Publications by authors named "Chaoyang Zhang"

127 Publications

Genome-wide identification, characterization and expression analysis of the LIM transcription factor family in quinoa.

Physiol Mol Biol Plants 2021 Apr 13;27(4):787-800. Epub 2021 Apr 13.

College of Agronomy, Gansu Agricultural University, Lanzhou, 730070 China.

Lim family members play an important role in the regulation of plant cell development and stress response. However, there are few studies on LIM family in quinoa. In this study, we identified nine LIMS (named cqlim01-cqlim09) from quinoa, which were divided into three subfamilies (α Lim1, γ lim2 and δ lim2) according to phylogeny. The differences in gene structure and motif composition among different subfamilies have been observed. In addition, we studied the repetitive events of the members of the family. The Ka/Ks (non synchronous substitution rate / synchronous substitution rate) ratio analysis showed that the repetitive CqLIMs probably experienced purifying selection pressure. Promoter analysis showed that the family genes contained a variety of hormones, stress and tissue-specific expression elements, and protein interactions showed that these genes had actin stabilizing effect. In addition, QRT PCR results showed that all CqLIM genes were positively regulated under three stresses (low temperature, salt and ABA). These results provide a theoretical basis of further study of LIM gene in quinoa.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-021-00988-2.
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http://dx.doi.org/10.1007/s12298-021-00988-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055757PMC
April 2021

Energy density of high-pressure nitrogen-rich MN compounds.

Phys Chem Chem Phys 2021 Mar 22;23(12):7313-7320. Epub 2021 Mar 22.

Institute of Chemical Materials, China Academy of Engineering Physics, P. O. Box 919-311, Mianyang, Sichuan 621999, China.

In the past decade, a large number of nitrogen-rich MN compounds have been discovered under high-pressure conditions. In this work, we have evaluated the energy densities of MN structures with thermodynamic and dynamical stability through first-principles calculations. The results show that the energy densities of MN consisting of alkali metals and cyclo-N are less than ∼0.5 TNT equivalence, whereas the group-III metal nitrides have high-energy density regardless of the type of nitrogen oligomers in the structures. To clarify the energy density difference for MN composed of different impurities, bivariate Pearson correlation analysis is performed, which reveals that the high-energy density of MN is related to the large N density, small M atomic radius, short M-N bond length, small MN ionicity, long N-N bond length and large M formal oxidation state. According to this correlation, H, Be, B, Al, Si and P elements have been proposed as the candidate impurities to synthesize high-energy density MN.
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http://dx.doi.org/10.1039/d1cp00527hDOI Listing
March 2021

Anti-VEGF therapy prevents Müller intracellular edema by decreasing VEGF-A in diabetic retinopathy.

Eye Vis (Lond) 2021 Apr 17;8(1):13. Epub 2021 Apr 17.

Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, 100 Haining Road, Hongkou District, Shanghai, 200080, China.

Background: Although vascular endothelial growth factor A (VEGF-A) is known to play a key role in causing retinal edema, whether and how VEGF-A induces intracellular edema in the retina still remains unclear.

Methods: Sprague-Dawley rats were rendered diabetic with intraperitoneal injection of streptozotocin. Intravitreal injection of ranibizumab was performed 8 weeks after diabetes onset. rMC-1 cells (rat Müller cell line) were treated with glyoxal for 24 h with or without ranibizumab. The expression levels of inwardly rectifying K channel 4.1 (Kir4.1), aquaporin 4 (AQP4), Dystrophin 71 (Dp71), VEGF-A, glutamine synthetase (GS) and sodium-potassium-ATPase (Na-K-ATPase) were examined using Western blot. VEGF-A in the supernatant of the cell culture was detected with ELISA. The intracellular potassium and sodium levels were detected with specific indicators.

Results: Compared with normal control, protein expressions of Kir4.1 and AQP4 were down-regulated significantly in diabetic rat retinas, which were prevented by ranibizumab. The above changes were recapitulated in vitro. Similarly, the intracellular potassium level in glyoxal-treated rMC-1 cells was increased, while the intracellular sodium level and Na-K-ATPase protein level remained unchanged, compared with control. However, ranibizumab treatment decreased intracellular sodium, but not potassium.

Conclusion: Ranibizumab protected Müller cells from diabetic intracellular edema through the up-regulation of Kir4.1 and AQP4 by directly binding VEGF-A. It also caused a reduction in intracellular osmotic pressure.
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http://dx.doi.org/10.1186/s40662-021-00237-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053282PMC
April 2021

Density Prediction Models for Energetic Compounds Merely Using Molecular Topology.

J Chem Inf Model 2021 Apr 12. Epub 2021 Apr 12.

Institute of Chemical Materials, China Academy of Engineering Physics (CAEP), P.O. Box 919-311, Mianyang 621999, Sichuan, China.

Newly developed high-throughput methods for property predictions make the process of materials design faster and more efficient. Density is an important physical property for energetic compounds to assess detonation velocity and detonation pressure, but the time cost of recent density prediction models is still high owing to the time-consuming processes to calculate molecular descriptors. To improve the screening efficiency of potential energetic compounds, new methods for density prediction with more accuracy and less time cost are urgently needed, and a possible solution is to establish direct mappings between the molecular structure and density. We propose three machine learning (ML) models, support vector machine (SVM), random forest (RF), and Graph neural network (GNN), using molecular topology as the only known input. The widely applied quantitative structure-property relationship based on the density functional theory (DFT-QSPR) is adopted as the benchmark to evaluate the accuracies of the models. All these four models are trained and tested by using the same data set enclosing over 2000 reported nitro compounds searched out from the Cambridge Structural Database. The proportions of compounds with prediction error less than 5% are evaluated by using the independent test set, and the values for the models of SVM, RF, DFT-QSPR, and GNN are 48, 63, 85, and 88%, respectively. The results show that, for the models of SVM and RF, fingerprint bit vectors alone are not facilitated to obtain good QSPRs. Mapping between the molecular structure and density can be well established by using GNN and molecular topology, and its accuracy is slightly better than that of the time-consuming DFT-QSPR method. The GNN-based model has higher accuracy and lower computational resource cost than the widely accepted DFT-QSPR model, so it is more suitable for high-throughput screening of energetic compounds.
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http://dx.doi.org/10.1021/acs.jcim.0c01393DOI Listing
April 2021

3D fusion between fluoroscopy angiograms and SPECT myocardial perfusion images to guide percutaneous coronary intervention.

