Publications by authors named "Wanqi Yang"

25 Publications

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HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity.

Cell Death Dis 2021 Jul 26;12(8):738. Epub 2021 Jul 26.

Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, China.

Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited HO-induced endothelial senescence. Overexpression of ΔHO-1, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.
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http://dx.doi.org/10.1038/s41419-021-04035-6DOI Listing
July 2021

Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial.

Lancet Infect Dis 2021 Jun 28. Epub 2021 Jun 28.

Sinovac Life Sciences, Beijing, China. Electronic address:

Background: A vaccine against SARS-CoV-2 for children and adolescents will play an important role in curbing the COVID-19 pandemic. Here we aimed to assess the safety, tolerability, and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in children and adolescents aged 3-17 years.

Methods: We did a double-blind, randomised, controlled, phase 1/2 clinical trial of CoronaVac in healthy children and adolescents aged 3-17 years old at Hebei Provincial Center for Disease Control and Prevention in Zanhuang (Hebei, China). Individuals with SARS-CoV-2 exposure or infection history were excluded. Vaccine (in 0·5 mL aluminum hydroxide adjuvant) or aluminum hydroxide only (alum only, control) was given by intramuscular injection in two doses (day 0 and day 28). We did a phase 1 trial in 72 participants with an age de-escalation in three groups and dose-escalation in two blocks (1·5 μg or 3·0 μg per injection). Within each block, participants were randomly assigned (3:1) by means of block randomisation to receive CoronaVac or alum only. In phase 2, participants were randomly assigned (2:2:1) by means of block randomisation to receive either CoronaVac at 1·5 μg or 3·0 μg per dose, or alum only. All participants, investigators, and laboratory staff were masked to group allocation. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint assessed in the per-protocol population was seroconversion rate of neutralising antibody to live SARS-CoV-2 at 28 days after the second injection. This study is ongoing and is registered with ClinicalTrials.gov, NCT04551547.

Findings: Between Oct 31, 2020, and Dec 2, 2020, 72 participants were enrolled in phase 1, and between Dec 12, 2020, and Dec 30, 2020, 480 participants were enrolled in phase 2. 550 participants received at least one dose of vaccine or alum only (n=71 for phase 1 and n=479 for phase 2; safety population). In the combined safety profile of phase 1 and phase 2, any adverse reactions within 28 days after injection occurred in 56 (26%) of 219 participants in the 1·5 μg group, 63 (29%) of 217 in the 3·0 μg group, and 27 (24%) of 114 in the alum-only group, without significant difference (p=0·55). Most adverse reactions were mild and moderate in severity. Injection site pain was the most frequently reported event (73 [13%] of 550 participants), occurring in 36 (16%) of 219 participants in the 1·5 μg group, 35 (16%) of 217 in the 3·0 μg group, and two (2%) in the alum-only group. As of June 12, 2021, only one serious adverse event of pneumonia has been reported in the alum-only group, which was considered unrelated to vaccination. In phase 1, seroconversion of neutralising antibody after the second dose was observed in 27 of 27 participants (100·0% [95% CI 87·2-100·0]) in the 1·5 μg group and 26 of 26 participants (100·0% [86·8-100·0]) in the 3·0 μg group, with the geometric mean titres of 55·0 (95% CI 38·9-77·9) and 117·4 (87·8-157·0). In phase 2, seroconversion was seen in 180 of 186 participants (96·8% [93·1-98·8]) in the 1·5 μg group and 180 of 180 participants (100·0% [98·0-100·0]) in the 3·0 μg group, with the geometric mean titres of 86·4 (73·9-101·0) and 142·2 (124·7-162·1). There were no detectable antibody responses in the alum-only groups.

Interpretation: CoronaVac was well tolerated and safe and induced humoral responses in children and adolescents aged 3-17 years. Neutralising antibody titres induced by the 3·0 μg dose were higher than those of the 1·5 μg dose. The results support the use of 3·0 μg dose with a two-immunisation schedule for further studies in children and adolescents.

