Publications by authors named "Yingying Ma"

100 Publications

Design, synthesis and biological evaluation of anilide (dicarboxylic acid) shikonin esters as antitumor agents through targeting PI3K/Akt/mTOR signaling pathway.

Bioorg Chem 2021 Mar 29;111:104872. Epub 2021 Mar 29.

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address:

Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC = 4.52 ± 0.28 μM; SK: IC = 7.62 ± 0.26 μM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/β-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure-activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy.
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http://dx.doi.org/10.1016/j.bioorg.2021.104872DOI Listing
March 2021

Oral probiotics vaccine expressing koi herpesvirus (KHV) ORF81 protein delivered by chitosan-alginate capsules is a promising strategy for mass oral vaccination of carps against KHV infection.

J Virol 2021 Apr 7. Epub 2021 Apr 7.

Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Northeast Agricultural University, Harbin, P.R. China

Koi herpesvirus (KHV) is highly contagious and lethal to cyprinid fish, causing significant economic losses to the carp aquaculture industry, particularly to koi carp breeders. Vaccines delivered through intramuscular needle injection or gene gun are not suitable for mass vaccination of carp. So, the development of cost-effective, oral vaccines that are easily applicable at farm level is highly desirable. In this study, we utilized chitosan-alginate capsules as oral delivery system for a live probiotic () vaccine pYG-KHV-ORF81/LR CIQ249 expressing KHV ORF81 protein. The tolerance of the encapsulated recombinant to various digestive environments and the ability of the probiotics strain to colonize the intestine of carp was tested. The immunogenicity and the protective efficacy of the encapsulated probiotic vaccine was evaluated by determining IgM levels, lymphocyte proliferation, expression of immune-related genes, and viral challenge to vaccinated fish. It was clear that the chitosan-alginate capsules protected the probiotics vaccine effectively against extreme digestive environments, and significant level ( < 0.01) of antigen-specific IgM with KHV-neutralizing activity was detected, which provided protection rate of ca. 85% for koi carp against KHV challenge. The strategy of using chitosan-alginate capsules to deliver probiotic vaccines is easily applicable for mass oral vaccination of fish.An oral probiotic vaccine pYG-KHV-ORF81/LR CIQ249 encapsulated by chitosan-alginate capsules as oral delivery system was developed for koi carp against KHV infection. This encapsulated probiotic vaccine can be protected from various digestive environments and maintain effectively high viability, showing a good tolerance to digestive environments. This encapsulated probiotic vaccine has a good immunogenicity in koi carp via oral vaccination, and the significant level of antigen-specific IgM was effectively induced after oral vaccination, displaying effective KHV-neutralizing activity. This encapsulated probiotic vaccine can provide effective protection for koi carp against KHV challenge, which is handling stress-free for the fish, cost-effective, and suitable for the mass oral vaccination of koi carp at farm level, suggesting a promising vaccine strategy for fish.
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http://dx.doi.org/10.1128/JVI.00415-21DOI Listing
April 2021

Leukocyte proteomics coupled with serum metabolomics identifies novel biomarkers and abnormal amino acid metabolism in Kawasaki disease.

J Proteomics 2021 May 15;239:104183. Epub 2021 Mar 15.

Department of Cardiology, Children's Hospital of Soochow University, Suzhou 215025, China. Electronic address:

Kawasaki disease (KD) is a systemic vasculitis that can lead to severe cardiovascular complications, whereas the development and clinical usage of specific biomarkers might help diagnose KD and avoid certain complications. To this end, the molecular profiles of acute KD patients with coronary artery lesions (CAL) were first investigated through leukocyte proteomics and serum metabolomics assays. A total of 269 differentially abundant proteins and 35 differentially abundant metabolites with the top fold-changed levels were identified in acute KD patients compared to those in the healthy controls. Among them, several highly promising candidate marker proteins and metabolites indicative of KD progression were further analysed, such as the increased proteins ALPL, NAMPT, and S100P, as well as the decreased proteins C1QB and apolipoprotein family members. Moreover, metabolites, including succinic acid, dGMP, hyaluronic acid, L-tryptophan, propionylcarnitine, inosine, and phosphorylcholine, were found to be highly accurate at distinguishing between KD patients and healthy controls. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon intravenous immunoglobulin (IVIG) treatment. Overall, this work has revealed novel biomarkers and abnormal amino-acid metabolism as a prominent feature involved in KD patients with CAL. SIGNIFICANCE: KD is frequently concomitant with the development of life-threatening coronary vasculitis. Here, the profiles of leukocyte proteomics and serum metabolomics in acute KD patients with CALs were first investigated, and several hub molecules identified here could be used as supplemental biomarkers for KD diagnosis. Moreover, the metabolomic abnormalities especially the amino acids are particularly prominent in KD patients. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon IVIG treatment. Therefore, these findings might help understand the IVIG activities and also the underlying mechanisms of IVIG-resistant patients, thereby providing a new perspective for the exploration of mechanisms related to KD.
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http://dx.doi.org/10.1016/j.jprot.2021.104183DOI Listing
May 2021

Effects of biochar amendment and reduced irrigation on growth, physiology, water-use efficiency and nutrients uptake of tobacco (Nicotiana tabacum L.) on two different soil types.

Sci Total Environ 2021 May 25;770:144769. Epub 2021 Jan 25.