J Nucl Cardiol 2021 Apr 6. Epub 2021 Apr 6.

Department of Applied Computing, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, 49931, USA.

Background: Percutaneous coronary intervention (PCI) in stable coronary artery disease (CAD) is commonly triggered by abnormal myocardial perfusion imaging (MPI). However, due to the possibilities of multivessel disease, serial stenoses and variability of coronary artery perfusion distribution, an opportunity exists to better align anatomic stenosis with perfusion abnormalities to improve revascularization decisions. This study aims to develop a multi-modality fusion approach to assist decision-making for PCI.

Methods And Results: Coronary arteries from fluoroscopic angiography (FA) were reconstructed into 3D artery anatomy. Left ventricular (LV) epicardial surface was extracted from SPECT. The artery anatomy and epicardial surface were non-rigidly fused. The accuracy of the 3D fusion was evaluated via both computer simulation and real patient data. Simulated FA and MPI were integrated and then compared with the ground truth from a digital phantom. The distance-based mismatch errors between simulated fluoroscopy and phantom arteries were 1.86 ± 1.43 mm for left coronary arteries (LCA) and 2.21 ± 2.50 mm for right coronary arteries (RCA). FA and SPECT images in 30 patients were integrated and then compared with the ground truth from CT angiograms. The distance-based mismatch errors between the fluoroscopy and CT arteries were 3.84 ± 3.15 mm for LCA and 5.55 ± 3.64 mm for RCA. The presence of the corresponding fluoroscopy and CT arteries in the AHA-17-segment model agreed well with a Kappa value of 0.91 (CI 0.89-0.93) for LCA and a Kappa value of 0.80 (CI 0.67-0.92) for RCA.

Conclusions: Our fusion approach is technically accurate to assist PCI decision-making and is clinically feasible to be used in the catheterization laboratory. Future studies are necessary to determine if fusion improves PCI-related outcomes.
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http://dx.doi.org/10.1007/s12350-021-02574-1DOI Listing
April 2021

Imaging Hyperreflective Foci as an Inflammatory Biomarker after Anti-VEGF Treatment in Neovascular Age-Related Macular Degeneration Patients with Optical Coherence Tomography Angiography.

Biomed Res Int 2021 3;2021:6648191. Epub 2021 Feb 3.

Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Purpose: To investigate the hyperreflective foci (HRF) as an inflammatory biomarker using optical coherence tomography angiography (OCTA) in neovascular age-related macular degeneration (AMD) patients after antivascular endothelial growth factor (anti-VEGF) treatment and its association with the retinal microcapillary density.

Methods: Twenty-five eyes from 25 patients with neovascular AMD were included in the study. All eyes were imaged with OCTA at baseline (M0) and after 3 consecutive injections (M3; injection performed each month) of anti-VEGF. The number of HRF in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and outer retina was counted. The vascular density of the fovea, parafovea, and the whole macula, as well as the area of the foveal avascular zone (FAZ), was measured.

Results: The mean interval between baseline and follow-up with OCTA was 93.08 ± 5.00 (range, 85-101) days. Compared with the baseline, the number of HRF significantly decreased in DCP (7.52 ± 3.06 vs. 3.76 ± 1.48, < 0.01) and outer retina (12.04 ± 4.91 vs. 5.88 ± 3.32, < 0.01) after treatment. There was no significant difference for HRF number in the SCP, the vascular density (containing foveal, parafoveal, and whole macular), and FAZ area before and after treatments.

Conclusion: The number of HRF in DCP and outer retina might serve as an inflammatory biomarker in patients with neovascular AMD. The reduced HRF possibly represents the alleviation of inflammation after anti-VEGF treatment in patients with AMD.
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http://dx.doi.org/10.1155/2021/6648191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878069PMC
February 2021

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in Aβ-injected mice.

J Mol Med (Berl) 2021 May 11;99(5):713-728. Epub 2021 Feb 11.

Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Age-related macular degeneration (AMD) is mainly characterized by the progressive accumulation of drusen deposits and loss of photoreceptors and retinal pigment epithelial (RPE) cells. Because amyloid β (Aβ) is the main component of drusen, Aβ-induced activated microglia most likely lead to neuroinflammation and play a critical role in the pathogenesis of AMD. However, the relationship between activated microglia-mediated neuroinflammatory cytokines and photoreceptor death has not been clarified. By subretinal injection of Aβ in mice, we mimicked an inflammatory milieu of AMD to better understand how activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in the AMD progression. We demonstrated that subretinal injection of Aβ induces microglial activation and increases inflammatory cytokine release, which gives rise to photoreceptor apoptosis in mice. Our results were verified in vitro by co-culture of Aβ activated primary microglia and the photoreceptor cell line 661W. We also demonstrated that the p38 mitogen-activated protein kinase (MAPK) signaling pathway was involved in Aβ-induced microglial activation and inflammatory cytokine release. Overall, our findings indicate that activated microglia-derived neuroinflammatory cytokines could contribute to photoreceptor apoptosis under the stimulation of Aβ. Moreover, this study may provide a potential therapeutic approach for AMD. KEY MESSAGES: Further explore the association between activated microglia-derived neuroinflammatory cytokine secretion and photoreceptor apoptosis under the stimulation of Aβ. Subretinal injection of Aβ induces the activation of microglia and increases proinflammatory cytokines IL-1β and COX-2 expression in the retina, which could give rise to the deterioration of visual function and aggravate photoreceptor apoptosis in mice. Primary microglial are activated and the levels of proinflammatory cytokines are increased by Aβ stimulation, which could increase the apoptosis of photoreceptor cell line 661W in vitro. The p38 MAPK signaling pathway is involved in microglial activation and photoreceptor apoptosis under Aβ treatment.
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http://dx.doi.org/10.1007/s00109-021-02046-6DOI Listing
May 2021

Assessing the Reliability of Relevant Tweets and Validation Using Manual and Automatic Approaches for Flood Risk Communication.