Funding: The Chinese National Key Research and Development Program and the Beijing Science and Technology Program.
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http://dx.doi.org/10.1016/S1473-3099(21)00319-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238449PMC
June 2021

SAIL: a new conserved anti-fibrotic lncRNA in the heart.

Basic Res Cardiol 2021 03 6;116(1):15. Epub 2021 Mar 6.

Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang, People's Republic of China.

Long non-coding RNAs (lncRNAs) account for a large proportion of genomic transcripts and are critical regulators in various cardiac diseases. Though lncRNAs have been reported to participate in the process of diverse cardiac diseases, the contribution of lncRNAs in cardiac fibrosis remains to be fully elucidated. Here, we identified a novel anti-fibrotic lncRNA, SAIL (scaffold attachment factor B interacting lncRNA). SAIL was reduced in cardiac fibrotic tissue and activated cardiac fibroblasts. Gain- and loss-of-function studies showed that knockdown of SAIL promoted proliferation and collagen production of cardiac fibroblasts with or without TGF-β1 (transforming growth factor beta1) treatment, while overexpression of SAIL did the opposite. In mouse cardiac fibrosis induced by myocardial infarction, knockdown of SAIL exacerbated, whereas overexpression of SAIL alleviated cardiac fibrosis. Mechanically, SAIL inhibited the fibrotic process by directly binding with SAFB via 23 conserved nucleotide sequences, which in turn blocked the access of SAFB to RNA pol II (RNA polymerase II) and reduced the transcription of fibrosis-related genes. Intriguingly, the human conserved fragment of SAIL (hSAIL) significantly suppressed the proliferation and collagen production of human cardiac fibroblasts. Our findings demonstrate that SAIL regulates cardiac fibrosis by regulating SAFB-mediated transcription of fibrotic related genes. Both SAIL and SAFB hold the potential to become novel therapeutic targets for cardiac fibrosis.
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http://dx.doi.org/10.1007/s00395-021-00854-yDOI Listing
March 2021

Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.

Lancet Infect Dis 2021 06 3;21(6):803-812. Epub 2021 Feb 3.

Sinovac Biotech, Beijing, China. Electronic address:

Background: A vaccine against COVID-19 is urgently needed for older adults, in whom morbidity and mortality due to the disease are increased. We aimed to assess the safety, tolerability, and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in adults aged 60 years and older.

Methods: We did a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial of CoronaVac in healthy adults aged 60 years and older in Renqiu (Hebei, China). Vaccine or placebo was given by intramuscular injection in two doses (days 0 and 28). Phase 1 comprised a dose-escalation study, in which participants were allocated to two blocks: block 1 (3 μg inactivated virus in 0·5 mL of aluminium hydroxide solution per injection) and block 2 (6 μg per injection). Within each block, participants were randomly assigned (2:1) using block randomisation to receive CoronaVac or placebo (aluminium hydroxide solution only). In phase 2, participants were randomly assigned (2:2:2:1) using block randomisation to receive either CoronaVac at 1·5 μg, 3 μg, or 6 μg per dose, or placebo. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint was seroconversion rate at 28 days after the second injection (which was assessed in all participants who had received the two doses of vaccine according to their random assignment, had antibody results available, and did not violate the trial protocol). Seroconversion was defined as a change from seronegative at baseline to seropositive for neutralising antibodies to live SARS-CoV-2 (positive cutoff titre 1/8), or a four-fold titre increase if the participant was seropositive at baseline. This study is ongoing and is registered with ClinicalTrials.gov (NCT04383574).

