Publications by authors named "Zhili Li"

144 Publications

[email protected]: a magnetic polyaniline nanomaterial for highly efficient and handy enrichment of intact N-glycopeptides.

Analyst 2021 Jul 8;146(13):4261-4267. Epub 2021 Jun 8.

Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, 5 Dongdan San Tiao, Beijing 100005, China.

Glycosylation of proteins plays important roles in the occurrence and development of chronic diseases. In this study, we report an enrichment method of intact N-glycopeptides using a magnetic polyaniline nanomaterial ([email protected]). Under the synergistic effect of hydrogen bonding and electrostatic adsorption, [email protected] can rapidly and easily enrich N-glycopeptides derived from standard protein (bovine fetuin and transferrin) tryptic digests and serum haptoglobin tryptic digests. Finally we have detected 63 glycopeptides in the glycosylation sites of both N204 and N211 from the serum haptoglobin beta chain using MALDI FTICR MS. Compared with non-magnetic materials, [email protected] can achieve complete separation from complex biological samples, meeting the requirement of the high purity of samples for mass spectrometric detection. Overall, [email protected] exhibits great application potential in the highly efficient enrichment of intact N-glycopeptides due to its stability and convenient preparation.
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http://dx.doi.org/10.1039/d1an00580dDOI Listing
July 2021

Robustness of aerosol delivery of amikacin liposome inhalation suspension using the eFlow® Technology.

Eur J Pharm Biopharm 2021 Sep 1;166:10-18. Epub 2021 Jun 1.

Insmed Incorporated, 700 US 206 North, Bridgewater, NJ 08807, USA. Electronic address:

The purpose of these studies was to understand the effect on product performance of batch-to-batch variability in both the amikacin liposome inhalation suspension (ALIS) formulation and its delivery device, the Lamira® nebulizer system, designed and manufactured by PARI (PARI Pharma GmbH, Munich, Germany). Three batches of ALIS spanning a range of lipid concentrations (43, 48 and 54 mg/mL) were tested with nine PARI inhalation devices that varied within the production process of the vibrating membrane with respect to hole geometry. Three hole geometry clusters were built including a geometry close to the mean geometry (median) and two geometries deviating from the mean geometry with smaller (smaller) and larger (larger) holes. The output parameters included the nebulization rate, the aerosol droplet size distribution, the liposome vesicle size post-nebulization, and the fraction of amikacin that remained encapsulated post-nebulization. Across the 27 experimental combinations of three formulation batches and nine devices, the nebulization time varied between 12 and 15 min with the fastest nebulization rate occurring with the combination of low lipid concentration and larger hole geometry (0.68 g/min) and the slowest nebulization rate occurring with the combination of high lipid concentration and the smaller hole geometry (0.59 g/min). The mean liposome vesicle size post-nebulization ranged from 269 to 296 nm across all experimental combinations which was unchanged from the control samples (276-292 nm). While all three batches contained > 99% encapsulated amikacin prior to nebulization, the nebulization process resulted in a consistent generation of ~ 35% unencapsulated amikacin (range: 33.8% to 37.6%). There was no statistically significant difference in the generated aerosol particle size distributions. The mass median aerodynamic diameters (MMAD) ranged from 4.78 µm to 4.98 µm, the geometric standard deviations (GSD) ranged from 1.61 to 1.66, and the aerosol fine particle fraction (FPF < 5 µm) ranged from 50.3 to 53.5%. The emitted dose (ED) of amikacin ranged from 473 to 523 mg (80.2 to 89.3% of loaded dose (LD)) and the fine particle dose (FPD < 5 µm) ranged from 244 to 278 mg (41.4 to 47.1% of label claim (LC)). In conclusion, while variations in the lipid concentration of the ALIS formulation and the device hole geometry had a small but significant impact on nebulization time, the critical aerosol performance parameters were maintained and remained within acceptable limits.
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http://dx.doi.org/10.1016/j.ejpb.2021.05.021DOI Listing
September 2021

Ultrasonic Backscatter Measurements of Human Cortical and Trabecular Bone Densities in a Head-Down Bed-Rest Study.

Ultrasound Med Biol 2021 08 26;47(8):2404-2415. Epub 2021 May 26.

Center for Biomedical Engineering, School of Information Science and Technology, Fudan University, Shanghai, China; Academy for Engineering and Technology, Fudan University, Shanghai, China. Electronic address:

This study aims to investigate the feasibility of quantitative ultrasonic backscatter in evaluating human cortical and trabecular bone densities in vivo based on a head-down-tilt bed rest study, with 36 participants tested through 90 d of bed rest and 180 d of recovery. Backscatter measurements were performed using an ultrasonic backscatter bone diagnostic instrument. Backscatter parameters were calculated with a dynamic signal-of-interest method, which was proposed to ensure the same ultrasonic interrogated volume in cortical and trabecular bones. The backscatter parameters exhibited significant correlations with site-matched bone densities provided by high-resolution peripheral quantitative computed tomography (0.33 < |R| < 0.72, p < 0.05). Some bone densities and backscatter parameters exhibited significant changes after the 90-d bed rest. The proposed method can be used to characterize bone densities, and the portable ultrasonic backscatter bone diagnostic device might be used to non-invasively reveal mean bone loss (across a group of people) after long-term bed rest and microgravity conditions of spaceflight missions.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.04.002DOI Listing
August 2021

Serum phospholipids are potential biomarkers for the early diagnosis of gastric cancer.

Clin Chim Acta 2021 Aug 12;519:276-284. Epub 2021 May 12.

Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address:

Background And Aims: Early diagnosis is key to improving the prognosis of gastric cancer. Altered phospholipid metabolism has been observed in different types of cancer. This study assessed serum phospholipid levels of patients with gastric cancer to explore biomarkers for its early diagnosis.

Materials And Methods: A total of 199 participants were enrolled, including patients with early gastric cancer or precancerous gastric lesions and healthy controls. Serum phospholipids were extracted and identified using mass spectrometry. The relative abundances of these phospholipids were compared among patients at different disease stages. Twenty-four patients with early gastric cancer were followed up, and their serum phospholipid levels were compared beween before and after resection.