ISPRS Int J Geoinf 2020 Sep 5;9(9). Epub 2020 Sep 5.

National Institute on Minority and Health Disparities, National Institutes of Health, Bethesda, MD 20814, USA.

While Twitter has been touted as a preeminent source of up-to-date information on hazard events, the reliability of tweets is still a concern. Our previous publication extracted relevant tweets containing information about the 2013 Colorado flood event and its impacts. Using the relevant tweets, this research further examined the reliability (accuracy and trueness) of the tweets by examining the text and image content and comparing them to other publicly available data sources. Both manual identification of text information and automated (Google Cloud Vision, application programming interface (API)) extraction of images were implemented to balance accurate information verification and efficient processing time. The results showed that both the text and images contained useful information about damaged/flooded roads/streets. This information will help emergency response coordination efforts and informed allocation of resources when enough tweets contain geocoordinates or location/venue names. This research will identify reliable crowdsourced risk information to facilitate near real-time emergency response through better use of crowdsourced risk communication platforms.
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http://dx.doi.org/10.3390/ijgi9090532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839990PMC
September 2020

Melatonin maintains inner blood-retinal barrier via inhibition of p38/TXNIP/NF-κB pathway in diabetic retinopathy.

J Cell Physiol 2021 Jan 11. Epub 2021 Jan 11.

Department of Regenerative Medicine, and Department of Pharmacology, Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.

The pathophysiology of diabetic retinopathy (DR) was complex. Under hyperglycemic conditions, the release of proinflammatory cytokines and the adhesion of leukocytes to retinal capillaries contribute to endothelial damage and the subsequent increase in vascular permeability resulting in macular edema. Melatonin, produced in the retina to regulate redox reactions and dopamine metabolism, plays protective roles against inflammation and oxidative stress. Considering its anti-inflammatory and antioxidative properties, melatonin was speculated to exert beneficial effects in DR. In this study, we characterized the protective effects of melatonin on the inner blood-retinal barrier (iBRB), as well as the possible mechanisms in experimental DR. Results showed that in diabetic rat retinas, the leakage of iBRB and the expression of inflammatory factors (VEGF, TNF-α, IL-1β, ICAM-1, and MMP9) increased dramatically, while the expression of tight junction proteins (ZO-1, occludin, JAM-A, and claudin-5) decreased significantly. The above changes were largely ameliorated by melatonin. The in vivo data were confirmed in vitro. In addition, the protein expressions of p38 MAPK, NF-κB, and TXNIP were upregulated significantly in diabetes and were downregulated following melatonin treatment. Melatonin could maintain the iBRB integrity by upregulating the expression of tight junction proteins via inhibiting p38/TXNIP/NF-κB pathway, thus decreasing the production of inflammatory factors. This study may shed light on the development of melatonin-based DR therapy.
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http://dx.doi.org/10.1002/jcp.30269DOI Listing
January 2021

Efficacy and safety of warm acupuncture in the treatment of ankylosing spondylitis: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Jan;100(1):e24116

The First Clinical Medical College of Shaanxi University of Chinese Medicine, Xianyang China.

Background: Ankylosing spondylitis refers to a type of autoimmune disease, which is commonly characterized by joint pain and stiffness, since the disease progression can exhibit joint deformity and other activities limited symptoms. Has significantly impacts on people's work and life. Warm acupuncture as a traditional Chinese therapy, showing several advantages (eg, safety, economy, and less side effects), has been extensively used to treat ankylosing spondylitis. However, its curative effect is supported by limited evidence. Accordingly, the present study aims to comprehensively assess the reliability of warm acupuncture in ankylosing spondylitis treatment.

Methods: Randomized controlled trials were searched from the Chinese Biomedical Literature Database, Chongqing VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, Wanfang, Web of Science, Cochrane Library, PubMed, and EMBASE, regardless of their publication status. The deadline was November 6th, 2020. Two experienced researchers adopted RevMan V.5.3 software for literature selection, data collection, data analysis, and synthesis, respectively. In addition, the quality of the trials involved in this study was measured with the Cochrane Bias risk assessment tool, regardless of language or publication status.

Results: The protocol will be used to assess the efficacy and safety of warm acupuncture in ankylosing spondylitis treatment.

Conclusion: This review reliably evidences whether warm acupuncture is a reliable method for the intervention of ankylosing spondylitis.

Inplasy Registration Number: INPLASY2020110096.
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http://dx.doi.org/10.1097/MD.0000000000024116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793462PMC
January 2021

Structure-activity relationship-based chemical classification of highly imbalanced Tox21 datasets.

J Cheminform 2020 Oct 27;12(1):66. Epub 2020 Oct 27.

Environmental Laboratory, U.S. Army Engineer Research and Development Center, Vicksburg, MS, 39180, USA.

The specificity of toxicant-target biomolecule interactions lends to the very imbalanced nature of many toxicity datasets, causing poor performance in Structure-Activity Relationship (SAR)-based chemical classification. Undersampling and oversampling are representative techniques for handling such an imbalance challenge. However, removing inactive chemical compound instances from the majority class using an undersampling technique can result in information loss, whereas increasing active toxicant instances in the minority class by interpolation tends to introduce artificial minority instances that often cross into the majority class space, giving rise to class overlapping and a higher false prediction rate. In this study, in order to improve the prediction accuracy of imbalanced learning, we employed SMOTEENN, a combination of Synthetic Minority Over-sampling Technique (SMOTE) and Edited Nearest Neighbor (ENN) algorithms, to oversample the minority class by creating synthetic samples, followed by cleaning the mislabeled instances. We chose the highly imbalanced Tox21 dataset, which consisted of 12 in vitro bioassays for > 10,000 chemicals that were distributed unevenly between binary classes. With Random Forest (RF) as the base classifier and bagging as the ensemble strategy, we applied four hybrid learning methods, i.e., RF without imbalance handling (RF), RF with Random Undersampling (RUS), RF with SMOTE (SMO), and RF with SMOTEENN (SMN). The performance of the four learning methods was compared using nine evaluation metrics, among which F score, Matthews correlation coefficient and Brier score provided a more consistent assessment of the overall performance across the 12 datasets. The Friedman's aligned ranks test and the subsequent Bergmann-Hommel post hoc test showed that SMN significantly outperformed the other three methods. We also found that a strong negative correlation existed between the prediction accuracy and the imbalance ratio (IR), which is defined as the number of inactive compounds divided by the number of active compounds. SMN became less effective when IR exceeded a certain threshold (e.g., > 28). The ability to separate the few active compounds from the vast amounts of inactive ones is of great importance in computational toxicology. This work demonstrates that the performance of SAR-based, imbalanced chemical toxicity classification can be significantly improved through the use of data rebalancing.
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http://dx.doi.org/10.1186/s13321-020-00468-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592558PMC
October 2020

Subsequent monitoring of ferric ion and ascorbic acid using graphdiyne quantum dots-based optical sensors.