Findings: Between May 22 and June 1, 2020, 72 participants (24 in each intervention group and 24 in the placebo group; mean age 65·8 years [SD 4·8]) were enrolled in phase 1, and between June 12 and June 15, 2020, 350 participants were enrolled in phase 2 (100 in each intervention group and 50 in the placebo group; mean age 66·6 years [SD 4·7] in 349 participants). In the safety populations from both phases, any adverse reaction within 28 days after injection occurred in 20 (20%) of 100 participants in the 1·5 μg group, 25 (20%) of 125 in the 3 μg group, 27 (22%) of 123 in the 6 μg group, and 15 (21%) of 73 in the placebo group. All adverse reactions were mild or moderate in severity and injection site pain (39 [9%] of 421 participants) was the most frequently reported event. As of Aug 28, 2020, eight serious adverse events, considered unrelated to vaccination, have been reported by seven (2%) participants. In phase 1, seroconversion after the second dose was observed in 24 of 24 participants (100·0% [95% CI 85·8-100·0]) in the 3 μg group and 22 of 23 (95·7% [78·1-99·9]) in the 6 μg group. In phase 2, seroconversion was seen in 88 of 97 participants in the 1·5 μg group (90·7% [83·1-95·7]), 96 of 98 in the 3 μg group (98·0% [92·8-99·8]), and 97 of 98 (99·0% [94·5-100·0]) in the 6 μg group. There were no detectable antibody responses in the placebo groups.

Interpretation: CoronaVac is safe and well tolerated in older adults. Neutralising antibody titres induced by the 3 μg dose were similar to those of the 6 μg dose, and higher than those of the 1·5 μg dose, supporting the use of the 3 μg dose CoronaVac in phase 3 trials to assess protection against COVID-19.

Funding: Chinese National Key Research and Development Program and Beijing Science and Technology Program.
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http://dx.doi.org/10.1016/S1473-3099(20)30987-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906628PMC
June 2021

SA-LuT-Nets: Learning Sample-Adaptive Intensity Lookup Tables for Brain Tumor Segmentation.

IEEE Trans Med Imaging 2021 05 30;40(5):1417-1427. Epub 2021 Apr 30.

In clinics, the information about the appearance and location of brain tumors is essential to assist doctors in diagnosis and treatment. Automatic brain tumor segmentation on the images acquired by magnetic resonance imaging (MRI) is a common way to attain this information. However, MR images are not quantitative and can exhibit significant variation in signal depending on a range of factors, which increases the difficulty of training an automatic segmentation network and applying it to new MR images. To deal with this issue, this paper proposes to learn a sample-adaptive intensity lookup table (LuT) that dynamically transforms the intensity contrast of each input MR image to adapt to the following segmentation task. Specifically, the proposed deep SA-LuT-Net framework consists of a LuT module and a segmentation module, trained in an end-to-end manner: the LuT module learns a sample-specific nonlinear intensity mapping function through communication with the segmentation module, aiming at improving the final segmentation performance. In order to make the LuT learning sample-adaptive, we parameterize the intensity mapping function by exploring two families of non-linear functions (i.e., piece-wise linear and power functions) and predict the function parameters for each given sample. These sample-specific parameters make the intensity mapping adaptive to samples. We develop our SA-LuT-Nets separately based on two backbone networks for segmentation, i.e., DMFNet and the modified 3D Unet, and validate them on BRATS2018 and BRATS2019 datasets for brain tumor segmentation. Our experimental results clearly demonstrate the superior performance of the proposed SA-LuT-Nets using either single or multiple MR modalities. It not only significantly improves the two baselines (DMFNet and the modified 3D Unet), but also wins a set of state-of-the-art segmentation methods. Moreover, we show that, the LuTs learnt using one segmentation model could also be applied to improving the performance of another segmentation model, indicating the general segmentation information captured by LuTs.
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http://dx.doi.org/10.1109/TMI.2021.3056678DOI Listing
May 2021

Pterostilbene and its nicotinate derivative ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of sirtuin 1.

Can J Physiol Pharmacol 2021 Feb 2:1-10. Epub 2021 Feb 2.

Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences; National and Local United Engineering Lab of Druggability and New Drugs Evaluation; Guangdong Engineering Laboratory of Druggability and New Drug Evaluation; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, P.R. China.

Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study evaluated the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction. All the tested compounds at the concentrations from 10 M to 10 M did not show cytotoxicity in endothelial cells by MTT assay. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated β-galactosidase, downregulated p21 and p53, and increased the production of nitric oxide (NO) in both angiotensin II - and hydrogen peroxide - induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations, which were attenuated in the presence of endothelial NO synthase (eNOS) inhibitor L-NAME or sirtuin 1 (SIRT1) inhibitor sirtinol. Pts and Pts nicotinate did not alter SIRT1 expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1, according to surface plasmon resonance results and the molecular docking analysis. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate. Moreover, Pts and Pts nicotinate shared similar ADME (absorption, distribution, metabolism, excretion) profiles and physiochemical properties. This study suggests that the Pts and Pts nicotinate ameliorate vascular endothelial senescence and elicit endothelium-dependent relaxations via activation of SIRT1. These two compounds may be potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.
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http://dx.doi.org/10.1139/cjpp-2020-0583DOI Listing
February 2021

Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts.

FASEB J 2021 02 5;35(2):e21162. Epub 2020 Nov 5.

Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P.R. China.

Cardiac fibrosis is characterized by the activation of cardiac fibroblasts and accumulation of extracellular matrix. METTL3, a component of methyltransferase complex, participates in multiple biological processes associated with mammalian development and disease progression. However, the role of METTL3 in cardiac fibrosis is still unknown. We performed fibroblasts activation with TGF-β1 (20 ng/mL) in vitro and established in vivo mouse models with lentivirus to assess the effects of METTL3 on cardiac fibroblasts proliferation and collagen formation. Methylated RNA immunoprecipitation (MeRIP) was used to define the potential fibrosis-regulated gene. The expression level of METTL3 was increased in cardiac fibrotic tissue of mice with chronic myocardial infarction and cultured cardiac fibroblats (CFs) treated with TGF-β1. Enforced expression of METTL3 promoted proliferation and fibroblast-to-myofibroblast transition and collagens accumulation, while silence of METTL3 did the opposite. Silence of METTL3 by lentivirus carrying METTL3 siRNA markedly alleviated cardiac fibrosis in MI mice. Transcriptome and N6-methyladenosine (m A) profiling analyses revealed that the expression and m A level of collagen-related genes were altered after silence of METTL3. METTL3-mediated m A modification is critical for the development of cardiac fibrosis, providing a molecular target for manipulating fibrosis and the associated cardiac diseases.
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http://dx.doi.org/10.1096/fj.201903169RDOI Listing
February 2021

Rhamnocitrin extracted from Nervilia fordii inhibited vascular endothelial activation via miR-185/STIM-1/SOCE/NFATc3.

Phytomedicine 2020 Dec 19;79:153350. Epub 2020 Sep 19.

Mathematical Engineering Academy of Chinese Medicine; Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China. Electronic address:

Background: Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown.

Purpose: The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation.

Methods: The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation.

Results: RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10 M-10 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway.

Conclusion: The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.
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http://dx.doi.org/10.1016/j.phymed.2020.153350DOI Listing
December 2020

Prostacyclin facilitates vascular smooth muscle cell phenotypic transformation via activating TP receptors when IP receptors are deficient.

Acta Physiol (Oxf) 2021 02 20;231(2):e13555. Epub 2020 Sep 20.

Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangdong, PR China.

Aim: By activating prostacyclin receptors (IP receptors), prostacyclin (PGI ) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI produces detrimental effects that are opposite to its physiological protective effects via thromboxane-prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI action.

Methods: The effects of PGI and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR-Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IP .

Results: PGI /iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI /iloprost promotes VSMC phenotypic transformation in IP-deficient cells. The effect of PGI /iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane.

Conclusion: PGI induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases.
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http://dx.doi.org/10.1111/apha.13555DOI Listing
February 2021

Learning-Based Computer-Aided Prescription System for Parkinson's Disease Patients: A Data-Driven Perspective.

IEEE J Biomed Health Inform 2020 Jul 21;PP. Epub 2020 Jul 21.

