ Res Public Health 2021 Sep 16;18(18). Epub 2021 Sep 16.

Logistics Management, Delivery Hero Co., LTD, Phnom Penh 12309, Cambodia.

With global aging trends and prosperity in the medicine market, the number of unused or expired household unused or expired medicines is increasing. Medicines which are discarded improperly result in serious pollution. From the perspective of behavioral science, the main contribution of this paper is the construction of a chain mediation model to analyze the influence mechanism between consequences awareness of the public environment and proper return behavior of unused or expired medicines. The model explores the moderating effect of personal health awareness with through observation of to the mediating effect of personal norms and return intention. Using a sample size of 366 residents from China, the proposed hypotheses are empirically tested. The results show: firstly, the direct effect of residents' consequences awareness of public environmental awareness on the proper medicine return behavior is not significant; secondly, return intention plays a mediating role in the positive effect of consequences awareness of the public environment on proper return behavior; thirdly, personal norms and return intention play a chain mediating role in the positive impact of consequences awareness of the public environment on proper return behavior; and lastly, personal health awareness moderates the chain mediation path by strengthening the positive effect of return intention on proper return behavior.
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http://dx.doi.org/10.3390/ijerph18189756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471998PMC
September 2021

Synthetic Analogue of Butenolide as an Antifouling Agent.

Mar Drugs 2021 Aug 25;19(9). Epub 2021 Aug 25.

Department of Ocean Science, Division of Life Science and Hong Kong Branch of the Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Hong Kong, China.

Butenolide derivatives have the potential to be effective and environmentally friendly antifouling agents. In the present study, a butenolide derivative was structurally modified into Boc-butenolide to increase its melting point and remove its foul smell. The structurally modified Boc-butenolide demonstrated similar antifouling capabilities to butenolide in larval settlement bioassays but with significantly lower toxicity at high concentrations. Release-rate measurements demonstrated that the antifouling compound Boc-butenolide could be released from polycaprolactone-polyurethane (PCL-PU)-based coatings to inhibit the attachment of foulers. The coating matrix was easily degraded in the marine environment. The performance of the Boc-butenolide antifouling coatings was further examined through a marine field test. The coverage of biofouler on the Boc-butenolide coatings was low after 2 months, indicating the antifouling potential of Boc-butenolide.
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http://dx.doi.org/10.3390/md19090481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465062PMC
August 2021

Modelling and optimization of high-pressure homogenization of not-from-concentrate juice: Achieving better juice quality using sustainable production.

Food Chem 2021 Sep 7;370:131058. Epub 2021 Sep 7.

Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Beijing 100193, China.

The present work optimized high-pressure homogenization (HPH) parameters for not-from-concentrate combined peach and carrot juices, based on a two-step comprehensive model using factor analysis and analytic hierarchy process methods. Treating combined juice with pressures over 200 MPa retained more amounts of the bioactive compounds (carotenoids and polyphenols) than non-homogenization. Nutrition-oriented optimization, with higher judgement weight on nutritional properties, and sense-oriented optimization, with higher weight on sensory properties, were set up. Combined juice (250 MPa, 1 pass and 25 °C) had the best quality, based on the nutrition- and sense-oriented models. Back propagation neural network (BPNN) models could predict antioxidant capacities of the combined juice with greater accuracy compared with stepwise linear regression. The relative errors of BPNN prediction model were ≤ 5%.
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http://dx.doi.org/10.1016/j.foodchem.2021.131058DOI Listing
September 2021

Robust three-dimensional nanotube-in-micropillar array electrodes to facilitate size independent electroporation in blood cell therapy.

Lab Chip 2021 Sep 21. Epub 2021 Sep 21.

Center for Biomedical Engineering and Rehabilitations, Institute for Micromanufacturing, Louisiana Tech University, PO Box 10137, Ruston, LA, 71272, USA.

Blood is an attractive carrier for plasmid and RNA-based medicine in cell therapy. Electroporation serves as a favorable delivery tool for simple operation, quick internalization, minimum cell culture involvement, and low contamination risk. However, the delivery outcome of electroporation heavily depends on the treated cells such as their type, size, and orientation to the electric field, not ideal for highly heterogeneous blood samples. Herein, a new electroporation system was developed towards effective transfection to cells in blood regardless of their large diversity. By coupling replica molding and infiltration-coating processes, we successfully configured a three-dimensional electrode comprised of a polymer micropillar array on which carbon nanotubes (CNTs) are partially embedded. During electroporation, cells sag between micropillars and deform to form a conformal contact with their top and side surfaces. The implanted CNTs not only provide a robust conductive coating for polymer micropattern but also have their protruded ends face the cell membrane vertically everywhere with maximum transmembrane potential. Regardless of their largely varied sizes and random dispersion, both individual blood cell type and whole blood samples were effectively transfected with plasmid DNA (85% after 24 h and 95% after 72 h, or 2.5-3.0 folds enhancement). High-dose RNA probes were also introduced, which regulate better the expression levels of exogenous and endogenous genes in blood cells. Besides its promising performance on non-viral delivery routes to cell-related studies and therapy, the involved new fabrication method also provides a convenient and effective way to construct flexible electronics with stable micro/nano features on the surface.
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http://dx.doi.org/10.1039/d1lc00690hDOI Listing
September 2021

Effect of high pressure homogenization on water-soluble pectin characteristics and bioaccessibility of carotenoids in mixed juice.