Mikrochim Acta 2020 Nov 16;187(12):657. Epub 2020 Nov 16.

College of Materials Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.

Graphdiyne (GDY) as an emerging carbon nanomaterial has attracted increasing attention because of its uniformly distributed pores, highly π-conjugated, and tunable electronic properties. These excellent characteristics have been widely explored in the fields of energy storage and catalysts, yet there is no report on the development of sensors based on the outstanding optical property of GDY. In this paper, a new sensing mechanism is reported built upon the synergistic effect between inner filter effect and photoinduced electron transfer. We constructed a novel nanosensor based upon the newly-synthesized nanomaterial and demonstrated a sensitive and selective detection for both Fe ion and ascorbic acid, enabling the measurements in real clinical samples. For the first time fluorescent graphdiyne oxide quantum dots (GDYO-QDs) were prepared using a facile ultrasonic protocol and they were characterized with a range of techniques, showing a strong blue-green emission with 14.6% quantum yield. The emission is quenched efficiently by Fe and recovered by ascorbic acid (AA). We have fabricated an off/on fluorescent nanosensors based on this unique property. The nanosensors are able to detect Fe as low as 95 nmol L with a promising dynamic range from 0.25 to 200 μmol L. The LOD of AA was 2.5 μmol L, with range of 10-500 μmol L. It showed a promising capability to detect Fe and AA in serum samples. Graphical abstract.
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http://dx.doi.org/10.1007/s00604-020-04624-wDOI Listing
November 2020

A Review of Integrative Imputation for Multi-Omics Datasets.

Front Genet 2020 15;11:570255. Epub 2020 Oct 15.

Tulane Center of Biomedical Informatics and Genomics, School of Medicine, Tulane University, New Orleans, LA, United States.

Multi-omics studies, which explore the interactions between multiple types of biological factors, have significant advantages over single-omics analysis for their ability to provide a more holistic view of biological processes, uncover the causal and functional mechanisms for complex diseases, and facilitate new discoveries in precision medicine. However, omics datasets often contain missing values, and in multi-omics study designs it is common for individuals to be represented for some omics layers but not all. Since most statistical analyses cannot be applied directly to the incomplete datasets, imputation is typically performed to infer the missing values. Integrative imputation techniques which make use of the correlations and shared information among multi-omics datasets are expected to outperform approaches that rely on single-omics information alone, resulting in more accurate results for the subsequent downstream analyses. In this review, we provide an overview of the currently available imputation methods for handling missing values in bioinformatics data with an emphasis on multi-omics imputation. In addition, we also provide a perspective on how deep learning methods might be developed for the integrative imputation of multi-omics datasets.
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http://dx.doi.org/10.3389/fgene.2020.570255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594632PMC
October 2020

Erythropoietin protects the inner blood-retinal barrier by inhibiting microglia phagocytosis via Src/Akt/cofilin signalling in experimental diabetic retinopathy.

Diabetologia 2021 Jan 26;64(1):211-225. Epub 2020 Oct 26.

Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.

Aims/hypothesis: Microglial activation in diabetic retinopathy and the protective effect of erythropoietin (EPO) have been extensively studied. However, the regulation of microglia in the retina and its relationship to inner blood-retinal barrier (iBRB) maintenance have not been fully characterised. In this study, we investigated the role of microglia in iBRB breakdown in diabetic retinopathy and the protective effects of EPO in this context.

Methods: Male Sprague Dawley rats were injected intraperitoneally with streptozotocin (STZ) to establish the experimental model of diabetes. At 2 h after STZ injection, the right and left eyes were injected intravitreally with EPO (16 mU/eye, 2 μl) and an equivalent volume of normal saline (NaCl 154 mmol/l), respectively. The rats were killed at 2 or 8 weeks after diabetes onset. Microglia activation was detected by ionised calcium binding adaptor molecule (IBA)-1 immunolabelling. Leakage of the iBRB was evaluated by albumin staining and FITC-dextran permeability assay. BV cells and primary rat microglia under hypoxic conditions were used to model microglial activation in diabetic retinopathy. Phagocytosis was examined by confocal microscopy in flat-mounted retina preparations and in microglia and endothelial cell cocultures. Protein levels of IBA-1, CD11b, complement component 1r (C1r), and Src/Akt/cofilin signalling pathway components were assessed by western blotting.

Results: In diabetic rat retinas, phagocytosis of endothelial cells by activated microglia was observed at 8 weeks, resulting in an increased number of acellular capillaries (increased by 426.5%) and albumin leakage. Under hypoxic conditions, activated microglia transmigrated to the opposite membrane of the transwell, where they disrupted the endothelial cell monolayer by engulfing endothelial cells. The activation and phagocytic activity of microglia was blocked by intravitreal injection of EPO. In vitro, IBA-1, CD11b and C1r protein levels were increased by 50.9%, 170.0% and 135.5%, respectively, by hypoxia, whereas the phosphorylated proteins of Src/Akt/cofilin signalling pathway components were decreased by 74.2%, 47.8% and 39.7%, respectively, compared with the control; EPO treatment abrogated these changes.