In this paper, we study a novel problem: "automatic prescription recommendation for PD patients." To realize this goal, we first build a dataset by collecting 1) symptoms of PD patients, and 2) their prescription drug provided by neurologists. Then, we build a novel computer-aided prescription model by learning the relation between observed symptoms and prescription drug. Finally, for the new coming patients, we could recommend (predict) suitable prescription drug on their observed symptoms by our prescription model. From the methodology part, our proposed model, namely Prescription viA Learning lAtent Symptoms (PALAS), could recommend prescription using the multi-modality representation of the data. In PALAS, a latent symptom space is learned to better model the relationship between symptoms and prescription drug, as there is a large semantic gap between them. Moreover, we present an efficient alternating optimization method for PALAS. We evaluated our method using the data collected from 136 PD patients at Nanjing Brain Hospital, which can be regarded as a large dataset in PD research community. The experimental results demonstrate the effectiveness and clinical potential of our method in this recommendation task, if compared with other competing methods.
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http://dx.doi.org/10.1109/JBHI.2020.3010946DOI Listing
July 2020

DUOX2, a common modulator in preventive effects of monoamine-based antidepressants on water immersion restraint stress- and indomethacin- induced gastric mucosal damage.

Eur J Pharmacol 2020 Jun 1;876:173058. Epub 2020 Mar 1.

Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China. Electronic address:

Multiple kinds of monoamine-based antidepressants have been shown prophylactic effects in experimentally induced gastric ulcer. The loss of redox homeostasis plays a principle role in the development of peptic mucosal damage. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are one of the most important sources of reactive oxygen species within the gastrointestinal tract. It is unclear whether there are some common NADPH oxidases modulated by monoamine-based antidepressants in different gastric mucosal damage models. We explored the effects of selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine on the reactive oxygen species production and antioxidant capacity in the gastric mucosa of water immersion restraint (WIRS) or indomethacin treated rats, and examined the role of NADPH oxidases in the protective effects. Pretreated duloxetine prevented the increase of gastric mucosal NADPH oxidase activity and NADPH oxidase inhibitor apocynin dose-dependently protected gastric mucosa from damage by the two factors. Furthermore, dual oxidase 2 (DUOX2) and NADPH oxidase4 (NOX4) are involved in the protective effects of duloxetine in both models. We then examined NADPH oxidases expression modulated by the other monoamine-based antidepressants including selective serotonin reuptake inhibitor (SSRIs) fluoxetine, tricyclic agent (TCAs) amitriptyline and monoamine oxidase inhibitor (MAOs) moclobemide in the two models, and all the three antidepressants reduced the DUOX2 expression in the gastric mucosa. So DUOX2 was a common modulator in the preventive effects of all the monoamine-based antidepressants on WIRS- and indomethacin-induced gastric lesion. Our work provided a peripheral joint molecular target for monoamine modulatory antidepressants, which may be helpful to reveal the mechanisms of this kind of drugs more than monoamine regulation.
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http://dx.doi.org/10.1016/j.ejphar.2020.173058DOI Listing
June 2020

Interchangeability of two Enterovirus 71 inactivated vaccines in Chinese children: A phase IV, open-label, and randomized controlled trial.

Vaccine 2020 03 14;38(12):2671-2677. Epub 2020 Feb 14.

Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention, Jinan, China; Academy of Preventive Medicine, Shandong University, Jinan, China. Electronic address:

Background: In China, three inactivated Enterovirus 71 (EV71) vaccines have been approved. Although the vaccines in an immunization series should be from a single manufacture, children sometimes have to receive EV71 vaccines from more than one manufacturers. The aim of this study was to evaluate the interchangeability and safety of vaccination with EV71 vaccines from two manufacturers among Chinese children.

Methods: We conducted an open label and randomized controlled study among children aged 6-35 months from November 2018 to January 2019. The participants were randomly assigned (1:1:1:1) to receive EV71 vaccines in one of the four different schedules (two using a single vaccine for all doses from one manufacture, and two mixed schedules using vaccines from two manufactures). Blood samples were collected pre-vaccination (Day 0) and one month after the second dose (Day 60) for neutralizing antibody assay. Immunogenicity was assessed in the per-protocol cohort and safety was assessed in the total vaccinated cohort.