Results: Fifty-four phospholipids were identified. Phosphatidylethanolamine (36:3), phosphatidylethanolamine (36:2), phosphatidylcholine (32:0), and sphingomyelin (d18:0/18:1(9Z)) were more abundant in patients with early gastric cancer than in healthy controls. The area under the receiver operating curve of sphingomyelin (d18:0/18:1(9Z)) reached 0.883 in the training set (sensitivity 81.08%, specificity 78.82%) and 0.874 in the validation set. The levels of phosphatidylethanolamine (36:2), phosphatidylcholine (32:0), and sphingomyelin (d18:0/18:1(9Z)) significantly declined after the cancerous lesions were resected.

Conclusion: Serum phospholipids can serve as potential biomarkers for the early diagnosis of gastric cancer.
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http://dx.doi.org/10.1016/j.cca.2021.05.002DOI Listing
August 2021

Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections.

Antimicrob Agents Chemother 2021 06 17;65(7):e0031621. Epub 2021 Jun 17.

Insmed Incorporated, Bridgewater, New Jersey, USA.

Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity , with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.
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http://dx.doi.org/10.1128/AAC.00316-21DOI Listing
June 2021

Genome-Wide Association Study of Meat Quality Traits in a Three-Way Crossbred Commercial Pig Population.

Front Genet 2021 17;12:614087. Epub 2021 Mar 17.

School of Life Sciences and Engineering, Foshan University, Foshan, China.

Meat quality is an important trait for pig-breeding programs aiming to meet consumers' demands. Geneticists must improve meat quality based on their understanding of the underlying genetic mechanisms. Previous studies showed that most meat-quality indicators were low-to-moderate heritability traits; therefore, improving meat quality using conventional techniques remains a challenge. Here, we performed a genome-wide association study of meat-quality traits using the GeneSeek Porcine SNP50K BeadChip in 582 crossbred Duroc × (Landrace × Yorkshire) commercial pigs (249 males and 333 females). Meat conductivity, marbling score, moisture, meat color, pH, and intramuscular fat (IMF) content were investigated. The genome-wide association study was performed using both fixed and random model Circulating Probability Unification (FarmCPU) and a mixed linear model (MLM) with the rMVP software. The genomic heritability of the studied traits ranged from 0.13 ± 0.07 to 0.55 ± 0.08 for conductivity and meat color, respectively. Thirty-two single-nucleotide polymorphisms (SNPs) were identified for meat quality in the crossbred pigs using both FarmCPU and MLM. Among the detected SNPs, five, nine, seven, four, six, and five were significantly associated with conductivity, IMF, marbling score, meat color, moisture, and pH, respectively. Several candidate genes for meat quality were identified in the detected genomic regions. These findings will contribute to the ongoing improvement of meat quality, meeting consumer demands and improving the economic outlook for the swine industry.
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http://dx.doi.org/10.3389/fgene.2021.614087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010252PMC
March 2021

Assessing asymptomatic, pre-symptomatic and symptomatic transmission risk of SARS-CoV-2.

Clin Infect Dis 2021 Mar 27. Epub 2021 Mar 27.

Division of Infectious disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.

Background: The relative contributions of asymptomatic, pre-symptomatic and symptomatic transmission of SARS-CoV-2 have not been clearly measured although control measures may differ in response to the risk of spread posed by different types of cases.

Methods: We collected detailed information on transmission events and symptom status based on laboratory-confirmed patient data and contact tracing data from four provinces and one municipality in China. We estimated the variation in risk of transmission over time, and the severity of secondary infections, by symptomatic status of the infector.

Results: There were 393 symptomatic index cases with 3136 close contacts and 185 asymptomatic index cases with 1078 close contacts included into the study. The secondary attack rate among close contacts of symptomatic and asymptomatic index cases were 4.1% (128/3136) and 1.1% (12/1078), respectively, corresponding to a higher transmission risk from symptomatic cases than from asymptomatic cases (OR: 3.79, 95% CI: 2.06, 6.95). Approximately 25% (32/128) and 50% (6/12) of the infected close contacts were asymptomatic from symptomatic and asymptomatic index cases, respectively, while more than one third (38%) of the infections in the close contacts of symptomatic cases were attributable to exposure to the index cases before symptom onset. Infected contacts of asymptomatic index cases were more likely to be asymptomatic and less likely to be severe.

Conclusions: Asymptomatic and pre-symptomatic transmission play an important role in spreading infection, although asymptomatic cases pose a lower risk of transmission than symptomatic cases. Early case detection and effective test-and-trace measures are important to reduce transmission.
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http://dx.doi.org/10.1093/cid/ciab271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083716PMC
March 2021

Electroacupuncture stimulation at BL20, BL23 and SP6 prevents hind limb unloading-induced osteoporosis in rats.

Acupunct Med 2021 Mar 15:964528421995494. Epub 2021 Mar 15.

State Key Lab of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.

Background: Bone loss induced by microgravity is a serious problem in space flight. However, the effects of acupuncture stimulation on osteoporosis induced by microgravity have not been studied. With the goal of developing an effective countermeasure, our aim was to evaluate the effects of electroacupuncture (EA) stimulation at BL20, BL23, and SP6 on osteoporosis induced by simulated microgravity in rats.

Methods: Thirty male Wistar rats (aged 10 weeks) were randomly divided into three groups: healthy control group (CON,  = 10), hind limb unloading by tail-suspension group (T-S,  = 10), and EA treatment group (TRE,  = 10). Rats in the T-S and TRE groups were subjected to tail-suspension at -30° for 30 days, while the CON group experienced freedom of activity. In this period, the TRE group received EA treatment at BL20, BL23, and SP6 for 30 min every other day, which continued for 30 days. The microarchitecture of the proximal tibia and the biomechanical features of the femur in the rats were analyzed. In addition, the levels of serum biomarkers bone alkaline phosphatase (BALP) and osteocalcin (BGP) were measured.