Conclusions/interpretation: In experimental diabetic retinopathy, activated microglia penetrate the basement membrane of the iBRB and engulf endothelial cells, leading to iBRB breakdown. EPO exerts a protective effect that preserves iBRB integrity via activation of Src/Akt/cofilin signalling in microglia, as demonstrated in vitro. These data support a causal role for activated microglia in iBRB breakdown and highlight the therapeutic potential of EPO for the treatment of diabetic retinopathy. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05299-xDOI Listing
January 2021

Atomic Perspective about the Reaction Mechanism and H Production during the Combustion of Al Nanoparticles/HO Bipropellants.

J Phys Chem A 2020 Sep 1;124(37):7399-7410. Epub 2020 Sep 1.

Institute of Chemical Materials, China Academy of Engineering Physics (CAEP), P.O. Box 919-311, Mianyang, Sichuan 621900, China.

The combination of Al nanoparticles (ANPs) and hydrogen peroxide (HO) can serve as environmentally friendly bipropellants and maximize the energetic benefits through harnessing heat release and chemical energy stored in H. This work presents an atomic insight into the combustion mechanism of ANPs/HO. Two main paths, including the ANPs oxidation by HO to produce H and Al oxides, and the catalytic decomposition of HO on ANP surface to generate O and HO, are confirmed to maintain the combustion. OH and HOO radicals as well as HO, O, H, and Al oxides are detected as dominant intermediates and products therein. It is evidenced that higher temperature, smaller ANP size, and higher HO concentration enhance the combustion. Moreover, atomic details show that the H desorption from ANPs/Al clusters is a critical step for both H production and ANP oxidation. In addition, microexplosion that has been confirmed in hot and dense O is not observed in HO, even with a high concentration, possibly due to a slower heat release. Besides, the observed excellent specific impulse of the ANP/HO bipropellants could be attributed to the considerable H production, instead of heat release. This work is expected to present an overall atomic perspective about the combustion mechanism of ANP/HO bipropellants.
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http://dx.doi.org/10.1021/acs.jpca.0c05901DOI Listing
September 2020

Erythropoietin maintains VE-cadherin expression and barrier function in experimental diabetic retinopathy via inhibiting VEGF/VEGFR2/Src signaling pathway.

Life Sci 2020 Oct 12;259:118273. Epub 2020 Aug 12.

Department of Ophthalmology of Shanghai Tenth People's Hospital, Tongji Eye Institute, Department of Regenerative Medicine, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, China; Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China. Electronic address:

Aims: To explore the mechanisms of erythropoietin (EPO)'s protection on inner blood-retinal barrier (iBRB) in experimental diabetic retinopathy.

Material And Methods: Male SD rats were rendered diabetic with streptozotocin, followed by intravitreal injection of EPO. The permeability of iBRB was examined with fluorescein isothiocyanate (FITC)-dextran. Human retinal microvascular endothelial cells (HRMECs) and human umbilical vein endothelial cells (HUVECs) were treated with glyoxal and studied for cell viability and barrier function. The expressions of vascular endothelial (VE)-cadherin, Src kinase, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR2) were analyzed with Western blot, ELISA, qPCR, or immunofluorescence.

Key Findings: VE-cadherin in rat retinas was down-regulated with diabetes progression. EPO treatment could increase VE-cadherin expression at week 8 and week 16. The expressions of p-Src and p-VE-cadherin were increased at week 2, while decreased at week 8 of diabetes; which were prevented by EPO. The leakage of FITC-dextran in 8-week diabetic rat retinas was ameliorated by EPO. In vitro results showed the expressions of VEGF, p-Src and p-VE-cadherin were increased significantly, accompanied with the decreased barrier function, which were prevented by EPO. Ranibizumab and CGP77675 also inhibited the glyoxal-induced phosphorylation of Src and VE-cadherin. Cellular fractionation showed EPO mitigated the VE-cadherin internalization in glyoxal-treated cells.

Significance: EPO maintained the expression of VE-cadherin in experimental diabetic retinopathy by inhibiting its phosphorylation and internalization through VEGF/VEGFR2/Src pathway, thus improved the integrity of iBRB.
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http://dx.doi.org/10.1016/j.lfs.2020.118273DOI Listing
October 2020

Review of the molecular and crystal correlations on sensitivities of energetic materials.

J Hazard Mater 2020 Nov 14;398:122910. Epub 2020 May 14.

Institute of Chemical Materials, China Academy of Engineering Physics (CAEP), P. O. Box 919-311, Mianyang, Sichuan 621999, China; Beijing Computational Science Research Center, Beijing 100048, China. Electronic address:

Highly efficient design on the levels of molecule and crystal, as well as formulation, is highly desired for accelerating the development of energetic materials (EMs). Sensitivity is one of the most important characteristics of EMs and should be compulsorily considered in the design. However, owing to multiple factors responsible for the sensitivity, it usually undergoes a low predictability. Thus, it becomes urgent to clarify which factors govern the sensitivity and what is the importance of these factors. The present article focuses upon the progress of the molecular and crystal correlations on the sensitivity, and the molecule-based numerical models for sensitivity prediction in the past decades. On the molecular level, composition, geometric structure, electronic structure, energy and reactivity can be correlated with the sensitivity; while the sensitivity can be also related with molecular packing pattern, intermolecular interaction, crystal morphology, crystal size and distribution, crystal surface/interface and crystal defect on the crystal level. And most of these factors, in particle on the crystal level, have been employed as variables in numerical models for predicting sensitivity of categorized EMs. Besides, we stress that more attention should be paid to the sensitivity correlations on the inherent structures of EMs, molecule and crystal packing, because they can be readily dealt by molecular simulations nowadays, facilitating to reveal the physical nature of sensitivity.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122910DOI Listing
November 2020

Capsular serotypes, antimicrobial susceptibility, and the presence of transferable oxazolidinone resistance genes in Streptococcus suis isolated from healthy pigs in China.