Department of Plant and Environmental Science, Faculty of Science, University of Copenhagen, Højbakkegaard Alle 13, DK-2630 Taastrup, Denmark; Key Laboratory of Agricultural Soil and Water Engineering in Arid and Semiarid Areas, Ministry of Education, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address:

Biochar has shown beneficial effects in agricultural production, yet the combined effects of biochar and reduced irrigation on crop growth and water-use efficiency (WUE) in diverse soil types have not been fully explored. A split-root pot experiment was conducted to investigate the effects of addition of 2% softwood (SWB) and wheat straw biochar (WSB) on growth, physiology, WUE and nutrients uptake of tobacco (Nicotiana tabacum L.) plants grown in a Ferrosol and an Anthrosol, respectively, under three irrigation treatments. The plants were either irrigated daily to 90% of water-holding capacity (FI), or irrigated with 70% volume of water used for FI to the whole root-zone (DI) or alternately to half root-zone (PRD). The results showed that plants grown in Anthrosol possessed greater leaf gas exchange rates, dry biomass and WUE while lower nutrients content compared to those grown in Ferrosol. Despite a negative effect on plant N content and WUE, WSB addition increased water-holding capacity, consequently improved leaf gas exchange, water uptake, biomass and K content resulting in an improved in the leaf quality of tobacco as exemplified by an increased leaf K content and a more appropriate N to K stoichiometric ratio. However, these effects were not evident upon SWB addition. Moreover, these responses to biochar addition were stronger in Ferrosol than in Anthrosol might be associated with its lower pH. Compared to FI, PRD slightly reduced photosynthetic rate but significantly decreased stomatal conductance, transpiration rate and leaf area, leading to a significant increase in intrinsic, instantaneous and plant WUE. Additionally, PRD was superior over DI in improving yield, WUE, N uptake under a same irrigation volume. It was concluded that WSB combined with PRD could be a promising practice to synergistically improve tobacco yield, quality and WUE by improving soil hydro-physical properties and nutrients bioavailability.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144769DOI Listing
May 2021

Synergistic effect of polystyrene nanoplastics and contaminants on the promotion of insulin fibrillation.

Ecotoxicol Environ Saf 2021 May 7;214:112115. Epub 2021 Mar 7.

State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China.

Nanoplastics (NPs) are becoming an emerging pollutant of global concern. A potential risk of NPs is that they can serve as carriers and synergistically function with other contaminants to cause diseases. A variety of diseases such as Alzheimer's disease are related to the generation of amyloid fibrils, and insulin is typically used as a model to study the fibrillation process. In this study, we examined the fibrillation of insulin promoted by polystyrene nanoplastics (PSNPs) alone and synergistically with organic contaminants (denoted as X, X = pyrene, bisphenol A, 2,2',4,4'-tetrabromodiphenyl ether, 4,4'-dihydroxydiphenylmethane, or 4-nonylphenol) having different polarities using thioflavin T fluorescence assays, dynamic light scattering, and circular dichroism spectroscopy. The presence of PSNPs and small organic contaminants decreased the lag phase time (t) for insulin fibrillation from 54.6 h to 35-51 h and their combination (PS-X) enhanced this process (t = 21-30 h). Notably, the lag phase time for insulin fibrillation with PS-nonpolar contaminants, PS-weakly polar contaminants, and PS-polar contaminants is around 20.8, 26.7, and 30.1 h, respectively, indicating the synergistic effect of PS-nonpolar contaminants or PS-weakly polar contaminants was more obvious than that of PS-polar contaminants. Moreover, molecular dynamic simulation reveal the interactions between insulin and PSs or small organic contaminants are primarily driven by van der Waals forces and hydrophobic interactions. Overall, the findings of this study underscore the potentially significant environmental impact of small organic contaminants assisting NPs in promoting insulin fibrillation.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112115DOI Listing
May 2021

Celecoxib-Loaded Electrospun Fibrous Antiadhesion Membranes Reduce COX-2/PGE Induced Inflammation and Epidural Fibrosis in a Rat Failed Back Surgery Syndrome Model.

Neural Plast 2021 23;2021:6684176. Epub 2021 Feb 23.

Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, China.

To date, failed back surgery syndrome (FBSS) remains a therapy-refractory clinical condition after spinal surgery. The antiadhesion membrane is applied to prevent FBSS by isolating fibrosis; however, the inflammation stimulated by the foreign body and surgical trauma needs to be further resolved simultaneously. Therefore, we developed new electrospun polycaprolactone (PCL) fibrous membranes loaded with celecoxib (CEL) to prevent fibrosis and inflammation associated with FBSS. The CEL-loaded PCL fibers were randomly distributed, and the drug was released over two weeks. Fluorescence micrographs revealed that the fibroblasts proliferated less on the PCL-CEL fibrous membranes than in the PCL group and the blank control. In the rat laminectomy model after 4 weeks, magnetic resonance imaging of epidural fibrosis was least in the PCL-CEL group. Expression of COX-2 and PGE was lower in the PCL-CEL group. It concluded that the CEL-loaded PCL membrane could reduce fibrosis and inflammation in a rat model of FBSS via COX-2/PGE signaling pathways.
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http://dx.doi.org/10.1155/2021/6684176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925049PMC
February 2021

A Novel 2-dimensional Multiplex qPCR Assay for Single-Tube Detection of Nine Human Herpesviruses.

Virol Sin 2021 Feb 26. Epub 2021 Feb 26.

Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.

Human herpesviruses are double-stranded DNA viruses that are classified into nine species. More than 90% of adults are ever infected with one or more herpesviruses. The symptoms of infection with different herpesviruses are diverse ranging from mild or asymptomatic infections to deadly diseases such as aggressive lymphomas and sarcomas. Timely and accurate detection of herpesvirus infection is critical for clinical management and treatment. In this study, we established a single-tube nonuple qPCR assay for detection of all nine herpesviruses using a 2-D multiplex qPCR method with a house-keeping gene as the internal control. The novel assay can detect and distinguish different herpesviruses with 30 to 300 copies per 25 µL single-tube reaction, and does not cross-react with 20 other human viruses, including DNA and RNA viruses. The robustness of the novel assay was evaluated using 170 clinical samples. The novel assay showed a high consistency (100%) with the single qPCR assay for HHVs detection. The features of simple, rapid, high sensitivity, specificity, and low cost make this assay a high potential to be widely used in clinical diagnosis and patient treatment.
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http://dx.doi.org/10.1007/s12250-021-00354-2DOI Listing
February 2021

Revisiting the π-Back-Donation in the NHC-B≡B-NHC Molecule.