Results: Compared with the CON group, the value of bone volume/total volume (BV/TV) and trabecular number (Tb.N) of the tibias in the TRE group remarkably decreased (  0.01). However, these changes were markedly less than those of the T-S group after 4 weeks of EA treatment (  0.05). Moreover, the serum concentration of BGP in the TRE group was also significantly higher than that of the T-S group (  0.05).

Conclusions: These findings indicate that EA stimulation at BL20, BL23, and SP6 retards osteoporosis induced by hind limb unloading in rats.
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http://dx.doi.org/10.1177/0964528421995494DOI Listing
March 2021

Characterisation of cough evoked by inhaled treprostinil and treprostinil palmitil.

ERJ Open Res 2021 Jan 15;7(1). Epub 2021 Feb 15.

Insmed Incorporated, Bridgewater, NJ, USA.

Cough is induced by inhaled prostacyclin analogues including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved in TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS). Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously. In guinea pigs, cough with inhaled TRE (1.23 µg·kg) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg) to induce cough. TRE cough was blocked with IP and tachykinin NK receptor antagonists but not with EP, EP, EP, DP or bradykinin B antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnoea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects. The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibres in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves.
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http://dx.doi.org/10.1183/23120541.00592-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882781PMC
January 2021

MicroRNA-301a-3p promotes diabetic retinopathy via regulation of six-transmembrane epithelial antigen of prostate 4.

Inflamm Res 2021 Apr 20;70(4):445-457. Epub 2021 Feb 20.

Department of Clinical Medicine, Second Affiliated Hospital of Xingtai Medical College, Hebei, 054000, China.

Objective And Design: Diabetic retinopathy (DR) is one of the most serious microvascular complications of diabetes mellitus (DM). MicroRNAs (miRNAs) have been discovered to play a crucial role in DR, but the mechanisms underlying the effects of miR-301a-3p on DR are poorly understood. This paper was designed to explore the possible role of miR-301a-3p in DR.

Methods: The diabetic rat model was established by a single intraperitoneal injection of streptozotocin (STZ). The effects of miR-301a-3p on the biological functions of HRECs were determined through a series of experiments in vitro/vivo.

Results: The results revealed that interference with miR-301a-3p could decrease the expressions of inflammatory factors and apoptosis in the retinal tissue of DR. Furthermore, it can alleviate the oxidative stress in DR serum, reduce VEGF expression, increase endothelial cell marker expression, and inhibit (High Glucose) HG-induced apoptosis of HRECs. Six-transmembrane epithelial antigen of prostate 4 (STEAP4) was the target of miR-301a-3p. All the effects of miR-301a-3p in DR model were reversed by STEAP4 inhibitor.

Conclusion: miR-301a-3p promotes diabetic retinopathy via regulation of STEAP4. The findings in this study may provide a vital reference for the drug research and development in DR treatment.
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http://dx.doi.org/10.1007/s00011-020-01431-0DOI Listing
April 2021

An overview of the biology of a long-acting inhaled treprostinil prodrug.

Pulm Pharmacol Ther 2020 12 15;65:102002. Epub 2021 Feb 15.

Insmed Incorporated, 202/206 North, Bridgewater, NJ, 08807, USA.

Treprostinil (TRE) is a prostanoid analog pulmonary vasodilator drug marketed with subcutaneous, intravenous (i.v.), oral, and inhaled routes of administration for the treatment of pulmonary arterial hypertension (PAH). Due to its short half-life, TRE requires either continuous infusion or multiple dosing, which exacerbates its side effects. Therefore, a long-acting prostanoid analog that maintains the positive attributes of TRE but has fewer TRE-related side effects could be of clinical benefit. In this report, we describe the discovery, preclinical development, and biology of the TRE ester prodrug, treprostinil palmitil (TP), which is formulated in a lipid nanoparticle (LNP) for administration as a nebulized inhaled suspension (TPIS). In screening assays focused on the conversion of prodrug to TRE, TP (16 carbon alkyl chain) had the slowest rate of conversion compared with short-alkyl chain TRE prodrugs (i.e., 2-8 carbon alkyl chain). Furthermore, TP is a pure prodrug and possesses no inherent binding to G-protein coupled receptors including prostanoid receptors. Pharmacokinetic studies in rats and dogs demonstrated that TPIS maintained relatively high concentrations of TP in the lungs yet had a low maximum plasma concentrations (C) of both TP and, more importantly, the active product, TRE. Efficacy studies in rats and dogs demonstrated inhibition of pulmonary vasoconstriction induced by exposure to hypoxic air or i.v.-infused U46619 (thromboxane mimetic) over 24 h with TPIS. Cough was not observed with TPIS at an equivalent dose at which TRE caused cough in guinea pigs and dogs, and there was no evidence of desensitization to the inhibition of pulmonary vasoconstriction in rats with repeat inhaled dosing. TPIS was also more efficacious than i.v.-infused TRE in a sugen/hypoxia rat model of PAH to inhibit pulmonary vascular remodeling, an effect likely driven by local activities of TRE within the lungs. TPIS also demonstrated antifibrotic and anti-inflammatory activity in the lungs in rodent models of pulmonary fibrosis and asthma. In a phase 1 study in healthy human participants, TPIS (referred to as INS1009) had a lower plasma TRE C and fewer respiratory-related side effects at equimolar doses compared with inhaled TRE. We have now formulated TP as an aerosol powder for delivery by a dry powder inhaler (referred to as treprostinil palmitil inhalation powder-TPIP), and as an aerosol solution in a fluorohydrocarbon solvent for delivery by a metered dose inhaler. These options may reduce drug administration time and involve less device maintenance compared with delivery by nebulization.
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http://dx.doi.org/10.1016/j.pupt.2021.102002DOI Listing
December 2020

Influenza Vaccine Effectiveness in Mainland China: A Systematic Review and Meta-Analysis.

Vaccines (Basel) 2021 Jan 23;9(2). Epub 2021 Jan 23.

Chinese Center for Disease Control and Prevention, Beijing 102206, China.