Vet Microbiol 2020 Aug 10;247:108750. Epub 2020 Jun 10.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China; Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety and Beijing Laboratory for Food Quality and Safety, China Agricultural University, Beijing, China. Electronic address:

Streptococcus suis is a pig pathogen and a vector of zoonotic diseases that can cause severe systemic infection in humans. S. suis can colonize the nasal cavity, tonsils, and upper respiratory, genital, and digestive tracts in healthy pigs. Here, to determine prevalence, serotype distribution, and antimicrobial susceptibility of S. suis in healthy pigs, we collected 1813 nasal cavity samples from healthy pigs raised on 17 independent farms in six Chinese provinces between 2016 and 2018. We obtained 223 S. suis isolates (12.3 %) and the antimicrobial susceptibility to a panel of 11 antimicrobial agents was measured by microbroth dilution. Most S. suis isolates (98.7 %) were resistant to at least three classes of antimicrobial agents. The optrA gene conferring resistance to oxazolidinones and phenicols was identified in the chromosome of 27 isolates and on a ∼40-kb plasmid in one isolate; to the best of our knowledge, this was the first report of plasmid-borne optrA gene in S. suis. The genetic environment of optrA showed substantial diversity and could be divided into eleven different types. Interestingly, some fragments of the 89 K pathogenicity island (PAI) were observed together with optrA in 3 isolates, which warrants further attention. Capsular serotypes of S. suis isolates were determined by multiplex PCR. Serotype 29 was the most prevalent, followed by serotype 7 and serotype 2. The presence of highly virulent serotype 2 strains may pose a threat to public health.
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http://dx.doi.org/10.1016/j.vetmic.2020.108750DOI Listing
August 2020

Metformin Protects ARPE-19 Cells from Glyoxal-Induced Oxidative Stress.

Oxid Med Cell Longev 2020 9;2020:1740943. Epub 2020 Jul 9.

Department of Ophthalmology of Shanghai Tenth People's Hospital, Tongji Eye Institute, Department of Regenerative Medicine, And Department of Pharmacology, Tongji University School of Medicine, Shanghai, China.

The protective effects and mechanisms of metformin against oxidative stress were evaluated both and . ARPE-19 cells comprised the normal group, the glyoxal-treated group (0.5 mM glyoxal), and the glyoxal+metformin group (0.5 mM glyoxal and 0.1 mM metformin). In the model, differences in cell viability, ROS production, NO products, cellular apoptosis, and the expressions of phospho-AMPK, total-AMPK, Sirt1, Nrf2, TXNIP, ZO-1, and Occludin were assessed. In the glyoxal-treated group, cell viability and NO production were decreased, while ROS production and cell apoptosis were increased ( < 0.05), compared with the control group. These changes were prevented by metformin treatment. Protein expressions of phospho-AMPK, Sirt1, TXNIP, ZO-1, and Occludin, but not Nrf2, were decreased significantly in the glyoxal-treated group compared to normal controls. Metformin treatment significantly increased the above protein expressions and slightly increased TXNIP expression. Immunofluorescence showed that metformin prevented the glyoxal-induced, disorganized tight junctions in ARPE-19 cells. To confirm metformin's protection, Sprague-Dawley rats were injected intravenously with sodium iodate (SI) to induce oxidative stress in the retinal pigment epithelium (RPE). Metformin was then delivered intraperitoneally or intravitreally. One day and three days after SI and metformin treatments, the RPE-Bruch's membrane-choriocapillaris complex was isolated and immune-stained with ZO-1 antibodies. The morphology of the RPE showed enlarged cellular bodies and disorganized ZO-1 staining in SI-treated rats. Metformin treatment prevented these changes. The results indicated that metformin maintained the barrier functions of RPE cells both and . Metformin exerted its protection against oxidative stress possibly via activating AMPK/Sirt1 and increasing TXNIP. Metformin has been proposed as a candidate drug for age-related macular degeneration (AMD) by both preclinical and clinical studies. The cellular and animal models used in this study might be useful for the interpretation of the molecular mechanisms involved in the drug activity.
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http://dx.doi.org/10.1155/2020/1740943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368933PMC
December 2020

TLR4 knockout upregulates the expression of Mfn2 and PGC-1α in a high-fat diet and ischemia-reperfusion mice model of liver injury.

Life Sci 2020 Aug 11;254:117762. Epub 2020 May 11.

Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Aims: Patients with nonalcoholic fatty liver disease (NAFLD) have less tolerance to ischemia-reperfusion injury (IRI) of the liver than those with the healthy liver; hence have a higher incidence of severe complications after surgery. This study aimed to investigate the dynamics of the liver and mitochondrial damage and the impact of TLR4 knockout (TLR4KO) on Mfn2 expression in the composite model of NAFLD and IRI.

Main Methods: We performed high-fat diet (HFD) feeding and ischemia reperfusion (IR) on wild type (WT) and TLR4 knockout TLR4KO mice.

Key Findings: The degree of structural and functional injuries to the liver and mitochondria (NAFLD and IRI) is greater than that caused by a single factor (NAFLD or IRI) or a simple superposition of both. The IL-6 and TNF-α expressions were significantly suppressed (P < .05), while PGC-1α and Mfn2 expressions were up-regulated considerably (P < .05) after TLR4KO. Furthermore, mitochondrial fusion increased, while ATP consumption and ROS production decreased significantly after TLR4KO (P < .05). The degree of reduction of compound injury by TLR4KO is more significant than the reduction degree of single factor injury. Also, TNF-α and IL-6 levels can be used predictive markers for mitochondrial damage and liver tolerance to NAFLD and IRI.

Significance: TLR4KO upregulates the expression of Mfn2 and PGC-1α in the composite model of NAFLD and IRI. This pathway may be related to IL-6 and TNF-α. This evidence provides theoretical and experimental basis for the subsequent Toll-like receptor 4 (TLR4) receptor targeted therapy.
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http://dx.doi.org/10.1016/j.lfs.2020.117762DOI Listing
August 2020

Peptide nucleic acid restores colistin susceptibility through modulation of MCR-1 expression in Escherichia coli.

J Antimicrob Chemother 2020 08;75(8):2059-2065

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.

Background: Plasmid-mediated mechanisms of drug resistance accelerate the spread of polymyxin resistance, leaving clinicians with few or no antibacterial options for the treatment of infections caused by MDR bacteria, especially carbapenemase-producing strains.

Objectives: To evaluate the associations among promoter sequence variation, mcr-1 expression, host factors and levels of colistin resistance and to propose antisense agents such as peptide nucleic acids (PNAs) targeting mcr-1 as a tool to restore colistin susceptibility through modulation of MCR-1 expression in Escherichia coli.