Food Chem 2021 Sep 16;371:131073. Epub 2021 Sep 16.

Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Beijing 100193, China.

The effect of high pressure homogenization (HPH) compared with simple blending and milling on mixed juice properties, including water-soluble pectin (WSP) characteristics and total carotenoid bioaccessibility (TCB) was investigated. Overall, HPH treatments, which comprised of varied pressures, passes and inlet temperature (IT) affected WSP characteristics. Increased pressure showed decreased molecular weight (M), galacturonic acid (GalA) content and branching, and enhanced degree of methylesterification (DM) and chain linearity, suggesting degradation of RG-I fragments. Two passes at 140 MPa enhanced GalA content, nevertheless it reduced DM, implying rearrangement of depolymerized fractions. Besides, elevated IT combined with high pressure increased GalA content and DM signifying thermo-solubilization of certain HG-rich pectin. Notably, the TCB was enhanced by higher pressure and elevated temperature, which had positive relationship with DM and chain linearity of WSP and negative correlations with GalA content and M Results highlighted the potential of HPH to improve WSP characteristics to enhance TCB.
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http://dx.doi.org/10.1016/j.foodchem.2021.131073DOI Listing
September 2021

Tomatidine Suppresses the Destructive Behaviors of Fibroblast-Like Synoviocytes and Ameliorates Type II Collagen-Induced Arthritis in Rats.

Front Pharmacol 2021 26;12:670707. Epub 2021 Aug 26.

Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.

Fibroblast-like synoviocytes (FLSs) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Searching for natural compounds that may suppress the pathological phenotypes of FLSs is important for the development of RA treatment. Tomatidine (Td), a steroidal alkaloid derived from the solanaceae family, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effect on RA remains unknown. Here, we examined the inhibitory effect of Td on TNFα-induced arthritic FLSs, and subsequently investigated its therapeutic effect on collagen-induced arthritis (CIA) rats. Our results revealed that Td significantly inhibited TNFα-induced proliferation and migration of arthritic FLSs. In addition, we found that Td treatment could efficaciously ameliorate synovial inflammation and joint destruction of rats with CIA. Both and studies showed that Td significantly suppressed the production of pro-inflammatory cytokines including IL-1β, IL-6 and TNFα, and downregulated the expression of MMP-9 and RANKL. Further molecular mechanism studies revealed that the inhibitory effect of Td on RA might attribute to the decreased activations of MAPKs (ERK and JNK) and NF-κB. These findings provide evidence that Td has the potential to be developed into a complementary or alternative agent for RA therapy.
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http://dx.doi.org/10.3389/fphar.2021.670707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426578PMC
August 2021

MVGCN: data integration through multi-view graph convolutional network for predicting links in biomedical bipartite networks.

Bioinformatics 2021 Sep 9. Epub 2021 Sep 9.

College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.

Motivation: There are various interaction/association bipartite networks in biomolecular systems. Identifying unobserved links in biomedical bipartite networks helps to understand the underlying molecular mechanisms of human complex diseases and thus benefits the diagnosis and treatment of diseases. Although a great number of computational methods have been proposed to predict links in biomedical bipartite networks, most of them heavily depend on features and structures involving the bioentities in one specific bipartite network, which limits the generalization capacity of applying the models to other bipartite networks. Meanwhile, bioentities usually have multiple features, and how to leverage them has also been challenging.

Results: In this study, we propose a novel multi-view graph convolution network (MVGCN) framework for link prediction in biomedical bipartite networks. We first construct a multi-view heterogeneous network (MVHN) by combining the similarity networks with the biomedical bipartite network, and then perform a self-supervised learning strategy on the bipartite network to obtain node attributes as initial embeddings. Further, a neighborhood information aggregation (NIA) layer is designed for iteratively updating the embeddings of nodes by aggregating information from inter- and intra-domain neighbors in every view of the MVHN. Next, we combine embeddings of multiple NIA layers in each view, and integrate multiple views to obtain the final node embeddings, which are then fed into a discriminator to predict the existence of links. Extensive experiments show MVGCN performs better than or on par with baseline methods and has the generalization capacity on six benchmark datasets involving three typical tasks.