J Phys Chem A 2021 Mar 17;125(8):1681-1687. Epub 2021 Feb 17.

Department of Chemistry, Key Laboratory of Functional Inorganic Materials of Anhui Province, Anhui University, Hefei, Anhui 230601, People's Republic of China.

As the first thermal stable molecule with a B≡B bond, the diboryne complex protected by N-heterocyclic carbene ligands (NHC-B≡B-NHC) has attracted much interest. Researchers point out that π-back-donation highly stabilizes the B≡B bond besides σ-donation, both of which are induced by NHC ligands. In this work, details of the π-back-donation are revisited by using DFT calculations. There are two delocalized π* orbitals in NHC, and the symmetry of one π* orbital is highly adaptive to the π orbitals in B≡B bond, whereas the other cannot be involved in the π-back-donation. In staggered configuration, two orthogonal π orbitals of B≡B interact with this π* orbital in each NHC ligand, respectively, to form π-back-donations in both sides. This interaction has proven to be more intensive than π-conjunction, resulting in the lower energy of the staggered isomer compared with the eclipsed one containing greater π-conjunction. Moreover, intensity of the π-back-donation can be enhanced by reducing the energy levels of the matched π* orbitals in ligands, which gives references for the design of stable diborynes.
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http://dx.doi.org/10.1021/acs.jpca.0c10207DOI Listing
March 2021

5-HT Receptor and 5-HT Degradation Play a Crucial Role in Atherosclerosis by Modulating Macrophage Foam Cell Formation, Vascular Endothelial Cell Inflammation, and Hepatic Steatosis.

J Atheroscler Thromb 2021 Feb 2. Epub 2021 Feb 2.

Department of Physiology, China Pharmaceutical University.

Aim: Previously, we found that diabetes-related liver dysfunction is due to activation of the 5-HT receptor (5-HTR) and increased synthesis and degradation of 5-HT. Here, we investigated the role of 5-HT in the development of atherosclerosis.

Methods: The study was conducted using high-fat diet-fed male ApoE mice, THP-1 cell-derived macrophages, and HUVECs. Protein expression and biochemical indexes were determined by Western blotting and quantitative analysis kit, respectively. The following staining methods were used: oil red O staining (showing atherosclerotic plaques and intracellular lipid droplets), immunohistochemistry (showing the expression of 5-HTR, 5-HT synthase, and CD68 in the aortic wall), and fluorescent probe staining (showing intracellular ROS).

Results: In addition to improving hepatic steatosis, insulin resistance, and dyslipidemia, co-treatment with a 5-HT synthesis inhibitor and a 5-HTR antagonist significantly suppressed the formation of atherosclerotic plaques and macrophage infiltration in the aorta of ApoE mice in a synergistic manner. Macrophages and HUVECs exposed to oxLDL or palmitic acid in vitro showed that activated 5-HTR regulated TG synthesis and oxLDL uptake by activating PKCε, resulting in formation of lipid droplets and even foam cells; ROS production was due to the increase of both intracellular 5-HT synthesis and mitochondrial MAO-A-catalyzed 5-HT degradation, which leads to the activation of NF-κB and the release of the inflammatory cytokines TNF-α and IL-1β from macrophages and HUVECs as well as MCP-1 release from HUVECs.

Conclusion: Similar to hepatic steatosis, the pathogenesis of lipid-induced atherosclerosis is associated with activation of intracellular 5-HTR, 5-HT synthesis, and 5-HT degradation.
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http://dx.doi.org/10.5551/jat.58305DOI Listing
February 2021

Differential relieving effects of shikonin and its derivatives on inflammation and mucosal barrier damage caused by ulcerative colitis.

PeerJ 2021 7;9:e10675. Epub 2021 Jan 7.

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, China.

Background: Ulcerative colitis (UC) is one of the most challenging human diseases. Natural shikonin (SK) and its derivatives (with have higher accumulation) isolated from the root of have numerous beneficial effects, such as wound healing and anti-inflammatory activities. Some researchers have reported that hydroxynaphthoquinone mixture (HM) and SK attenuate the acute UC induced by dextran sulfate sodium (DSS). However, no existing study has systemically investigated the effectiveness of SK and other hydroxynaphthoquinone natural derivative monomers on UC.

Methods: In this study, mice were treated with SK and its derivatives (25 mg/kg) and mesalazine (200 mg/kg) after DSS administration daily for one week. Disease progression was monitored daily by observing the changes in clinical signs and body weight.

Results: Intragastric administration natural single naphthoquinone attenuated the malignant symptoms induced by DSS. SK or its derivatives remarkably suppressed the serum levels of pro-inflammatory cytokines while increasing the inflammatory cytokine interleukin (IL)-10 . Additionally, both SK and alkanin restrained the activities of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) in serum and colonic tissues. SK and its derivatives inhibited the activation of nucleotide binding oligomerization domain-like receptors (NLRP3) inflammasome and NF-κB signaling pathway, thereby relieving the DSS-induced disruption of epithelial tight junction (TJ) in colonic tissues.

Conclusions: Our findings shed more lights on the pharmacological efficacy of SK and its derivatives in UC against inflammation and mucosal barrier damage.
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http://dx.doi.org/10.7717/peerj.10675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797173PMC
January 2021

A survey of jaagsiekte sheep retrovirus (JSRV) infection in sheep in the three northeastern provinces of China.

Arch Virol 2021 Mar 24;166(3):831-840. Epub 2021 Jan 24.

Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Northeast Agricultural University, Harbin, People's Republic of China.