Methods: A β-galactosidase assay was performed to study mcr-1 promoter activity. Quantitative real-time PCR and western blot assays were used to identify the expression level of MCR-1 in WT strains and transformants. Three PNAs targeting different regions of mcr-1 were designed and synthesized to determine whether they can effectively inhibit MCR-1 expression. MIC was measured to test colistin susceptibility in the presence or absence of PNA-1 in mcr-1-carrying E. coli.

Results: Variation in the mcr-1 promoter sequence and host species affect promoter activity, MCR-1 expression levels and colistin MICs. One PNA targeting the ribosome-binding site fully inhibited the expression of mcr-1 at a concentration of 4 μM, resulting in significantly increased susceptibility to colistin. The MIC90 of colistin decreased from 8 to 2 mg/L (P < 0.05) in the presence of 4 μM PNA.

Conclusions: These findings suggest that the antisense approach is a possible strategy to combat mcr-1-mediated resistance as well as other causes of emerging global resistance.
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http://dx.doi.org/10.1093/jac/dkaa140DOI Listing
August 2020

Editorial: Deep Learning for Toxicity and Disease Prediction.

Front Genet 2020 26;11:175. Epub 2020 Feb 26.

Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, United States.

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http://dx.doi.org/10.3389/fgene.2020.00175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055598PMC
February 2020

Axisymmetric lattice Boltzmann model for simulating the freezing process of a sessile water droplet with volume change.

Phys Rev E 2020 Feb;101(2-1):023314

School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.

Droplet freezing not only is of fundamental interest but also plays an important role in numerous natural and industrial processes. However, it is challenging to numerically simulate the droplet freezing process due to its involving a complex three-phase system with dynamic phase change and heat transfer. Here we propose an axisymmetric lattice Boltzmann (LB) model to simulate the freezing process of a sessile water droplet with consideration of droplet volume expansion. Combined with the multiphase flow LB model and the enthalpy thermal LB model, our proposed approach is applied to simulate the sessile water droplet freezing on both hydrophilic and hydrophobic surfaces at a fixed subcooled temperature. Through comparison with the experimental counterpart, the comparison results show that our axisymmetric LB model can satisfactorily describe such sessile droplet freezing processes. Moreover, we use both LB simulations and analytical models to study the effects of contact angle and volume expansion on the freezing time and the cone shape formed on the top of frozen droplets. The analytical models are obtained based on heat transfer and geometric analyses. Additionally, we show analytically and numerically that the freezing front-to-interface angle keeps nearly constant (smaller than 90°).
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http://dx.doi.org/10.1103/PhysRevE.101.023314DOI Listing
February 2020

Unraveling the Mechanism of -N Production through Selective C-N Bond Cleavage of Arylpentazole with Ferrous Bisglycinate and -Chloroperbenzonic Acid: A Theoretical Perspective.

J Phys Chem Lett 2020 Feb 27;11(3):1030-1037. Epub 2020 Jan 27.

State Key Laboratory of Molecular Reaction Dynamics , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China.

Very recently, the bulk synthesis of -N from arylpentazole through the treatment with -chloroperbenzonic acid (-CPBA) and ferrous bisglycinate ([Fe(Gly)]) (Zhang, C., et al. , , 374) has greatly promoted the application of pentazolate anion as a novel high-performance energetic material. Yet the mechanism for this reaction is still unexplored. Herein we perform mechanistic studies on the selective C-N bond cleavage in arylpentazole by using density functional theory methods. The direct C-N bond activation by -CPBA was computed to be kinetically inaccessible. Instead, the oxidation of [Fe(Gly)] by -CPBA is much favorable, which leads to the generation of a high-valent iron(IV)-oxo product. The Fe(IV)-oxo intermediate has been examined by UV-vis absorption spectra experiments and further verified by excited-state calculations. It is found that the Fe(IV)-oxo serves as the key intermediate for the C-N bond activation of arylpentazole and the -N generation. Our calculations clarified the key mechanistic details of the -N generation, and the factors that affect the production yield are further discussed.
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http://dx.doi.org/10.1021/acs.jpclett.9b03762DOI Listing
February 2020

Analyze Informant-Based Questionnaire for The Early Diagnosis of Senile Dementia Using Deep Learning.

IEEE J Transl Eng Health Med 2020 16;8:2200106. Epub 2019 Dec 16.

3College of ComputingMichigan Technological UniversityHoughtonMI49931USA.

Objective: This paper proposes a multiclass deep learning method for the classification of dementia using an informant-based questionnaire.

Methods: A deep neural network classification model based on Keras framework is proposed in this paper. To evaluate the advantages of our proposed method, we compared the performance of our model with industry-standard machine learning approaches. We enrolled 6,701 individuals, which were randomly divided into training data sets (6030 participants) and test data sets (671 participants). We evaluated each diagnostic model in the test set using accuracy, precision, recall, and F1-Score.

Results: Compared with the seven conventional machine learning algorithms, the DNN showed higher stability and achieved the best accuracy with 0.88, which also showed good results for identifying normal (F1-score = 0.88), mild cognitive impairment (MCI) (F1-score = 0.87), very mild dementia (VMD) (F1-score = 0.77) and Severe dementia (F1-score = 0.94).

Conclusion: The deep neural network (DNN) classification model can effectively help doctors accurately screen patients who have normal cognitive function, mild cognitive impairment (MCI), very mild dementia (VMD), mild dementia (Mild), moderate dementia (Moderate), and severe dementia (Severe).
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http://dx.doi.org/10.1109/JTEHM.2019.2959331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964964PMC
December 2019

Corrections of Molecular Morphology and Hydrogen Bond for Improved Crystal Density Prediction.

Molecules 2019 Dec 31;25(1). Epub 2019 Dec 31.

School of Chemistry and Chemical Engineering, Southwest Petroleum University, Chengdu 610500, China.