Availability: Source code and data can be downloaded from https://github.com/fuhaitao95/MVGCN.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab651DOI Listing
September 2021

Decreased expression is a novel predictor of poor survival in patients with hepatocellular carcinoma.

Biomark Med 2021 Oct 9;15(15):1319-1331. Epub 2021 Sep 9.

Department of Anatomy, Basic Medical College of Qiqihar Medical College, Qiqihar, Heilongjiang, 161006, People's Republic of China.

To investigate the effect of aberrant expression of DHRS1 on hepatocellular carcinoma (HCC). Kaplan-Meier and Cox regression analyses were performed to evaluate the correlation between DHRS1 and overall survival. Gene set enrichment analysis was performed to explore the potential function of DHRS1 in HCC. Multiple data analysis revealed that DHRS1 mRNA and protein expression level were remarkably lower in HCC than that in normal tissues. In survival analysis, patients with low DHRS1 expression presented a poorer prognosis, and was an independent risk factor for HCC. Decreased DHRS1 expression may be a potential predictor of poor prognosis in HCC.
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http://dx.doi.org/10.2217/bmm-2021-0041DOI Listing
October 2021

High-Fidelity NIR-II Multiplexed Lifetime Bioimaging with Bright Double Interfaced Lanthanide Nanoparticles.

Angew Chem Int Ed Engl 2021 Sep 6. Epub 2021 Sep 6.

Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers and iChem, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai, 200433, China.

Fluorescence lifetime imaging provides more possibility of in vivo multiplexing in second near infrared (NIR-II) window. However, it still faces the obstacle that fluorescent probes with differentiable lifetime often exhibit quite different fluorescence intensity, especially the short lifetime usually accompanies with a weak fluorescence intensity, resulting in the difficulty for simultaneously decoding multiplexed lifetime information due to the interference of background noise. To facilitate high-fidelity lifetime multiplexed imaging, we developed a series of Er doped double interface fluorescent nanoprobes (Er-DINPs): α-NaYF @NaErF : [email protected] @NaErF : [email protected] with strong fluorescence intensity and easily distinguishable fluorescence lifetime. Both in vitro and in vivo experimental results confirmed the advantage of these probes with comparable fluorescence intensity for high-fidelity multiplexed lifetime bioimaging.
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http://dx.doi.org/10.1002/anie.202108124DOI Listing
September 2021

Ultra-High Repetition Rate Terahertz Time-Domain Spectroscopy for Micrometer Layer Thickness Measurement.

Sensors (Basel) 2021 Aug 10;21(16). Epub 2021 Aug 10.

Chair of Communication Systems (NTS), Faculty of Engineering, University of Duisburg-Essen (UDE), 47057 Duisburg, Germany.

Terahertz time-domain spectroscopy systems driven by monolithic mode-locked laser diodes (MLLDs) exhibit bandwidths exceeding 1 THz and a peak dynamic range that can compete with other state-of-the-art systems. Their main difference compared to fiber-laser-driven systems is their ultra-high repetition rate of typically dozens of GHz. This makes them interesting for applications where the length of the terahertz path may not be precisely known and it enables the use of a very short and potentially fast optical delay unit. However, the phase accuracy of the system is limited by the accuracy with which the delay axes of subsequent measurements are synchronized. In this work, we utilize an all-fiber approach that uses the optical signal from the MLLD in a Mach-Zehnder interferometer to generate a reference signal that we use to synchronize the detected terahertz signals. We demonstrate transmission-mode thickness measurements of stacked layers of 17μm thick low-density polyethylene (LDPE) films.
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http://dx.doi.org/10.3390/s21165389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400559PMC
August 2021

In Utero Fetal Weight in Pigs Is Regulated by microRNAs and Their Target Genes.

Genes (Basel) 2021 Aug 19;12(8). Epub 2021 Aug 19.

Leibniz Institute for Farm Animal Biology, Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.