Ovine pulmonary adenomatosis (OPA) is caused by jaagsiekte sheep retrovirus (JSRV) and is a chronic, progressive, and infectious neoplastic lung disease in sheep, which causes significant economic losses to the sheep industry. Neither a vaccine nor serological diagnostic methods to detect OPA are available. We performed a JSRV infection survey in sheep using blood samples (n = 1,372) collected in the three northeastern provinces of China (i.e., Inner Mongolia, Heilongjiang, and Jilin) to determine JSRV infection status in sheep herds using a real-time PCR assay targeting the gag gene of JSRV. The ovine endogenous retrovirus sequence was successfully amplified in all sheep samples tested (296 from the Inner Mongolia Autonomous Region, 255 from Jilin province, and 821 from Heilongjiang province). Subsequently, we attempted to distinguish exogenous JSRV (exJSRV) and endogenous JSRV (enJSRV) infections in these JSRV-positive samples using a combination assay that identifies a ScaI restriction site in an amplified 229-bp fragment of the gag gene of JSRV and a "LHMKYXXM" motif in the cytoplasmic tail region of the JSRV envelope protein. The ScaI restriction site is present in all known oncogenic JSRVs but absent in ovine endogenous retroviruses, while the "LHMKYXXM" motif is in all known exJSRVs but not in enJSRVs. Interestingly, one JSRV strain (HH13) from Heilongjiang province contained the "LHMKYXXM" motif but not the ScaI enzyme site. Phylogenetic analysis showed that strain HH13 was closely related to strain enJSRV-21 reported in the USA, indicating that HH13 could be an exogenous virus. Our results provide valuable information for further research on the genetic evolution and pathogenesis of JSRV.
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http://dx.doi.org/10.1007/s00705-020-04919-6DOI Listing
March 2021

Interplay between Locally Excited and Charge Transfer States Governs the Photoswitching Mechanism in the Fluorescent Protein Dreiklang.

J Phys Chem B 2021 01 7;125(3):757-770. Epub 2021 Jan 7.

Department of Chemistry, University of Southern California, Los Angeles, California 90089-0482, United States.

We present the results of high-level electronic structure and dynamics simulations of the photoactive protein Dreiklang. With the goal of understanding the details of the Dreiklang photocycle, we carefully characterize the excited states of the ON- and OFF-forms of Dreiklang. The key finding of our study is the existence of a low-lying excited state of a charge-transfer character in the neutral ON form and that population of this state, which is nearly isoenergetic with the locally excited bright state, initiates a series of steps that ultimately lead to the formation of the hydrated dark chromophore (OFF state). These results allow us to refine the mechanistic picture of Dreiklang's photocycle and photoactivation.
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http://dx.doi.org/10.1021/acs.jpcb.0c09221DOI Listing
January 2021

On the Capacity Regions of Degraded Relay Broadcast Channels with and without Feedback.

Entropy (Basel) 2020 Jul 17;22(7). Epub 2020 Jul 17.

School of Information Science and Technology, ShanghaiTech University, Shanghai 201210, China.

The four-node relay broadcast channel (RBC) is considered, in which a transmitter communicates with two receivers with the assistance of a relay node. We first investigate three types of physically degraded RBCs (PDRBCs) based on different degradation orders among the relay and the receivers' observed signals. For the discrete memoryless (DM) case, only the capacity region of the second type of PDRBC is already known, while for the Gaussian case, only the capacity region of the first type of PDRBC is already known. In this paper, we step forward and make the following progress: (1) for the first type of DM-PDRBC, a new outer bound is established, which has the same rate expression as an existing inner bound, with only a slight difference on the input distributions; (2) for the second type of Gaussian PDRBC, the capacity region is established; (3) for the third type of PDRBC, the capacity regions are established both for DM and Gaussian cases. Besides, we also consider the RBC with relay feedback where the relay node can send the feedback signal to the transmitter. A new coding scheme based on a hybrid relay strategy and a layered Marton's coding is proposed. It is shown that our scheme can strictly enlarge Behboodi and Piantanida's rate region, which is tight for the second type of DM-PDRBC. Moreover, we show that capacity regions of the second and third types of PDRBCs are exactly the same as that without feedback, which means feedback cannot enlarge capacity regions for these types of RBCs.
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http://dx.doi.org/10.3390/e22070784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517346PMC
July 2020

A Graph-Based Author Name Disambiguation Method and Analysis via Information Theory.

Entropy (Basel) 2020 Apr 7;22(4). Epub 2020 Apr 7.

University of Science and Technology of China, Heifei 230026, China.

Name ambiguity, due to the fact that many people share an identical name, often deteriorates the performance of information integration, document retrieval and web search. In academic data analysis, author name ambiguity usually decreases the analysis performance. To solve this problem, an author name disambiguation task is designed to divide documents related to an author name reference into several parts and each part is associated with a real-life person. Existing methods usually use either attributes of documents or relationships between documents and co-authors. However, methods of feature extraction using attributes cause inflexibility of models while solutions based on relationship graph network ignore the information contained in the features. In this paper, we propose a novel name disambiguation model based on representation learning which incorporates attributes and relationships. Experiments on a public real dataset demonstrate the effectiveness of our model and experimental results demonstrate that our solution is superior to several state-of-the-art graph-based methods. We also increase the interpretability of our method through information theory and show that the analysis could be helpful for model selection and training progress.
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http://dx.doi.org/10.3390/e22040416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516896PMC
April 2020

The efficacy and safety of Xuebijing injection for corona virus disease 2019: A protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2020 Dec;99(49):e23401

First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Heilongjiang Province, China.

Background: Corona virus disease 2019 (COVID-19) is an epidemic respiratory infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 infection. Now it is popular all over the world on a large scale. COVID-19 has the characteristics of rapid transmission, atypical clinical symptoms, easy missed diagnosis and misdiagnosis, and so on. which has seriously affected social and economic development and people's health. Severe acute respiratory syndrome corona virus type 2 infection may lead to systemic cytokine storm, which leads to a sharp deterioration of the condition of ordinary patients. At present, no specific drug has been found in the clinical treatment of covid-19, while Xuebijing injection has been widely used in severe patients in China as a traditional Chinese medicine. The aim of this study is to assess the effificacy and safety of Xuebijing injection for COVID-19.