Density prediction is of great significance for molecular design of energetic materials, since detonation velocity linearly with density and detonation pressure increases with the density squared. However, the accuracy and generalization of former reported prediction models need further improvement, because most of them are derived from small data sets and few molecular descriptors. As shown in this paper, for molecules presenting brick-like shape or containing more hydrogen-bond donors the predicted densities have large negative deviations from experimental values. Thus, a molecular morphology descriptor and a hydrogen-bond descriptor are introduced as correction items to build 3 new QSPR models. Besides, 3694 nitro compounds are adopted as data set by this work. The accuracies are obviously improved, and the generalizations are verified by an independent test set. At the level of B3PW91/6-31G(d,p), the effective ratios (ERs) of the 3 Equations, for < 5%, are 92.7%, 91.8%, and 93.3%; for < 2%, the values are 53.5%, 51.3%, and 54.7%. At the level of B3LYP/6-31G**, for < 5%, the values are 92.3%, 91.4% and 92.9%; for < 2%, the values are 53.7%, 51.4% and 53.2%.
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http://dx.doi.org/10.3390/molecules25010161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983118PMC
December 2019

Correction: PPA1 promotes NSCLC progression via a JNK- and TP53-dependent manner.

Oncogenesis 2019 Dec 13;8(12):75. Epub 2019 Dec 13.

Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41389-019-0184-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923412PMC
December 2019

PPA1 promotes NSCLC progression via a JNK- and TP53-dependent manner.

Oncogenesis 2019 Sep 24;8(10):53. Epub 2019 Sep 24.

Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China.

Inorganic pyrophosphatase (PPA1) promotes tumor progression in several tumor types. However, the underlying mechanism remains elusive. Here, we disclosed that PPA1 expression is markedly upregulated in lung carcinoma tissue versus normal lung tissue. We also found that the non-small cell lung cancer (NSCLC) cell lines show increased PPA1 expression levels versus normal lung cell line control. Moreover, the knockdown of PPA1 promotes cell apoptosis and inhibits cell proliferation. Whereas, the ectopic expression of PPA1 reduces cell apoptosis and enhances cell proliferation. Most interestingly, the expression of mutant PPA1 (D117A) significantly abolishes PPA1-mediated effect on cell apoptosis and proliferation. The underlying mechanism demonstrated that TP53 expression deficiency or JNK inhibitor treatment could abolish PPA1-mediated NSCLC progression. In summary, the aforementioned findings in this study suggest a new pathway the PPA1 mediates NSCLC progression either via TP53 or JNK. Most important, the pyrophosphatase activity is indispensible for PPA1-mediated NSCLC progression. This may provide a promising target for NSCLC therapy.
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http://dx.doi.org/10.1038/s41389-019-0162-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760234PMC
September 2019

Erythropoietin protects outer blood-retinal barrier in experimental diabetic retinopathy by up-regulating ZO-1 and occludin.

Clin Exp Ophthalmol 2019 Dec 15;47(9):1182-1197. Epub 2019 Sep 15.

Department of Ophthalmology of Shanghai Tenth People's Hospital, Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.

Purpose: To explore the mechanisms of erythropoietin (EPO) in maintaining outer blood-retinal barrier (BRB) in diabetic rats.

Methods: Sprague-Dawley rats were rendered diabetic with intraperitoneal injection of streptozotocin, and then followed by intravitreal injection of EPO. Two and four weeks later, the permeability of outer BRB was examined with FITC-dextran leakage assay, following a method to demarcate the inner and outer retina based on retinal blood supply. The glyoxal-treated ARPE-19 cells, incubated with EPO, soluble EPO receptor (sEPOR), Gö6976, or digoxin, were studied for cell viability and barrier function. The expressions of ZO-1, occludin, VEGFR2, HIF-1α, MAPKs, and AKT were examined with Western blot and immunofluorescence.

Results: The major Leakage of FITC-dextran was detected in the outer nuclear layer in both 2- and 4-week diabetic rats. The leakage was largely ameliorated in EPO-treated diabetic rats. The protein expressions of ZO-1 and occludin in the RPE-Bruch's membrane choriocapillaris complex were significantly decreased, whereas HIF-1α and JNK pathways were activated, in 4-week diabetic rats. These changes were prevented by EPO treatment. The in vitro study with ARPE-19 cells confirmed these changes, and the protective effect of EPO was abolished by sEPOR. Gö6976 and digoxin rescued the tight junction and barrier function in glyoxal-treated ARPE-19 cells.

Conclusions: In early diabetic rats, the outer BRB might be more severely damaged and its breakdown is the major factor for retinal oedema. EPO maintains the outer BRB integrity through down-regulation of HIF-1α and JNK signallings, and thus up-regulating ZO-1 and occludin expressions in RPE cells.
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http://dx.doi.org/10.1111/ceo.13619DOI Listing
December 2019

Deep Learning-Based Structure-Activity Relationship Modeling for Multi-Category Toxicity Classification: A Case Study of 10K Tox21 Chemicals With High-Throughput Cell-Based Androgen Receptor Bioassay Data.

Front Physiol 2019 13;10:1044. Epub 2019 Aug 13.

Environmental Laboratory, U.S. Army Engineer Research and Development Center, Vicksburg, MS, United States.

Deep learning (DL) has attracted the attention of computational toxicologists as it offers a potentially greater power for predictive toxicology than existing shallow learning algorithms. However, contradicting reports have been documented. To further explore the advantages of DL over shallow learning, we conducted this case study using two cell-based androgen receptor (AR) activity datasets with 10K chemicals generated from the Tox21 program. A nested double-loop cross-validation approach was adopted along with a stratified sampling strategy for partitioning chemicals of multiple AR activity classes (i.e., agonist, antagonist, inactive, and inconclusive) at the same distribution rates amongst the training, validation and test subsets. Deep neural networks (DNN) and random forest (RF), representing deep and shallow learning algorithms, respectively, were chosen to carry out structure-activity relationship-based chemical toxicity prediction. Results suggest that DNN significantly outperformed RF ( < 0.001, ANOVA) by 22-27% for four metrics (precision, recall, F-measure, and AUPRC) and by 11% for another (AUROC). Further in-depth analyses of chemical scaffolding shed insights on structural alerts for AR agonists/antagonists and inactive/inconclusive compounds, which may aid in future drug discovery and improvement of toxicity prediction modeling.
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http://dx.doi.org/10.3389/fphys.2019.01044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700714PMC
August 2019