Impaired skeletal muscle growth in utero can result in reduced birth weight and poor carcass quality in pigs. Recently, we showed the role of microRNAs (miRNAs) and their target genes in prenatal skeletal muscle development and pathogenesis of intrauterine growth restriction (IUGR). In this study, we performed an integrative miRNA-mRNA transcriptomic analysis in longissimus dorsi muscle (LDM) of pig fetuses at 63 days post conception (dpc) to identify miRNAs and genes correlated to fetal weight. We found 13 miRNAs in LDM significantly correlated to fetal weight, including miR-140, miR-186, miR-101, miR-15, miR-24, miR-29, miR-449, miR-27, miR-142, miR-99, miR-181, miR-199, and miR-210. The expression of these miRNAs decreased with an increase in fetal weight. We also identified 1315 genes significantly correlated to fetal weight at 63 dpc, of which 135 genes were negatively correlated as well as identified as potential targets of the above-listed 13 miRNAs. These miRNAs and their target genes enriched pathways and biological processes important for fetal growth, development, and metabolism. These results indicate that the transcriptomic profile of skeletal muscle can be used to predict fetal weight, and miRNAs correlated to fetal weight can serve as potential biomarkers of prenatal fetal health and growth.
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http://dx.doi.org/10.3390/genes12081264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393551PMC
August 2021

Patterns of eHealth Website User Engagement Based on Cross-site Clickstream Data: Correlational Study.

J Med Internet Res 2021 Aug 13;23(8):e29299. Epub 2021 Aug 13.

Xi'an Research Institute of High Technology, Xi'an, China.

Background: User engagement is a key performance variable for eHealth websites. However, most existing studies on user engagement either focus on a single website or depend on survey data. To date, we still lack an overview of user engagement on multiple eHealth websites derived from objective data. Therefore, it is relevant to provide a holistic view of user engagement on multiple eHealth websites based on cross-site clickstream data.

Objective: This study aims to describe the patterns of user engagement on eHealth websites and investigate how platforms, channels, sex, and income influence user engagement on eHealth websites.

Methods: The data used in this study were the clickstream data of 1095 mobile users, which were obtained from a large telecom company in Shanghai, China. The observation period covered 8 months (January 2017 to August 2017). Descriptive statistics, two-tailed t tests, and an analysis of variance were used for data analysis.

Results: The medical category accounted for most of the market share of eHealth website visits (134,009/184,826, 72.51%), followed by the lifestyle category (46,870/184,826, 25.36%). The e-pharmacy category had the smallest market share, accounting for only 2.14% (3947/184,826) of the total visits. eHealth websites were characterized by very low visit penetration and relatively high user penetration. The distribution of engagement intensity followed a power law distribution. Visits to eHealth websites were highly concentrated. User engagement was generally high on weekdays but low on weekends. Furthermore, user engagement gradually increased from morning to noon. After noon, user engagement declined until it reached its lowest level at midnight. Lifestyle websites, followed by medical websites, had the highest customer loyalty. e-Pharmacy websites had the lowest customer loyalty. Popular eHealth websites, such as medical websites, can effectively provide referral traffic for lifestyle and e-pharmacy websites. However, the opposite is also true. Android users were more engaged in eHealth websites than iOS users. The engagement volume of app users was 4.85 times that of browser users, and the engagement intensity of app users was 4.22 times that of browser users. Male users had a higher engagement intensity than female users. Income negatively moderated the influence that platforms (Android vs iOS) had on user engagement. Low-income Android users were the most engaged in eHealth websites. Conversely, low-income iOS users were the least engaged in eHealth websites.

Conclusions: Clickstream data provide a new way to derive an overview of user engagement patterns on eHealth websites and investigate the influence that various factors (eg, platform, channel, sex, and income) have on engagement behavior. Compared with self-reported data from a questionnaire, cross-site clickstream data are more objective, accurate, and appropriate for pattern discovery. Many user engagement patterns and findings regarding the influential factors revealed by cross-site clickstream data have not been previously reported.
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http://dx.doi.org/10.2196/29299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398706PMC
August 2021

Long noncoding RNA NEAT1 promotes tumorigenesis in H. pylori gastric cancer by sponging miR-30a to regulate COX-2/BCL9 pathway.

Helicobacter 2021 Aug 16:e12847. Epub 2021 Aug 16.

Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Background: Helicobacter pylori (H. pylori) is a carcinogenic factor for gastric cancer. Our previous study demonstrated that H. pylori decreased the expression of micro-RNA (miRNA)-30a to promote the tumorigenesis of gastric cancer. However, the upstream regulatory molecules of miR-30a are not well elucidated. In this study, we found the long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) may sponge miR-30a to regulate COX-2/BCL9 pathway.

Methods: The expression of NEAT1 was detected in gastric cancer tissues and tumor-adjacent tissues by fluorescence in situ hybridization (FISH) analysis and RT-qPCR. LncRNA-miRNA interaction networks were constructed using the RNAhybrid and starBase v.2.0. and then validated using a dual-luciferase reporter assay. The effects of NEAT1 dysregulation on the proliferative, migratory, and invasive abilities of H. pylori filtrate-infected gastric cancer cells were observed by cell counting kit-8 (CCK-8), colony formation, wound healing test, and transwell assays. Western blot and RT-qPCR were performed to detect protein and RNA expression. Immunohistochemistry (IHC) was carried out to analyze the localization and expression of COX-2 and BCL9.