Methods: Before the research, we conducted a comprehensive search on relevant websites. Two professional researchers will gradually screen, read the title, abstract and full text if necessary, and independently select qualified documents according to the inclusion and exclusion criteria. We will conduct a meta-analysis of the results related to COVID-19 to assess the risks of bias and data extraction. The heterogeneity of data will be studied by Cochrane X and I tests. The evaluation of publication bias will be carried out by funnel chart analysis and Eger test.

Results: This review will be disseminated in print by peer-review.

Conclusion: Our research is to scientifically analyze the clinical evidence of Xuebijing injection in treating severe COVID-19 patients.
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http://dx.doi.org/10.1097/MD.0000000000023401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717801PMC
December 2020

Comprehensive analysis of lncRNA expression profiles in cytopathic biotype BVDV-infected MDBK cells provides an insight into biological contexts of host-BVDV interactions.

Virulence 2021 12;12(1):20-34

Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, College of Veterinary Medicine, Northeast Agricultural University , Harbin, P.R. China.

Bovine viral diarrhea virus (BVDV) is the causative agent of bovine viral diarrhea-mucosal disease, which significantly affects the production performance of cattle, causing serious economic losses to the cattle industries worldwide. Up to now, some mechanisms involved in host-BVDV interaction are still not fully understood. The discovery of long non-coding RNAs (lncRNAs) has provided a new perspective on gene regulation in diverse biological contexts, particularly in viral infection and host immune responses. However, little is known about the profiles and functions of lncRNAs in host cells in response to BVDV infection. Here, we utilized Illumina sequencing to explore lncRNAs profiles in cytopathic (CP) biotype BVDV-infected MDBK cells to further reveal the potential roles of lncRNAs in BVDV infection and host-BVDV interaction with integrated analysis of lncRNAs and mRNA expression profiles. A total of 1747 significantly differentially expressed genes, DEGs (156 lncRNAs and 1591 mRNAs) were obtained via RNA-seq in BVDV-infected MDBK cells compared to mock-infected cells. Next, these DE lncRNAs and mRNAs were subjected to construct lncRNAs-mRNAs co-expression network followed by the prediction of potential functions of the DE lncRNAs. Co-expression network analysis elucidated that DE lncRNAs were significant enrichment in NOD-like receptor, TNF, NF-ĸB, ErbB, Ras, apoptosis, and fatty acid biosynthesis pathways, indicating that DE lncRNAs play important roles in host-BVDV interactions. Our data give an overview of changes in transcriptome and potential roles of lncRNAs, providing molecular biology basis for further exploring the mechanisms of host-BVDV interaction.
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http://dx.doi.org/10.1080/21505594.2020.1857572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781660PMC
December 2021

Aerosol optical properties of haze episodes in eastern China based on remote-sensing observations and WRF-Chem simulations.

Sci Total Environ 2021 Feb 16;757:143784. Epub 2020 Nov 16.

State Key Laboratory of Information Engineering in Surveying, Mapping and Remote-sensing, Wuhan University, China.

The ability for remote-sensing sensors and global/regional models to describe aerosol optical properties (AOPs) is critical to reducing the uncertainty in aerosol radiative forcing associated with climate change, and improving model prediction accuracy. In this study, remote-sensing observations and WRF-Chem simulations were used to evaluate AOPs over Eastern China during a severe winter haze event, in terms of aerosol optical depth (AOD), Ångström exponent (AE) and aerosol extinction profiles (AEP). This study also characterizes whether the inclusion of aerosol radiative feedbacks (ARFs) may improve the ability of WRF-Chem to acquire AOPs during haze episodes. Three simulation scenarios were considered: the non-radiation feedback (NRF), aerosol direct effect (ADE), as well as combined ADE and aerosol indirect effect (ADE + AIE). The results indicate that the satellite AOD products could represent the spatiotemporal distribution characteristics of the haze event. The AOD retrieved by the MODIS C6.1 DB algorithm was highly consistent with ground-based observations. A comparison between simulations and observations demonstrated that WRF-Chem, including the ADE or ADE + AIE scheme, may improve AOPs simulation in heavily polluted areas. The most significant improvements occurred in the Sichuan basin (SB) and North China Plain (NCP) (AOD = 50-70%; AE = 10-20%). In particular, the ADE + AIE scheme was the most obvious for AOD improvement, followed by AE. The AEP was also qualitatively analyzed through simulations and observations, and the result showed that the model overestimates aerosol extinction coefficients in NCP. However, the model is still able to represent the entire AEP contour over East China. Similar to AOD and AE, the model can also improve AEP simulation by adding ADE or ADE + AIE scheme, especially in SB. In summary, it is found that the ability of WRF-Chem to simulate the AOPs was significantly enhanced, particularly for regions loading with heavy aerosol during haze events in Eastern China.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143784DOI Listing
February 2021

A semi-naphthorhodafluor-based red-emitting fluorescent probe for tracking of hydrogen polysulfide in living cells and zebrafish.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Feb 24;247:119105. Epub 2020 Oct 24.

Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital of Hainan Medical University, Institute of Functional Materials and Molecular Imaging, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China. Electronic address:

Hydrogen polysulfides (HS n ≥ 2) is recently regarded as a potential signaling molecule which shows a higher efficiency than hydrogen sulfides (HS) in regulating enzymes and ion channels. However, the development of specific fluorescent probes for HS with long-wavelength emission (>600 nm) are still rare. In this work, a semi-naphthorhodafluor-based red-emitting fluorescent probe SNARF-HS containing a phenyl 2-(benzoylthio) benzoate responsive unit was constructed. SNARF-HS was capable of selectively detecting HS over other reactive sulfur species. Treatment with HS would result in a > 1000-fold fluorescence enhancement within 10 min. SNARF-HS showed a low limit of detection down to 6.7 nM, and further enabled to visualize exogenous/endogenous HS in living A549 cells and zebrafish.
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http://dx.doi.org/10.1016/j.saa.2020.119105DOI Listing
February 2021

Comparative proteomic analysis identifies biomarkers for renal aging.