Influenza endangers human health but can be prevented in part by vaccination. Assessing influenza vaccine effectiveness (VE) provides scientific evidence for developing influenza vaccination policy. We conducted a systematic review and meta-analysis of studies that evaluated influenza VE in mainland China. We searched six relevant databases as of 30 August 2019 to identify studies and used Review Manager 5.3 software to analyze the included studies. The Newcastle-Ottawa scale was used to assess the risk of publication bias. We identified 1408 publications, and after removing duplicates and screening full texts, we included 21 studies in the analyses. Studies were conducted in Beijing, Guangzhou, Suzhou, and Zhejiang province from the 2010/11 influenza season through the 2017/18 influenza season. Overall influenza VE for laboratory confirmed influenza was 36% (95% CI: 25-46%). In the subgroup analysis, VE was 45% (95% CI: 18-64%) for children 6-35 months who received one dose of influenza vaccine, and 57% (95% CI: 50-64%) who received two doses. VE was 47% (95% CI: 39-54%) for children 6 months to 8 years, and 18% (95% CI: 0-33%) for adults ≥60 years. For inpatients, VE was 21% (95% CI: -11-44%). We conclude that influenza vaccines that were used in mainland China had a moderate effectiveness, with VE being higher among children than the elderly. Influenza VE should be continuously monitored in mainland China to provide evidence for policy making and improving uptake of the influenza vaccine.
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http://dx.doi.org/10.3390/vaccines9020079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912587PMC
January 2021

Transcription Factor ELF1 Activates MEIS1 Transcription and Then Regulates the GFI1/FBW7 Axis to Promote the Development of Glioma.

Mol Ther Nucleic Acids 2021 Mar 15;23:418-430. Epub 2020 Oct 15.

Department of Neurosurgery Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, P.R. China.

Glioma is the most common malignancy in the central nervous system with no immediate prospect of a cure. Comprehensive understanding on the pathogenesis of the disorder contributes to a better outcome. Herein, we aimed to investigate whether transcription factors erythroblast transformation-specific (ETS) transcription factor (ELF1), myeloid ecotropic viral integration site 1 (MEIS1), and growth factor independence 1 (GFI1)/F-box/WD repeat-containing protein 7 (FBW7) mediate progression of glioma. ELF1, MEIS1, and GFI1 were upregulated in glioma cells and tissues, as ELF1 was correlated with poor prognosis. Bioinformatics analysis identified the binding between ELF1 and MEIS1 as well as between GFI1 and FBW7, confirmed by chromatin immunoprecipitation (ChIP) experiments. Functional experiment indicated that silencing of ELT1 decreased MEIS1 expression and that overexpression of MEIS1 increased GFI1 expression by activating GFI1 enhancer but decreased FBW7 expression. Importantly, silencing of ELF1 decreased the capacities of proliferation, migration, and invasion of glioma cells whereas it increased apoptosis, supported by increased capase-3 and decreased matrix metalloproteinase-9 (MMP-9) and proliferating cell nuclear antigen (PCNA) expression. Moreover, an experiment confirmed the inhibitory role of silenced ELF1 in tumor growth, with a decreased level of MEIS1 and GFI1. Taken together, our study elucidated a potential mechanism that ELF1 promoted cell progression by increasing GFI1 and METS1 as well as decreasing FBW7 expression in glioma.
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http://dx.doi.org/10.1016/j.omtn.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787950PMC
March 2021

Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension.

Int J Mol Sci 2021 Jan 7;22(2). Epub 2021 Jan 7.

Insmed Incorporated, Bridgewater, NJ 08807, USA.

Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.
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http://dx.doi.org/10.3390/ijms22020548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828008PMC
January 2021

Third-order Riemann pulses in optical fibers.

Opt Express 2020 Dec;28(26):39827-39840

We introduce the concept of third-order Riemann pulses in nonlinear optical fibers. These pulses are generated when properly tailored input pulses propagate through optical fibers in the presence of higher-order dispersion and Kerr nonlinearity. The local propagation speed of these optical wave packets is governed by their local amplitude, according to a rule that remains unchanged during propagation. Analytical and numerical results exhibit a good agreement, showing controllable pulse steepening and subsequent shock wave formation. Specifically, we found that the pulse steepening dynamic is predominantly determined by the action of higher-order dispersion, while the contribution of group velocity dispersion is merely associated with a shift of the shock formation time relative to the comoving frame of the pulse evolution. Unlike standard Riemann waves, which exclusively exist within the strong self-defocusing regime of the nonlinear Schrödinger equation, such third-order Riemann pulses can be generated under both anomalous and normal dispersion conditions. In addition, we show that the third-order Riemann pulse dynamics can be judiciously controlled by a phase chirping parameter directly included in the initial chirp profile of the pulse.
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http://dx.doi.org/10.1364/OE.411736DOI Listing
December 2020

Treprostinil palmitil, an inhaled long-acting pulmonary vasodilator, does not show tachyphylaxis with daily dosing in rats.

Pulm Pharmacol Ther 2021 02 17;66:101983. Epub 2020 Dec 17.

Insmed Incorporated, 202/206 North, Bridgewater, NJ, 08807, USA.

Background: Treprostinil palmitil (TP) is an inhaled long-acting pulmonary vasodilator prodrug of treprostinil (TRE) that has been formulated for delivery as a suspension (treprostinil palmitil inhalation suspension; TPIS) and as a dry powder (treprostinil palmitil inhalation powder; TPIP). In humans, tachyphylaxis is frequently observed with continuous intravenous (IV) or subcutaneous (SC) infusion of TRE and requires dosage escalation to maintain activity. The aim of the present study was to determine whether tachyphylaxis occurs with repeat daily administration of inhaled TPIS.