Results: FISH and RT-qPCR demonstrated that the expression of NEAT1 was up-regulated in gastric cancer tissues, especially in H. pylori-infected gastric cancer tissues, and the expression of NEAT1 was negatively correlated with miR-30a (miR-30a-3p and miR-30a-5p). The upregulation of NEAT1 enhanced proliferation, migration, and invasion of H. pylori filtrate-infected gastric cancer cells, while the downregulation of NEAT1 decreased these abilities, and miR-30a could reverse the effect of NEAT1 on these abilities. The dual-luciferase reporter assay identified that NEAT1 directly targeted miR-30a (miR-30a-3p and miR-30a-5p). Because miR-30a (miR-30a-3p and miR-30a-5p) negatively regulates the expression of downstream COX-2 and BCL9, NEAT1 was identified to upregulate indirectly the expression of COX-2 and BCL9. IHC showed that the expression of COX-2 and BCL9 was increased in H. pylori gastric cancer tissues.

Conclusion: The study demonstrated that lncRNA NEAT1 may act as a promoter of tumorigenesis in H. pylori gastric cancer, by sponging miR-30a (miR-30a-3p and miR-30a-5p) to regulate the COX-2/BCL9 pathway.
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http://dx.doi.org/10.1111/hel.12847DOI Listing
August 2021

Ultralow-Fouling Zwitterionic Polyurethane-Modified Membranes for Rapid Separation of Plasma from Whole Blood.

Langmuir 2021 08 11;37(33):10115-10125. Epub 2021 Aug 11.

Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Illinois 60607, United States.

The separation of plasma from blood cells in whole blood is an essential step for many diagnostic and therapeutic applications. However, the current point-of-care plasma separation approaches have not yet satisfied the need for a rapid, high-flux, and low-cost process. Here, we report a portable, low-cost, disposable membrane-based plasma separation device that enables rapid plasma extraction from whole blood. Rapid separation of plasma can be obtained with a simple three-step operation: blood injection, separation, and plasma collection. Our device benefits from the zwitterionic polyurethane-modified cellulose acetate (PCBU-CA) membrane, which can greatly inhibit the surface fouling of blood cells and membrane flux decline. The zwitterionic coating is stable on the membrane surface during blood filtration and leads to a 60% decrease in surface fibrinogen adsorption than a nonmodified membrane surface. The ultralow-blood-fouling properties of the PCBU-CA membrane enable rapid, continuous separation of plasma: within 10 min, the device can yield 0.5-0.7 mL of plasma from 10 mL of whole blood. The extracted plasma is verified as cell-free, exhibits a low hemoglobin level, and has a high protein recovery. Our PCBU-CA membrane provides a pathway for developing a high-efficiency portable plasma separation device that can reduce the time to diagnosis, allow effective patient care, and eventually reduce hospital costs.
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http://dx.doi.org/10.1021/acs.langmuir.1c01477DOI Listing
August 2021

Dispersed Nano-Au on Zr-Suboxides as Active Cathode for Direct CO Electroreduction in Solid Oxide Electrolysis Cells.

Nano Lett 2021 Aug 6;21(16):6952-6959. Epub 2021 Aug 6.

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

CO electrochemical reduction in solid oxide electrolysis cells is an effective way to combine CO conversion and renewable electricity storage. A Au layer is often used as a current collector, whereas Au nanoparticles are rarely used as a cathode because it is difficult to keep nanosized Au at high temperatures. Here we dispersed a Au layer into Au nanoparticles (down to 2 nm) at 800 °C by applying high voltages. A 75-fold decrease in the polarization resistance was observed, accompanied by a 38-fold improvement in the cell current density. Combining electronic microscopy, near-ambient pressure X-ray photoelectron spectroscopy, and theoretical calculations, we found that the interface between the Au layer and the electrolyte (yttria-stabilized zirconia (YSZ)) was reconstructed into nano-Au/Zr-suboxide interfaces, which are active sites that show a much lower reaction activation energy than that of the Au/YSZ interface. The formation of Zr-suboxides promotes Au dispersion and Au nanoparticle stabilization due to the strong interaction between Au and Zr-suboxides.
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http://dx.doi.org/10.1021/acs.nanolett.1c02227DOI Listing
August 2021

Ubiquitination-Related miRNA-mRNA Interaction Is a Potential Mechanism in the Progression of Retinoblastoma.

Invest Ophthalmol Vis Sci 2021 08;62(10)

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou City, China.

Purpose: Retinoblastoma (RB) is the most common primary malignant intraocular cancer. The etiology of RB is complex, and the mechanisms driving its progression remain unclear. Here, we used a series of bioinformatics approaches and experimental methods to investigate the potential regulatory mechanism involved in RB progression.