Results: A total of 300 children were enrolled and randomized, of whom 89.0% (267/300) were included in the per-protocol cohort for immunogenicity analysis. The seroconversion rates of the EV71 neutralizing antibody in four groups ranged from 98.4% to 100.0%, and were not significantly different among the groups. Compared with other groups, geometric mean titer was higher in group D, in which the participants received Institute of Medical Biology Chinese Academy of Medical Sciences (CAMS) vaccine in the first dose and the Sinovac vaccine in the second dose. Safety profiles were similar among the four groups and no serious adverse events related to the vaccination were reported.

Conclusions: Interchangeability of EV71 vaccines from two manufactures to complete an immunization series showed good immunogenicity and safety. The antibody response levels may vary by vaccination sequences of EV71 vaccines from the two manufacturers.

Trial Registration: ClinicalTrials.govNCT03873740.
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http://dx.doi.org/10.1016/j.vaccine.2020.02.013DOI Listing
March 2020

An Effective MR-Guided CT Network Training for Segmenting Prostate in CT Images.

IEEE J Biomed Health Inform 2020 08 16;24(8):2278-2291. Epub 2019 Dec 16.

Segmentation of prostate in medical imaging data (e.g., CT, MRI, TRUS) is often considered as a critical yet challenging task for radiotherapy treatment. It is relatively easier to segment prostate from MR images than from CT images, due to better soft tissue contrast of the MR images. For segmenting prostate from CT images, most previous methods mainly used CT alone, and thus their performances are often limited by low tissue contrast in the CT images. In this article, we explore the possibility of using indirect guidance from MR images for improving prostate segmentation in the CT images. In particular, we propose a novel deep transfer learning approach, i.e., MR-guided CT network training (namely MICS-NET), which can employ MR images to help better learning of features in CT images for prostate segmentation. In MICS-NET, the guidance from MRI consists of two steps: (1) learning informative and transferable features from MRI and then transferring them to CT images in a cascade manner, and (2) adaptively transferring the prostate likelihood of MRI model (i.e., well-trained convnet by purely using MR images) with a view consistency constraint. To illustrate the effectiveness of our approach, we evaluate MICS-NET on a real CT prostate image set, with the manual delineations available as the ground truth for evaluation. Our methods generate promising segmentation results which achieve (1) six percentages higher Dice Ratio than the CT model purely using CT images and (2) comparable performance with the MRI model purely using MR images.
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http://dx.doi.org/10.1109/JBHI.2019.2960153DOI Listing
August 2020

LncRNA PCFL promotes cardiac fibrosis via miR-378/GRB2 pathway following myocardial infarction.

J Mol Cell Cardiol 2019 08 17;133:188-198. Epub 2019 Jun 17.

Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. Electronic address:

Long noncoding RNAs (lncRNAs) are a class of novel molecular regulators in cardiac development and diseases. However, the role of specific lncRNAs in cardiac fibrosis remains to be fully explored. The aim of the present study was to investigate the effects and underlying mechanisms of lncRNA PCFL (pro-cardiac fibrotic lncRNA) on cardiac fibrosis after myocardial infarction (MI). Cardiac fibroblasts (CFs) with gain and loss of function of PCFL and mice with global knockout or overexpression of PCFL were used to explore the effects of PCFL on cardiac fibrosis. The data showed that PCFL was significantly increased in hearts of mice subjected to MI and CFs treated with transforming growth factor-β1 (TGF-β1). Overexpression of PCFL promoted collagen production and CF proliferation, while silencing PCFL exhibited the opposite effects. Compared with wild type MI mice, heterozygous knockout of PCFL (PCFL) in mice significantly improved heart function and reduced cardiac fibrosis after MI. While overexpression of PCFL impaired cardiac function and aggravated MI-induced cardiac fibrosis. The mechanistic data demonstrated that PCFL functioned as a sponge of miR-378. Luciferase reporter assay confirmed the interaction of PCFL with miR-378. MiR-378 inhibited collagen production by suppressing its target gene, GRB2 (growth factor receptor bound protein 2). Knockdown of PCFL led to an increase of miR-378. Silencing of miR-378 reserved the inhibitory effects of PCFL knockdown on collagen production, cell proliferation and GRB2 expression. In conclusion, the study identifies a novel pro-fibrotic lncRNA, PCFL, and the mechanism involves the direct interaction of PCFL with miR-378, which in turn relieves the inhibition effect of miR-378 on GRB2 and promotes cardiac fibrosis.
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http://dx.doi.org/10.1016/j.yjmcc.2019.06.011DOI Listing
August 2019

Whole-body spatially-resolved metabolomics method for profiling the metabolic differences of epimer drug candidates using ambient mass spectrometry imaging.