Aging (Albany NY) 2020 11 6;12(21):21890-21903. Epub 2020 Nov 6.

MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, China.

Proteomics have long been applied into characterization of molecular signatures in aging. Due to different methods and instrumentations employed for proteomic analysis, inter-dataset validation needs to be performed to identify potential biomarkers for aging. In this study, we used comparative proteomics analysis to profile age-associated changes in proteome and glutathionylome in mouse kidneys. We identified 108 proteins that were differentially expressed in young and aged mouse kidneys in three different datasets; from these, 27 proteins were identified as potential renal aging biomarkers, including phosphoenolpyruvate carboxykinase (Pck1), CD5 antigen-like protein (Cd5l), aldehyde dehydrogenase 1 (Aldh1a1), and uromodulin. Our results also showed that peroxisomal proteins were significantly downregulated in aged mice, whereas IgGs were upregulated, suggesting that peroxisome deterioration might be a hallmark for renal aging. Glutathionylome analysis demonstrated that downregulation of catalase and glutaredoxin-1 (Glrx1) significantly increased protein glutathionylation in aged mice. In addition, nicotinamide mononucleotide (NMN) administration significantly increased the number of peroxisomes in aged mouse kidneys, indicating that NMN enhanced peroxisome biogenesis, and suggesting that it might be beneficial to reduce kidney injuries. Together, our data identify novel potential biomarkers for renal aging, and provide a valuable resource for understanding the age-associated changes in kidneys.
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http://dx.doi.org/10.18632/aging.104007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695359PMC
November 2020

Phylogenetic analyses of dengue virus serotypes imported to Shanghai, China.

J Travel Med 2020 Nov;27(7)

Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

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http://dx.doi.org/10.1093/jtm/taaa195DOI Listing
November 2020

Author Correction: Whole-genome and time-course dual RNA-Seq analyses reveal chronic pathogenicity-related gene dynamics in the ginseng rusty root rot pathogen Ilyonectria robusta.

Sci Rep 2020 Oct 8;10(1):17122. Epub 2020 Oct 8.

Institute of Special Wild Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Changchun, 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/s41598-020-73761-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542143PMC
October 2020

Glutathionylation Decreases Methyltransferase Activity of PRMT5 and Inhibits Cell Proliferation.

Mol Cell Proteomics 2020 11 31;19(11):1910-1920. Epub 2020 Aug 31.

MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, MOE Key Laboratory of Bioinformatics, Beijing, China. Electronic address:

Glutathionylation is an important posttranslational modification that protects proteins from further oxidative damage as well as influencing protein structure and activity. In the present study, we demonstrate that the cysteine-42 residue in protein arginine N-methyltransferase 5 (PRMT5) is glutathionylated in aged mice or in cells that have been exposed to oxidative stress. Deglutathionylation of this protein is catalyzed by glutaredoxin-1 (Grx1). Using mutagenesis and subsequent biochemical analyses, we show that glutathionylation decreased the binding affinity of PRMT5 with methylosome protein-50 (MEP50) and reduced the methyltransferase activity of PRMT5. Furthermore, overexpression of PRMT5-C42A mutant caused a significant increase in histone methylation in HEK293T and A549 cells and promoted cell growth, whereas overexpression of the PRMT5-C42D mutant, a mimic of glutathionylated PRMT5, inhibited cell proliferation. Taken together, our results demonstrate a new mechanism of regulation of PRMT5 methyltransferases activity and suggest that PRMT5 glutathionylation is partly responsible for reactive oxygen species-mediated cell growth inhibition.
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http://dx.doi.org/10.1074/mcp.RA120.002132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664116PMC
November 2020

Corrigendum to 'High proportion of coxsackievirus B3 genotype A in hand, foot and mouth disease in Zhenjiang, China, 2011-2016' International Journal of Infectious Diseases 87 (2019) 1-7.

Int J Infect Dis 2020 Jul 15;96:600. Epub 2020 Jun 15.

Pathogen Discovery and Big Data Center, CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2020.05.114DOI Listing
July 2020

Evaluation of the Secondary Transmission Pattern and Epidemic Prediction of COVID-19 in the Four Metropolitan Areas of China.

Front Med (Lausanne) 2020 7;7:171. Epub 2020 May 7.

Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Understanding the transmission dynamics of COVID-19 is crucial for evaluating its spread pattern, especially in metropolitan areas of China, as its spread could lead to secondary outbreaks. In addition, the experiences gained and lessons learned from China have the potential to provide evidence to support other metropolitan areas and large cities outside China with their emerging cases. We used data reported from January 24, 2020, to February 23, 2020, to fit a model of infection, estimate the likely number of infections in four high-risk metropolitan areas based on the number of cases reported, and increase the understanding of the COVID-19 spread pattern. Considering the effect of the official quarantine regulations and travel restrictions for China, which began January 23~24, 2020, we used the daily travel intensity index from the Baidu Maps app to roughly simulate the level of restrictions and estimate the proportion of the quarantined population. A group of SEIR model statistical parameters were estimated using Markov chain Monte Carlo (MCMC) methods and fitting on the basis of reported data. As a result, we estimated that the basic reproductive number, , was 2.91 in Beijing, 2.78 in Shanghai, 2.02 in Guangzhou, and 1.75 in Shenzhen based on the data from January 24, 2020, to February 23, 2020. In addition, we inferred the prediction results and compared the results of different levels of parameters. For example, in Beijing, the predicted peak number of cases was 467 with a peak time of March 01, 2020; however, if the city were to implement different levels (strict, moderate, or weak) of travel restrictions or regulation measures, the estimation results showed that the transmission dynamics would change and that the peak number of cases would differ by between 54% and 209%. We concluded that public health interventions would reduce the risk of the spread of COVID-19 and that more rigorous control and prevention measures would effectively contain its further spread, and awareness of prevention should be enhanced when businesses and social activities return to normal before the end of the epidemic. Further, the experiences gained and lessons learned from China offer the potential to provide evidence supporting other metropolitan areas and big cities with their emerging cases outside China.
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http://dx.doi.org/10.3389/fmed.2020.00171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221060PMC
May 2020