Methods: The common differentially expressed genes were obtained from the public dataset GSE97508. Protein-protein interaction (PPI) network, correlation, and functional enrichment analyses were carried out. The candidate genes were verified in different RB cell lines, and ARPE19 cells served as control. miRNA-mRNA interaction analysis was performed and confirmed by real-time PCR. The CCK-8 assay was conducted to detect cell viability, and the transwell assay was utilized for evaluating the abilities of cell migration and invasion.

Results: Overall, a total of 258 common differentially expressed genes associated with RB progression were screened out. The PPI network analysis further identified eight downregulated genes mainly enriched in the protein ubiquitination pathway. Moreover, we confirmed UBE2E1, SKP1, FBXO9, FBXO15, and RNF14 from among eight genes through experimental validation in vitro. Furthermore, miRNA-mRNA interaction and real-time PCR analysis of five hub genes revealed that ubiquitination-related miR-548k was involved in RB progression. Loss- and gain-of-function experiments demonstrated that miR-548k and its targets were essential for cell viability, migration, and invasion in the RB cells.

Conclusions: Our data indicate that the dysregulation of protein ubiquitination may play an important role in RB progression, and ubiquitination-related miR-548k may be a promising therapeutic target for RB.
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http://dx.doi.org/10.1167/iovs.62.10.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340667PMC
August 2021

Manually scanned single fiber optical coherence tomography for skin cancer characterization.

Sci Rep 2021 07 30;11(1):15570. Epub 2021 Jul 30.

Department of Electrical and Computer Engineering, New Jersey Institute of Technology, University Heights, Newark, NJ, 07102, USA.

Optical coherence tomography (OCT) is a cross-sectional imaging modality based on low coherence light interferometry. Within dermatology, it has found applications for in vivo diagnostic imaging purposes, as well as to guide Mohs micrographic surgery (MMS), due to its ability to visualize skin morphology up to several millimeters in depth. However, standard OCT probes have a large footprint and capture an extended area of the skin, making it difficult to precisely pinpoint clinically relevant location being imaged. Mohs surgeons stand to benefit from a handheld in vivo imaging device that can accurately trace surgical margins. In this study, we demonstrate the use of a single fiber OCT (sfOCT) instrument. Our imaging system features a miniature common path single fiber probe, and a novel speckle decorrelation technique that generates distortion free 2D images from manual scanning.By manually moving the single-fiber probe across the region of interest, the user can perform a lateral OCT scan while visualizing the location of the probe during data acquisition. Using the sfOCT, we have identified normal skin morphology, qualitatively correlated features of basal cell carcinoma and squamous cell carcinoma with histopathology, and quantified the disruption of the dermo-epidermal junction OCT pattern in skin tumors-each demonstrating the potential of utilizing sfOCT to differentiate tumor from normal skin. Using this imaging tool, a Mohs surgeon can enhance determination of surgical margins for the first stage of MMS, potentially decreasing the time and number of stages required for complete tumor removal.
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http://dx.doi.org/10.1038/s41598-021-95118-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324861PMC
July 2021

Analysis of conventional and alternative CRISPR/Cas9 genome editing to enhance a single-base pair knock-in mutation.

BMC Biotechnol 2021 07 27;21(1):45. Epub 2021 Jul 27.

Department of Biochemistry, University of California, Riverside, CA, 92521, USA.

Background: The use of CRISPR/Cas9 technologies in generating single-base pair knock-in mutations has recently exploded in the number of methods available. However, with the growing expansion of new technologies, it can be difficult to determine the best method for genome editing.

Results: In this study, we evaluated a number of CRISPR/Cas9 approaches for deriving cell lines with knock-in base pair edits to create a phosphorylation mutation and provide a breakdown of editing efficiencies and suggestions for improvement. Overall, our studies suggest that using pre-formed ribonucleoprotein (RNP) complexes is a reliable editing method to generate homozygous single-base pair mutations. We also show that antibiotic selection coupled homologous recombination is an efficient tool for generating highly specific heterozygous mutations.

Conclusion: The methods and/or combination of methods outlined in this study can be used to help other researchers with similar goals in single-base pair genome editing.
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http://dx.doi.org/10.1186/s12896-021-00707-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317408PMC
July 2021

Self-assembled AuCu/Au [email protected] tumor nanotheranostics with PT/fluorescence imaging-guided synergetic PTT/PDT.

J Mater Chem B 2021 Aug 27;9(32):6396-6405. Epub 2021 Jul 27.

School of Chemistry and Chemical Engineering, Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, P. R. China.