Talanta 2019 Sep 30;202:198-206. Epub 2019 Apr 30.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China; Center for Imaging and Systems Biology, School of Pharmacy, Minzu University of China, Beijing, 100081, PR China. Electronic address:

Investigation of the in vivo drug action and metabolic differences of epimer drugs is challenging. Whole-body MSI analysis can visually present the stereoscopic distribution of molecules related to the interaction of drugs and organisms, and can provide more comprehensive organ-specific profiling information. Herein, we developed a whole-body spatially-resolved imaging metabolomics method based on an air flow-assisted ionisation desorption electrospray ionisation (AFADESI)-MSI system coupled with a high-resolution mass spectrometer and highly discriminating imaging software. The epimeric sedative-hypnotic drug candidates YZG-331 and YZG-330 were selected as examples, and rats administered normal or high oral doses were used. By performing multivariate statistical data-mining on the combined MSI data, organ-specific differential ions were screened. By comparing the variations in the relative contents of the drugs, their metabolites, and endogenous neurotransmitters throughout whole-body tissue sections of the rats, rich information that could potentially explain the more significant sedative-hypnotic effects of YZG-330 compared to YZG-331 was obtained. Such as the increased ratio of gamma-aminobutyric acid in the brain and stomach of the rats (0.25, 0.47, 0.68, 0.30, and 0.89 for the control and YZG-331-H, YZG-330-H, YZG-331-L, and YZG-330-L, respectively) were interesting. This study provided a convenient and visual method to investigate in vivo molecular metabolic differences and provide insight towards a better understanding of the pharmacodynamic mechanisms of these sedative-hypnotic drug-candidates.
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http://dx.doi.org/10.1016/j.talanta.2019.04.068DOI Listing
September 2019

Involvement of lncR-30245 in Myocardial Infarction-Induced Cardiac Fibrosis Through Peroxisome Proliferator-Activated Receptor-γ-Mediated Connective Tissue Growth Factor Signalling Pathway.

Can J Cardiol 2019 04 16;35(4):480-489. Epub 2019 Feb 16.

Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. Electronic address:

Background: Long noncoding RNAs (lncRNAs) are emerging as important mediators of cardiac pathophysiology. The aim of the present study is to investigate the effects of lncR-30245, an lncRNA, on cardiac fibrogenesis and the underlying mechanism.

Methods: Myocardial infarction (MI) and transforming growth factor (TGF)-β1 were used to induce fibrotic phenotypes. Cardiac fibrosis was detected by Masson's trichrome staining. Cardiac function was evaluated by echocardiography. Western blot, quantitative reverse transcription-polymerase chain reaction, and pharmacological approaches were used to investigate the role of lncR-30245 in cardiac fibrogenesis.

Results: Expression of lncR-30245 was significantly increased in MI hearts and TGF-β1-treated cardiac fibroblasts (CFs). LncR-30245 was mainly located in the cytoplasm. Overexpression of lncR-30245 promoted collagen production and CF proliferation. Knockdown of lncR-30245 significantly inhibited TGF-β1-induced collagen production and CF proliferation. LncR-30245 overexpression inhibited the antifibrotic role of peroxisome proliferator-activated receptor (PPAR)-γ and increased connective tissue growth factor (CTGF) expression, whereas lncR-30245 knockdown exerted the opposite effects. Rosiglitazone, a PPAR-γ agonist, significantly inhibited lncR-30245-induced CTGF upregulation and collagen production in CFs. In contrast, T0070907, a PPAR-γ antagonist, attenuated the inhibitory effects of lncR-30245 small interfering RNA (siRNA) on TGF-β1-induced CTGF expression and collagen production. LncR-30245 knockdown significantly enhanced ejection fraction and fractional shortening and attenuated cardiac fibrosis in MI mice.