The Phylodynamics of Seasonal Influenza A/H1N1pdm Virus in China Between 2009 and 2019.

Front Microbiol 2020 28;11:735. Epub 2020 Apr 28.

Chinese Academy of Sciences (CAS) Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences: University of Chinese Academy of Sciences, Shanghai, China.

Since its first introduction into China in 2009, influenza A/H1N1pdm virus has undergone a rapid expansion and replaced the classical seasonal A(H1N1) virus. To characterize the ongoing evolution and national transmission dynamics of this virus, we analyzed 335 complete genome, 1259 HA, and 1043 NA sequences of the A/H1N1pdm strains detected in China. We found that the dN/dS value and relative genetic diversity of the A/H1N1pdm virus experienced a decrease from 2009 to 2017, and then a rapid increase during 2018-2019. Importantly, elevated relative genetic diversity was observed in the A/H1N1pdm and the A/H3N2 viruses, as well as two lineages (Victoria and Yamagata) of influenza B virus during 2018-2019, suggesting the simultaneous changes of these viruses in terms of genetic diversity might be associated with the recent large outbreak of seasonal influenza epidemic in China during 2018-2019. Fifteen amino acid mutations were found to be fixed along the main trunks of both HA and NA phylogenetic trees, and some of them are located in the antigen binding site or the receptor binding site. A sequential accumulation of mutations relative to the 2009-vaccine strain was observed in the circulating A/H1N1pdm strains during 2009-2016, while a rapid accumulation of mutations relative to the 2015-vaccine strain appeared in the emerging variants in 2017 shortly after the release of the vaccine. Multiple introductions of the A/H1N1pdm lineages into China were observed during 2009-2019, and East China and South China were found to serve as two major epicenters responsible for the national migration of the virus. In summary, these data provide important insights into the understanding of the evolution, epidemiology and transmission of the A/H1N1pdm virus, and highlight the importance of strengthening influenza surveillance in East China and South China.
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http://dx.doi.org/10.3389/fmicb.2020.00735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228120PMC
April 2020

Improvement in hourly PM estimations for the Beijing-Tianjin-Hebei region by introducing an aerosol modeling product from MASINGAR.

Environ Pollut 2020 Sep 29;264:114691. Epub 2020 Apr 29.

School of Geosciences and Info-Physics, Central South University, Changsha, 410083, China.

This study improves traditional PM estimation models by combining an hourly aerosol optical depth from the Advanced Himawari Imager onboard Himawari-8 with a newly introduced predictor to estimate hourly PM concentrations in the Beijing-Tianjin-Hebei (BTH) region from November 1, 2018 to October 31, 2019. The new predictor is an hourly PM forecasting product from the Model of Aerosol Species IN the Global AtmospheRe (MASINGAR). Comparative experiments were conducted by utilizing three extensively used regression models, namely, multiple linear regression (MLR), geographically weighted regression (GWR), and linear mixed effects (LME). A ten-fold cross validation (CV) demonstrated that the MASINGAR product significantly improved the performances of these models. The introduced product increased the model's determination coefficients (from 0.316 to 0.379 for MLR, from 0.393 to 0.445 for GWR, and from 0.718 to 0.765 for LME), decreased their root mean square errors (from 38.2 μg/m to 36.4 μg/m for MLR, from 36.0 μg/m to 34.4 μg/m for GWR, and from 24.5 μg/m to 22.4 μg/m for LME) and mean absolute errors (from 25.2 μg/m to 23.3 μg/m for MLR, from 23.5 μg/m to 21.8 μg/m for GWR, and from 15.2 μg/m to 13.7 μg/m for LME). Then, a well-trained LME model was utilized to estimate the spatial distributions of hourly PM concentrations. Highly polluted localities were clustered in the central and southern areas of the BTH region, and the least polluted area was in northwestern Hebei. Seasonal PM levels averaged from the hourly estimations exhibited the highest concentrations (55.4 ± 56.8 μg/m) in the winter and lowest concentrations (25.1 ± 18.2 μg/m) in the summer. MAIN FINDING: Introducing the PM products from MASINGAR can significantly improve the performance of traditional models for surface PM estimations by 7-20%.
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http://dx.doi.org/10.1016/j.envpol.2020.114691DOI Listing
September 2020

Fluorescent silicon nanoparticles inhibit the amyloid fibrillation of insulin.

J Mater Chem B 2019 03 21;7(9):1397-1403. Epub 2019 Jan 21.

State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, P. R. China.