Exploring and developing a new type of nanoplatform with diagnosis and treatment to effectively cure tumors and reduce side effects has become a hot spot for researchers and is of great significance. Herein, a cancer theranostic nanoplatform with dual-imaging, dual-phototherapy and laser-responsiveness to tumor microenvironment was successfully assembled by liposome (Lip) co-loaded with oil-soluble AuCu nanoclusters (NCs) and water-soluble Au NCs via a simple film hydration method and subsequent extraction process. The prepared AuCu/[email protected] nanoplatform with core-shell structure and about 50 nm of uniform sphere shape presented highly biocompatible, stability and passive targeting due to the enhanced permeability and retention (EPR) effect. Furthermore, the Lip composed of lecithin and cholesterol has good affinity with the cell membrane, which can realize the effective accumulation of photosensitizers at the tumor site, so that improving phototherapy effect and reducing the damage to normal tissue. The loaded oil-soluble AuCu NCs were firstly and pleasantly surprised to find possessed not only ideal photodynamic effect, but also preferable catalysis towards endogenous hydrogen peroxide (HO) decomposition to produce oxygen (O) for improving the tumor hypoxic environment besides the excellent photoluminescence ability while the water-soluble Au NCs own outstanding photothermogenesis effect and also photoluminescence performance. The in vitro and in vivo experiment results proved that in the AuCu/[email protected] nanoplatform, the performances of both NCs were complementary, which presenting considerable photothermal/fluorescence imaging (PTI/FI)-guided synergistic photothermal therapy (PTT)/O-enhanced photodynamic therapy (PDT) effect for the tumor under the irradiation of near infrared (NIR) laser. This work provides a useful inspiration and paves a new way for the assembly of NCs or namomaterials with different properties into an integrated anti-tumor theranostic nanoplatform.
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http://dx.doi.org/10.1039/d1tb01092aDOI Listing
August 2021

Gene Polymorphisms Were Associated with Alcohol-Induced Osteonecrosis of the Femoral Head.

Int J Gen Med 2021 17;14:3583-3591. Epub 2021 Jul 17.

Department of Orthopedics, The Hospital of Yutian County, Tangshan, Hebei Province, 063000, People's Republic of China.

Introduction: Alcohol-induced osteonecrosis of the femoral head (ONFH), a progressive disease, is caused by excessive drinking and genetic factors. Currently, it remains to represent a significant challenge. The association between alcohol-induced ONFH and gene polymorphisms may provide a direction for the mechanism of alcoholic ONFH.

Methods: A total of 201 alcohol-induced ONFH patients and 201 healthy controls were recruited in this case-control study. The polymorphisms of gene were genotyped in blood samples by Agena MassARRAY RS1000. Pearson chi-square test was used to calculate difference in allele frequencies of gene polymorphisms between the cases and controls. Alcohol-induced ONFH risk was estimated using odds ratios (ORs) and 95% confidence intervals (CIs).

Results: In the overall analysis, the allele "G" of rs62030917 was significantly increased alcohol-induced ONFH risk (OR = 1.47, 95% CI = 1.07-2.02, = 0.017) in the allele model. In the genetic analysis, rs62030917 also increased the risk of alcohol-induced ONFH in the dominant model (adjusted OR = 1.52, 95% CI=1.02-2.26, = 0.039) and the log-additive model (adjusted OR = 1.42, 95% CI=1.05-1.93, = 0.025). Age stratification analysis suggested that rs62030917 increased the risk of alcohol-induced ONFH among the individuals younger than 42 years old. Moreover, carriers of AA, GA and GG genotypes in rs2269556 had LDL-C levels that were significantly different ( = 0.047). Among them, carriers of GG genotype had the highest LDL-C levels.

Conclusion: This study revealed rs62030917 in gene might increase the risk of alcohol-induced ONFH, providing a theoretical basis for the mechanism of in alcohol-induced ONFH.
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http://dx.doi.org/10.2147/IJGM.S316481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296705PMC
July 2021

Nomogram predict relapse-free survival of patients with thymic epithelial tumors after surgery.

BMC Cancer 2021 Jul 22;21(1):847. Epub 2021 Jul 22.

State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Hematological indicators and clinical characteristics play an important role in the evaluation of the progression and prognosis of thymic epithelial tumors. Therefore, we aimed to combine these potential indicators to establish a prognostic nomogram to determine the relapse-free survival (RFS) of patients with thymic epithelial tumors undergoing thymectomy.

Methods: This retrospective study was conducted on 156 patients who underwent thymectomy between May 2004 and August 2015. Cox regression analysis were performed to determine the potential indicators related to prognosis and combine these indicators to create a nomogram for visual prediction. The prognostic predictive ability of the nomogram was evaluated using the consistency index (C-index), receiver operating characteristic (ROC) curve, and risk stratification. Decision curve analysis was used to evaluate the net benefits of the model.