Methods: Experiments were performed in male Sprague-Dawley rats prepared with a telemetry probe implanted into the right ventricle to measure the change in right ventricular pulse pressure (ΔRVPP) induced by exposure to a 10% oxygen gas mixture. TPIS (6 mL) at concentrations of 0.25, 0.5, and 1 mM was given by nose-only inhalation using an Aeroneb Pro nebulizer, either as a single administration or daily for 16 or 32 consecutive days. In studies involving consecutive daily administrations of TPIS, the delivered TP dosage was 140.3 μg/kg at 1 mM and ranged from 40.2 to 72.2 μg/kg at 0.5 mM. A separate cohort of telemetered rats received continuous IV infusion of TRE via an Alzet mini-pump at a dosage rate of 250 ng/kg/min for 16 days. Blood and lung tissue samples were obtained, and the concentration of TRE in the plasma and TRE and TP in the lungs were measured approximately 1 h after TPIS administration.

Results: Dose-response studies with TPIS administered as a single administration inhibited the hypoxia-induced increase in RVPP in both a concentration-dependent (0.25, 0.5, and 1 mM) and time-dependent (1-24 h) manner. TPIS, given QD or BID at inhaled doses ranging from 40.2 to 140.3 μg/kg for 16 or 32 consecutive days, produced statistically significant (P < .05) inhibition of the increase of RVPP due to hypoxia over the full duration of the dosing periods. By contrast, the inhibition of the hypoxia-induced increase in RVPP observed with IV TRE infusion (250 ng/kg/min) disappeared after 16 days of infusion. The plasma concentrations of TRE were significantly higher after IV TRE (range, 2.85-13.35 ng/mL) compared to inhaled TPIS (range, 0.22-0.73 ng/mL) CONCLUSIONS: There was no evidence of tachyphylaxis with repeat daily dosing of TPIS for a period of up to 32 days. The absence of tachyphylaxis with TPIS is likely related to its local vasodilatory effects within the lungs, combined with an absence of sustained high plasma concentrations of TRE.
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http://dx.doi.org/10.1016/j.pupt.2020.101983DOI Listing
February 2021

Total Glucosides of Paeony Alleviate Cell Apoptosis and Inflammation by Targeting the Long Noncoding RNA XIST/MicroRNA-124-3p/ITGB1 Axis in Renal Ischemia/Reperfusion Injury.

Mediators Inflamm 2020 24;2020:8869511. Epub 2020 Nov 24.

Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.

Objective: Renal ischemia/reperfusion injury (RI/RI) is the main cause of acute kidney injury. Total glucosides of paeony (TGP) are a traditional Chinese medicine. This study was aimed at exploring the role of TGP in RI/RI and its underlying mechanism of action.

Methods: Rat RI/RI models were constructed by surgical operation. Serum creatinine (Scr) and blood urea nitrogen (BUN) were used to evaluate renal function. The levels of proinflammatory cytokines were detected by ELISA. RI/RI was simulated by hypoxia/reoxygenation (H/R) treatment in renal cells . The lncRNA XIST (XIST) expression was analyzed by qRT-PCR. Then, the viability and apoptosis of renal cells were detected by MTT and flow cytometry assay. Additionally, dual-luciferase reporter assay was used to determine the interactions among XIST, microRNA-124-3p (miR-124-3p), and ITGB1.

Results: TGP improved renal function and inhibited inflammatory responses after RI/RI. XIST expression was highly expressed in rat RI/RI models and H/R-treated renal cells, whereas treatment with TGP downregulated the XIST expression. Additionally, TGP increased viability and attenuated apoptosis and inflammation of H/R-treated renal cells via inhibiting XIST. Moreover, XIST was competitively bound to miR-124-3p, and ITGB1 was a target of miR-124-3p. miR-124-3p overexpression or ITGB1 inhibition rescued the reduction effect on viability and mitigated the promoting effects on cell apoptosis and inflammation caused by XIST overexpression in H/R-treated renal cells.

Conclusions: , TGP attenuated renal dysfunction and inflammation in RI/RI rats. , TGP inhibited XIST expression to modulate the miR-124-3p/ITGB1 axis, alleviating the apoptosis and inflammation of H/R-treated renal cells.
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http://dx.doi.org/10.1155/2020/8869511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710434PMC
November 2020

Pharmacokinetics and bioavailability of solid dispersion formulation of tilmicosin in pigs.

J Vet Pharmacol Ther 2021 May 3;44(3):359-366. Epub 2020 Dec 3.

School of Life Science and Engineering, Foshan University, Foshan, China.

Tilmicosin (TMS) is a semisynthetic macrolide antibiotic restricted to veterinary use but is only partially soluble in aqueous solutions, which limits its administration in treatments. We developed a strategy to enhance the supersaturated solubility of TMS using amorphous solid dispersion (SD). The dissolution profile shown that the dissolution rate of TMS-SD was obviously faster than TMS. The pharmacokinetics of tilmicosin (TMS) and tilmicosin solid dispersion (TMS-SD) in pigs after oral administration at a single dose of 50 mg/kg b.w were investigated. The t of TMS-SD (2.50 hr) was 1.80 times faster than TMS (4.50 hr) (p < .05). There were no significant differences in the other PK parameters (C , t , V/F, CL/F, MRT, and AUC ) (p > .05). The mean relative bioavailability of TMS-SD compared with TMS was 140.39%, according to the AUC values. These results demonstrated that the solid dispersion technique enhanced the bioavailability of TMS and the new formulation administered to animals via drinking water may be used as a therapeutic alternative for clinical treatments.
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http://dx.doi.org/10.1111/jvp.12929DOI Listing
May 2021

Prussian blue nanoparticles induce myeloid leukemia cells to differentiate into red blood cells through nanozyme activities.

Nanoscale 2020 Nov;12(45):23084-23091

Department of Biomedical Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.