Amyloid fibrillation of proteins is likely a key factor leading to the development of amyloidosis-associated diseases. Inhibiting amyloid fibrillation has become a crucial therapeutic strategy. Water-soluble, fluorescent silicon nanoparticles (SiNPs) have great potential in biomedicine for various therapeutic and diagnostic purposes; however, it is unclear whether SiNPs have the ability to inhibit amyloid fibrillation. Herein, insulin was chosen as a protein model, and SiNPs of varying sizes were synthesized upon UV irradiation. The influence of size and concentration of the SiNPs on insulin fibrillation was investigated, and it has been observed that these variables were crucial in regulating insulin fibrillation. Using an average particle size of 6.6 nm and increasing the concentration of the SiNPs to 5.0 μg mL, the Thioflavin T (ThT) fluorescence intensity decreased significantly by 90%, with an increased lag time of 76.8 h, compared to that of the control. Insulin aggregates were short, thin fibrils or clusters when incubated with SiNPs, compared to the long, thick fibrils formed for insulin alone. Additionally, we found that the SiNPs prevent the conformational transition of insulin from its initial structure to β-sheets, and thus inhibit nucleation, which is necessary for the formation of large fibrils. The inhibitory activity is attributed to the interactions between the SiNPs and insulin during the nucleation period. Our results demonstrate that the SiNPs disrupt insulin amyloid fibrillation, and thus, may play a useful role in new therapeutic and diagnostic strategies for amyloid-related disorders.
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http://dx.doi.org/10.1039/c8tb02964dDOI Listing
March 2019

Visualizing hydrogen sulfide in living cells and zebrafish using a red-emitting fluorescent probe via selenium-sulfur exchange reaction.

Anal Chim Acta 2020 May 27;1109:37-43. Epub 2020 Feb 27.

Institute of Functional Materials and Molecular Imaging, Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Trauma and Disaster Rescue, College of Clinical Medicine, College of Emergency and Trauma, Hainan Medical University, Haikou, 571199, China. Electronic address:

Hydrogen sulfide (HS) is an important endogenous gasotransmitter and has been implicated with a variety of biological processes. The development of an efficient method for monitor HS fluctuations in biological systems is of great significance to understand its roles in physiological and pathological conditions. In this work, two red-emitting fluorescent probes SNARF-SSPy and SNARF-SeSPy for HS detection with turn-on fluorescence signals were reported. Interestingly, SNARF-SeSPy exhibited excellent anti-interference via dual selenium-sulfur exchange reaction even in the presence of high concentrations of thiols, whereas SNARF-SSPy did not sense HS in the same condition. Additionally, in the present of HS, SNARF-SeSPy showed a rapid response and excellent sensitivity with a detection limit of 34 nM. Most importantly, SNARF-SeSPy featured low cytotoxicity and could be employed to detect and image exogenous/endogenous HS in living cells and zebrafish.
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http://dx.doi.org/10.1016/j.aca.2020.02.061DOI Listing
May 2020

Public-Private or Master-Servant? Examining the Implementation of the Serious Disease Insurance Scheme in China.

Int J Environ Res Public Health 2020 02 26;17(5). Epub 2020 Feb 26.

Lingnan (University) College, Sun Yat-Sen University, Guangzhou 510275, China.

China's Serious Disease Insurance Scheme (SDIS) was set up to relieve the financial burdens on serious disease patients. It is a crucial part of the national basic medical insurance scheme, which is regarded as one of the largest government-funded social security programs in the world. The most significant institutional innovation of the SDIS is that the approach of a public-private partnership (PPP) is applied in an attempt to facilitate the efficiency of its implementation. The objective of this paper is to evaluate the implementation of the SDIS in China through PPPs, and to identify the problems to be tackled if the Chinese government intends to make such a plan work better for the majority of urban and rural residents. With the effective support from local officials and practitioners, the authors of this paper collected copies of SDIS contracts of multiple cities in Guangdong, one of the most developed provinces of China. Guided by a research framework drawn from the PPP literature, details of contract enforcement were also examined. The authors discovered that the role of local states is rather dominant; they have manipulated contract drafting and implementation. Additionally, current mechanisms for profit sharing, risk sharing, and information exchange have placed insurance companies in a rather disadvantageous situation. To achieve the sustainable development of the SDIS, the authors suggest that a further reform on implementation of a PPP must be pushed forward.
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http://dx.doi.org/10.3390/ijerph17051490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084624PMC
February 2020

The novel llama-human chimeric antibody has potent effect in lowering LDL-c levels in hPCSK9 transgenic rats.

Clin Transl Med 2020 Feb 13;9(1):16. Epub 2020 Feb 13.

BGI-Shenzhen, Shenzhen, 518083, China.

Background: The advent of proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibiting drugs have provided an effective, but extremely expensive treatment for the management of low density lipoprotein (LDL). Our aim was to explore a cost-effective application of camelid anti-PCSK9 single domain antibodies (sdAbs), which are high variable regions of the camelid heavy chain antibodies (VHHs), as a human PCSK9 (hPCSK9) inhibitor. One female llama was immunized with hPCSK9. Screening of high affinity anti-PCSK9 VHHs was carried out based on surface plasmon resonance (SPR) technology. We reported a lysate kinetic analysis method improving the screening efficiency. To increase the serum half-life and targeting properties, the constant region fragment of the human immunoglobulin gamma sub-type 4 (IgG4 Fc) was incorporated to form a novel llama-human chimeric molecule (VHH-hFc).

Results: The PCSK9 inhibiting effects of the VHH proteins were analyzed in two human liver hepatocellular cells (HepG2 and Huh7) and in the hPCSK9 transgenic Sprague-Dawley (SD) rat model. The hPCSK9 antagonistic potency of the bivalent VHH-hFc exceeded the monovalent VHH (P < 0.001) in hepatocarcinoma cells. Furthermore, the llama-human chimeric VHH-Fc protein had a similar reduction (~ 40%) of the LDL-c and total cholesterol when compared to the approved evolocumab in transgenic SD rat model, but with low cost. More surprisingly, the chimeric heavy chain antibodies could be persevered for 3 months at room temperature with little loss of the affinity.

Conclusions: Due to the high yield and low cost of Pichia pastoris, lipid-lowering effect and strong stability, the llama-human chimeric antibody (VHH-Fc) offers a potent therapeutic candidate for the control of the serum lipid level.
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http://dx.doi.org/10.1186/s40169-020-0265-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018876PMC
February 2020