Results: Preoperative albumin levels, neutrophil-to-lymphocyte ratio (NLR), T stage, and WHO histologic types were included in the nomogram. In the training cohort, the nomogram showed well prognostic ability (C index: 0.902). Calibration curves for the relapse-free survival (RFS) were in good agreement with the standard lines in training and validation cohorts.

Conclusions: Combining clinical and hematologic factors, the nomogram performed well in predicting the prognosis and the relapse-free survival of this patient population. And it has potential to identify high-risk patients at an early stage. This is a relatively novel approach for the prediction of RFS in this patient population.
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http://dx.doi.org/10.1186/s12885-021-08585-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299634PMC
July 2021

A new class of biochar-based slow-release phosphorus fertilizers with high water retention based on integrated co-pyrolysis and co-polymerization.

Chemosphere 2021 Jul 9;285:131481. Epub 2021 Jul 9.

School of Environment and Resources, Zhejiang Agriculture and Forestry University, Hangzhou, 311300, PR China. Electronic address:

The development of slow-release phosphorus fertilizers (SRFs) with high water retention is of significance for modern agriculture. Herein, a new class of biochar-based SRFs are developed by an integrated co-pyrolysis and co-polymerization process (PSRFs). The water-retention performance and P slow-release behavior of PSRFs are evaluated, which are compared with other types of biochar-based SRFs derived from biochar-based phosphorus adsorption (MSRFs), co-pyrolysis of biomass-bentonite-nutrients (BSRFs), and the application of coating on BSRFs (CSRFs). The results show that the obtained PSRFs exhibits high water retention with the maximum swelling capacity of 94.2 g/g, far outstripping other tested SRFs. The water-retention performance of PSRFs is found to be positively correlated with their crosslinking agent contents. In addition, PSRFs has excellent P slow-release performance which is comparable with CSRFs (~51.5% of P release after 30 days), but much better than MSRFs and BSRFs with a complete P release after 30 days. Furthermore, pot experiments reveal that PSRFs has the highest P utilization efficiency (75.83% after 60 days), which can promote the growth of pepper seedlings better than other SRFs. Moreover, the soil burial tests indicate that PSRFs has a good biodegradability with the degradation ratio of 33.46% in 75 days. Finally, biological abundance analysis further reveals that Actinobacteria in soil is mainly responsible for the metabolism of starch and sodium alginate in PSRFs.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131481DOI Listing
July 2021

Retinoblastoma cell-derived exosomes promote angiogenesis of human vesicle endothelial cells through microRNA-92a-3p.

Cell Death Dis 2021 07 13;12(7):695. Epub 2021 Jul 13.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou City, China.

Exosomes derived from tumor cells play a key role in tumor development. In the present study, we identified the bioactivity of exosomes released from WERI-Rb1 retinoblastoma cells in tumor angiogenesis, as well as the underlying mechanism, through biochemical methods and animal experiments. Our in vitro data showed that exosomes could be engulfed by human vesicle endothelial cells (HUVECs), significantly promote cell viability and induce an inflammatory response in HUVECs by increasing the expression of a series of related genes, such as IL-1, IL-6, IL-8, MCP-1, VCAM1, and ICAM1. Significant increases in migration and tube formation were also observed in the HUVECs incubated with exosomes. Moreover, experiments with a nude mouse xenotransplantation model showed that exosomes injected near tumors could be strongly absorbed by tumor cells. The numbers of endothelial cells and blood vessels were significantly increased in tumor tissues treated with exosomes compared to control tissues. Furthermore, to reveal the mechanism underlying exosome-mediated angiogenesis in retinoblastoma, we analyzed the levels of 12 microRNAs in the exosomes. Specifically, our data showed that miR-92a-3p was enriched in RB exosomes. Accordingly, miR-92a-3p was increased in the HUVECs incubated with these exosomes. After treatment with a miR-92a-3p inhibitor, the promoting effect of exosomes on the migration and tube formation of HUVECs was significantly abrogated. The expression of the angiogenesis-related genes mentioned above was markedly decreased in HUVECs. Similarly, treatment with a microRNA mimic also demonstrated that miR-92a-3p was involved in the angiogenesis of HUVECs. More importantly, bioinformatics analysis predicted that Krüppel-like factor 2 (KLF2), a member of the KLF family of zinc-finger transcription factors, might be an active target of miR-92a-3p. Notably, this prediction was confirmed both in vitro and in vivo. Thus, our work suggests that exosomal miR-92a-3p is involved in tumor angiogenesis and might be a promising therapeutic candidate for retinoblastoma.
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http://dx.doi.org/10.1038/s41419-021-03986-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277798PMC
July 2021
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