Numerous types of diseases cause serious anemia, which is characterized by a significantly decreased number of circulating red blood cells. The key reason is retarded terminal erythroid differentiation, which is largely involved in the downregulation of intracellular reactive oxygen species (ROS) and insufficient iron uptake. Prussian blue nanoparticles (PBNPs) have been demonstrated to be capable of scavenging ROS via multienzyme-like activity and contain the iron element. The aim of this study was to figure out whether PBNPs can induce terminal erythroid differentiation in myeloid leukemia cells K562 and to investigate the underlying mechanisms. Our results showed that PBNPs were taken up by K562 cells, which reduced the intracellular ROS level in the cells, upregulated the late erythroid surface marker GYPA (CD235a) and downregulated the early erythroid surface marker TFRC (CD71), clearly indicating the occurrence of terminal erythroid differentiation. In addition, the cells became smaller in size after incubation with PBNPs, providing strong side evidence that the cells had undergone terminal differentiation. Mechanistic studies indicated that PBNP-induced terminal differentiation was associated with the upregulation of the nuclear transcriptional factor NFE2 and downregulation of GATA1, both of which are closely related to the variation of intracellular ROS levels. In conclusion, PBNPs demonstrated a novel function by effectively inducing terminal erythroid differentiation in myeloid leukemia cells, which is of great significance in improving the blood profiles of anemia patients.
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http://dx.doi.org/10.1039/d0nr06480gDOI Listing
November 2020

A rapid and simple single-step method for the purification of Toxoplasma gondii tachyzoites and bradyzoites.

Vet Med Sci 2021 03 26;7(2):357-361. Epub 2020 Sep 26.

National Animal Protozoa Laboratory & College of Veterinary Medicine, China Agricultural University, Beijing, China.

This study describes a simple method for the large-scale isolation of pure Toxoplasma gondii tachyzoites and bradyzoites. T. gondii tachyzoites were obtained from infected human foreskin fibroblasts (HFFs) and peritoneal exudates of mice, while tissue cysts containing bradyzoites were collected from chronically infected mice. Harvested cells and brain tissues were incubated in Hanks balanced salt solution (HBSS), containing 0.25% trypsin and 0.5% taurodeoxycholic acid (TDC) for 5 min. Subsequent washes in phosphate buffered saline (PBS) were conducted, and the cell viability of the preparations was good, as determined by flow cytometry and ability to reinfect HFF cells and propagate in mice. The purification procedure allowed for a rapid preparation of pure T. gondii tachyzoites and bradyzoites in sufficient quantity that can be used for downstream procedures. The advantage of the new method is that it is convenient and inexpensive.
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http://dx.doi.org/10.1002/vms3.364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025613PMC
March 2021

In situ probing changes in fatty-acyl chain length and desaturation of lipids in cancerous areas using mass spectrometry imaging.

J Mass Spectrom 2020 Jul 11;56(4):e4621. Epub 2020 Jul 11.

Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Aberrant changes in the expression levels and structure of lipids may shape tumor microenvironment. In this study, we have performed mass spectrometry imaging and profiling analysis of 63 tissues of five types of cancer, namely, breast, colorectal, esophageal, lung, and gastric cancer, using in situ liquid extraction electrosonic spray ionization mass spectrometry imaging. Alteration of fatty-acyl chain length of unsaturated phosphatidylcholines, phosphatidylinositols, and phosphatidylserines and of chain length of (un)saturated fatty acids are associated with different cancerous areas of five types of cancer. The ratios of the same fatty-acyl carbon atom lipids with one double bond difference and the ratios of the same chain-length fatty acids with one double bond difference exhibited significant differences among the cancerous areas of five types of cancer. Our data may reveal that there were different lipid metabolism networks among five types of cancer.
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http://dx.doi.org/10.1002/jms.4621DOI Listing
July 2020

Evidence for pre-symptomatic transmission of coronavirus disease 2019 (COVID-19) in China.

Influenza Other Respir Viruses 2021 01 7;15(1):19-26. Epub 2020 Aug 7.

The Chinese Center for Disease Control and Prevention, Beijing, China.

Background: Between mid-January and early February, provinces of mainland China outside the epicentre in Hubei province were on high alert for importations and transmission of COVID-19. Many properties of COVID-19 infection and transmission were still not yet established.

Methods: We collated and analysed data on 449 of the earliest COVID-19 cases detected outside Hubei province to make inferences about transmission dynamics and severity of infection. We analysed 64 clusters to make inferences on serial interval and potential role of pre-symptomatic transmission.

Results: We estimated an epidemic doubling time of 5.3 days (95% confidence interval (CI): 4.3, 6.7) and a median incubation period of 4.6 days (95% CI: 4.0, 5.2). We estimated a serial interval distribution with mean 5.7 days (95% CI: 4.7, 6.8) and standard deviation 3.5 days, and effective reproductive number was 1.98 (95% CI: 1.68, 2.35). We estimated that 32/80 (40%) of transmission events were likely to have occurred prior to symptoms onset in primary cases. Secondary cases in clusters had less severe illness on average than cluster primary cases.

Conclusions: The majority of transmissions are occurring around illness onset in an infected person, and pre-symptomatic transmission does play a role. Detection of milder infections among the secondary cases may be more reflective of true disease severity.
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http://dx.doi.org/10.1111/irv.12787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436222PMC
January 2021

Molecular characterization and phylogenetic analysis of fowl adenovirus serotype-4 from Guangdong Province, China.

Vet World 2020 May 24;13(5):981-986. Epub 2020 May 24.

Department of Microbiology, College of Life Science and Engineering, Foshan University, Foshan 528231, Guangdong Province, China.

Aim: Our aim in this study was to isolate potentially novel strains of fowl adenovirus serotype-4 (FAdV-4) that is currently circulating in broiler chicken flocks in Guangdong Province, China, and to compare nucleotide and amino acid (AA) sequences of their respective genes.

Materials And Methods: The experiment was carried out on poultry farms experiencing outbreaks of FAdV-4-associated hydropericardium syndrome (HPS). Tissue samples from the hearts and livers of deceased chickens were screened for FAdV-4 infection using gene-specific polymerase chain reaction (PCR).

Results: New virus isolates were used to infect 7-day-old chicks, which went onto reproduce typical HPS signs. The hypervariable region of the FAdV-4 gene was PCR-amplified and sequenced. The nucleotide and deduced AA sequence identities were 99.8-99.9% and 99.5-99.8%, respectively, among the four novel isolates. In addition, the new isolates were 97-100% and 96.4-99.9% identical to the nucleotide and deduced AA sequences, respectively, of FAdV-4 genes available in the National Center for Biotechnology Information GenBank database. Phylogenetic analyses, based on the gene sequence, revealed that the new isolates, clustered with FAdV-C; the FAdV-A, FAdV-B, FAdV-D, and FAdV-E viruses, were more distantly related.

Conclusion: New FAdV-4 isolates from Guangdong Province are similar to those identified in other regions of the world. This information provides critical insight into HPS epidemiology and provides a perspective for monitoring outbreaks and developing strategies for disease prevention.
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http://dx.doi.org/10.14202/vetworld.2020.981-986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311883PMC
May 2020

Benign paroxysmal positional vertigo as a complication of 90-day head-down bed rest.

Eur Arch Otorhinolaryngol 2021 Mar 16;278(3):683-688. Epub 2020 Jun 16.

The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, People's Republic of China.

Purpose: This study aimed to report the occurrence of benign paroxysmal positional vertigo (BPPV) in a 90-day head-down bed rest experiment and evaluate the potential relationship between BPPV-related seizures and bone metabolic changes.

Methods And Design: Five cases of lateral semicircular canal (LSC) BPPV were diagnosed during a 90-day head-down bed rest experiment. Five age-matched subjects who participated in this experiment and never felt dizziness or vertigo were assigned as controls. The differences between the BPPV and the controls in lumbar bone mineral density, 25-hydroxyvitamin D level, corrected serum calcium, potassium, sodium, phosphorus, iron, uric acid and N-terminal osteocalcin were analyzed to determine the cause of LSC-BPPV.

Results: BPPV occurred from Day 17 to Day 42 during head-down bed rest. The occurrences of BPPV were related to low 25-hydroxyvitamin D level (BPPV:20.70 ± 1.95 ng/L vs. control: 30.59 ± 2.75 ng/L at Day 30 during HDBR, p < 0.05). The relatively longer duration in the prone posture at 6° head down in this experiment may have a potential role in the involvement of the LSC. The maneuver used in the experiment effectively alleviated the acute symptoms of LSC-BPPV.

Conclusion: The cases of LSC-BPPV in the early period of 90-day of head-down bed rest were related to the low 25-hydroxyvitamin D level and the 6° head-down posture. These results suggest that the potential role of unloading-induced bone loss on BPPV-related seizures deserves attention in future studies of long-term bed rest.
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http://dx.doi.org/10.1007/s00405-020-06124-2DOI Listing
March 2021

Precise Regulation of Carrier Concentration in Thermoelectric BiSbTe Alloys via Magnetic Doping.

ACS Appl Mater Interfaces 2020 May 23;12(18):20653-20663. Epub 2020 Apr 23.

School of Materials Science and Engineering, Shanghai University, 99 Shangda Road, Shanghai 200444, China.

The BiTe-based alloy is the best commercial thermoelectric material around room temperature, although it is extremely difficult to further improve its thermoelectric performance. In this work, we demonstrate that magnetic doping is an effective strategy to regulate the thermoelectric performance of p-type BiSbTe. According to our experiments, it is much more difficult for ferromagnetic Fe/Co to enter the BiSbTe lattice in comparison with diamagnetic Pb, which can be understood by the "like dissolves like" rule. At the same doping content, Fe and Co provide much lower hole carriers than Pb due to their larger carrier thermal activation energies, indicating that Fe and Co as dopants are very applicable for the fine regulation of the carrier concentration. The Fe/Co-doped samples have higher Seebeck coefficients but less carrier mobilities than the Pb-doped sample since the doped magnetic atoms induce additional carrier scattering. Beyond the solid solubility limit, excess Fe/Co represents as the impurity, which can maintain a high carrier concentration due to the metal-semiconductor contact. Finally, the values of ∼1.05 and 1.15 near room temperature have been achieved for the samples with 1.71 at. % Co and 1.80 at. % Fe, respectively.
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http://dx.doi.org/10.1021/acsami.0c02408DOI Listing
May 2020

High Thermoelectric Performance of Cu-Doped PbSe-PbS System Enabled by High-Throughput Experimental Screening.

Research (Wash D C) 2020 7;2020:1736798. Epub 2020 Mar 7.

School of Materials Science and Engineering, Shanghai University, 99 Shangda Road, Shanghai 200444, China.

Recent advances in high-throughput (HTP) computational power and machine learning have led to great achievements in exploration of new thermoelectric materials. However, experimental discovery and optimization of thermoelectric materials have long relied on the traditional Edisonian trial and error approach. Herein, we demonstrate that ultrahigh thermoelectric performance in a Cu-doped PbSe-PbS system can be realized by HTP experimental screening and precise property modulation. Combining the HTP experimental technique with transport model analysis, an optimal Se/S ratio showing high thermoelectric performance has been efficiently screened out. Subsequently, based on the screened Se/S ratio, the doping content of Cu has been subtly adjusted to reach the optimum carrier concentration. As a result, an outstanding peak zT~1.6 is achieved at 873 K for a 1.8 at% Cu-doped PbSeS sample, which is the superior value among the -type Te-free lead chalcogenides. We anticipate that current work will stimulate large-scale unitization of the HTP experimental technique in the thermoelectric field, which can greatly accelerate the research and development of new high-performance thermoelectric materials.
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http://dx.doi.org/10.34133/2020/1736798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080995PMC
March 2020

A Multiple-Instance Densely-Connected ConvNet for Aerial Scene Classification.

IEEE Trans Image Process 2020 Mar 3. Epub 2020 Mar 3.

In contrast with nature scenes, aerial scenes are often composed of many objects crowdedly distributed on the surface in bird's view, the description of which usually demands more discriminative features as well as local semantics. However, when applied to scene classification, most of the existing convolution neural networks (ConvNets) tend to depict global semantics of images, and the loss of low- and mid-level features can hardly be avoided, especially when the model goes deeper. To tackle these challenges, in this paper, we propose a multiple-instance densely-connected ConvNet (MIDC-Net) for aerial scene classification. It regards aerial scene classification as a multiple-instance learning problem so that local semantics can be further investigated. Our classification model consists of an instance-level classifier, a multiple instance pooling and followed by a bag-level classification layer. In the instance-level classifier, we propose a simplified dense connection structure to effectively preserve features from different levels. The extracted convolution features are further converted into instance feature vectors. Then, we propose a trainable attention-based multiple instance pooling. It highlights the local semantics relevant to the scene label and outputs the bag-level probability directly. Finally, with our bag-level classification layer, this multiple instance learning framework is under the direct supervision of bag labels. Experiments on three widely-utilized aerial scene benchmarks demonstrate that our proposed method outperforms many state-of-the-art methods by a large margin with much fewer parameters.
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http://dx.doi.org/10.1109/TIP.2020.2975718DOI Listing
March 2020

A Low-Cost Biomimetic Heterostructured Multilayer Membrane with Geopolymer Microparticles for Broad-Spectrum Water Purification.

ACS Appl Mater Interfaces 2020 Mar 25;12(10):12133-12142. Epub 2020 Feb 25.

School of Chemistry & Chemical Engineering, Guangxi Key Lab of Petrochemical Resource Processing and Process Intensification Technology, Guangxi University, Nanning 530004, China.

Membranes have received wide interest in water purification. However, the development of a low-cost and eco-friendly membrane with the desired structure for broad-spectrum water purification still remains a great challenge. Inspired by the hierarchical structure and functions of wood, a heterostructured multilayer membrane fabricated through a facile and "green" layer-by-layer self-assembly method was reported in this study. Specifically, the hydrophilic geopolymer microparticles were doped into sodium alginate matrix to construct "xylem" layers with numerous microchannels, and chitosan was used to build "phloem" layers with dense structures. The resultant biomimetic multilayer membrane displayed a distinct heterostructure and provided the desired rejection to different kinds of pollutants including nanoparticles, soluble dyes, and heavy metal ions, as well as emulsified oil droplets. Furthermore, the biomimetic membrane exhibited a superior stability in a long-term operation and an excellent recyclability for multiple usages for oil droplets removal. The proposed biomimetic membrane prepared in a completely "green" way possesses great potential in practical application for water purification and separation.
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http://dx.doi.org/10.1021/acsami.0c00440DOI Listing
March 2020

A novel tumour suppressor lncRNA F630028O10Rik inhibits lung cancer angiogenesis by regulating miR-223-3p.

J Cell Mol Med 2020 03 13;24(6):3549-3559. Epub 2020 Feb 13.

Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Foshan University, Guangdong, China.

Lung cancer is the world's leading cause of cancer-related morbidity and mortality despite advances in surgery, chemotherapy and immunotherapy; thus, there is an urgent need to find new molecules to develop novel treatment strategies. Although ncRNAs were found to account for 98% transcripts, the number of lncRNAs with distinct function in lung cancer is extremely limited. We previously demonstrated that Plasmodium infection inhibits tumour growth and metastasis, but the exact mechanisms involved have not been fully understood. In this study, we carried out RNA sequencing (RNA-Seq) of tumour tissues isolated from LLC tumour-bearing mice treated with either Plasmodium yoelli (Py)-infected red blood cells or uninfected red blood cells. We found that F630028O10Rik (abbreviated as F63) is a novel lncRNA that was significantly up-regulated in tumours isolated from mice treated with Py-infected red blood cells compared to the control. By using gene silencing technique, F63 was found to inhibit both tumour Vascular Endothelial Growth Factor A (VEGFA) secretion and endothelial cells clone formation, migration, invasion and tube formation. Injection of cholesterol-modified siRNA-F63 into mice tumour tissues produced a significant increase in tumour volume, blood vessel formation and angiogenesis 17 days after injection. We further showed that inhibiting miR-223-3p results in the down-regulation of VEGFA and VEGFR2 which are vital molecules for angiogenesis. These results reveal that F63 inhibit tumour growth and progression by modulating tumour angiogenesis suggesting F63 can be a novel lncRNA with great potential as a candidate molecule for gene therapy in lung cancer.
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http://dx.doi.org/10.1111/jcmm.15044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131933PMC
March 2020

Taurine protects against cardiac dysfunction induced by pressure overload through SIRT1-p53 activation.

Chem Biol Interact 2020 Feb 1;317:108972. Epub 2020 Feb 1.

Department of Cardiology, Tangdu Hospital, AIR FORCE Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, China. Electronic address:

Background: Heart failure (HF) is an epidemic disease with increased incidence annually. It has been reported that taurine can improve cardiac function. This study investigated the cardioprotective effects of taurine in pressure-loaded HF mice and elucidated the possible mechanism.

Methods: HF models were established by transverse aortic constriction (TAC). Animals were treated with either taurine for 9 weeks and/or the SIRT1 inhibitor EX527 (5 mg/kg/day, every 2days) after TAC operation. Cardiac function and geometry were revealed by echocardiography. Myocardial hypertrophy and fibrosis were assessed using Fluorescent wheat germ agglutinin (WGA) staining and Masson's trichrome staining. Western blot and RT-PCR were performed to elucidate the expression of target proteins and genes respectively. Apoptosis in cardiomyocytes was detected by TUNEL staining. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD) and malonyldialdehyde (MDA) and reactive oxygen species (ROS). Taurine concentrations and NAD/NADH ratio were determined by taurine and NAD/NADH assay kit.

Results: Taurine notably relieved cardiac dysfunction after TAC. The mechanisms were attributed to reduced myocyte hypertrophy and fibrosis, and alleviated apoptosis and oxidative stress. Meanwhile, taurine increased NAD+/NADH ratio,promoted the expression of SIRT1 and suppressed p53 acetylation. However, EX-527(inhibitor of SIRT1) decreased NAD/NADH ratio and increased acetyl-p53 levels, and abolished the cardioprotective effects of taurine on mice subjected to TAC and increased apoptosis and oxidative stress.

Conclusion: The mechanism responsible for cardiac-protective effects of taurine in HF induced by pressure overload is associated with the activation of the SIRT1-p53 pathway.
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http://dx.doi.org/10.1016/j.cbi.2020.108972DOI Listing
February 2020
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