Conclusion: Our study indicates that the lncR-30245/PPAR-γ/CTGF pathway mediates MI-induced cardiac fibrosis and might be a therapeutic target for various cardiac diseases associated with fibrosis.
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http://dx.doi.org/10.1016/j.cjca.2019.02.005DOI Listing
April 2019

Does Manual Delineation only Provide the Side Information in CT Prostate Segmentation?

Med Image Comput Comput Assist Interv 2017 Sep 4;10435:692-700. Epub 2017 Sep 4.

Department of Radiology and BRIC, UNC Chapel Hill, Chapel Hill, USA.

Prostate segmentation, for accurate prostate localization in CT images, is regarded as a crucial yet challenging task. Nevertheless, due to the inevitable factors (, low contrast, large appearance and shape changes), the most important problem is how to learn the informative feature representation to distinguish the prostate from non-prostate regions. We address this challenging feature learning by leveraging the manual delineation as guidance: the manual delineation does not only indicate the category of patches, but also helps enhance the appearance of prostate. This is realized by the proposed cascaded deep domain adaptation (CDDA) model. Specifically, CDDA constructs several consecutive source domains by employing a mask of manual delineation to overlay on the original CT images with different mask ratios. Upon these source domains, convnet will guide better transferrable feature learning until to the target domain. Particularly, we implement two typical methods: (CDDA-CNN) and (CDDA-FCN). Also, we theoretically analyze the generalization error bound of CDDA. Experimental results show the promising results of our method.
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http://dx.doi.org/10.1007/978-3-319-66179-7_79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054464PMC
September 2017

Incomplete-Data Oriented Multiview Dimension Reduction via Sparse Low-Rank Representation.

IEEE Trans Neural Netw Learn Syst 2018 12 17;29(12):6276-6291. Epub 2018 May 17.

For dimension reduction on multiview data, most of the previous studies implicitly take an assumption that all samples are completed in all views. Nevertheless, this assumption could often be violated in real applications due to the presence of noise, limited access to data, equipment malfunction, and so on. Most of the previous methods will cease to work when missing values in one or multiple views occur, thus an incomplete-data oriented dimension reduction becomes an important issue. To this end, we mathematically formulate the above-mentioned issue as sparse low-rank representation through multiview subspace (SRRS) learning to impute missing values, by jointly measuring intraview relations (via sparse low-rank representation) and interview relations (through common subspace representation). Moreover, by exploiting various subspace priors in the proposed SRRS formulation, we develop three novel dimension reduction methods for incomplete multiview data: 1) multiview subspace learning via graph embedding; 2) multiview subspace learning via structured sparsity; and 3) sparse multiview feature selection via rank minimization. For each of them, the objective function and the algorithm to solve the resulting optimization problem are elaborated, respectively. We perform extensive experiments to investigate their performance on three types of tasks including data recovery, clustering, and classification. Both two toy examples (i.e., Swiss roll and -curve) and four real-world data sets (i.e., face images, multisource news, multicamera activity, and multimodality neuroimaging data) are systematically tested. As demonstrated, our methods achieve the performance superior to that of the state-of-the-art comparable methods. Also, the results clearly show the advantage of integrating the sparsity and low-rankness over using each of them separately.
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http://dx.doi.org/10.1109/TNNLS.2018.2828699DOI Listing
December 2018

Heterogeneous Face Recognition by Margin-Based Cross-Modality Metric Learning.

IEEE Trans Cybern 2018 Jun 26;48(6):1814-1826. Epub 2017 Jun 26.

Heterogeneous face recognition deals with matching face images from different modalities or sources. The main challenge lies in cross-modal differences and variations and the goal is to make cross-modality separation among subjects. A margin-based cross-modality metric learning (MCML) method is proposed to address the problem. A cross-modality metric is defined in a common subspace where samples of two different modalities are mapped and measured. The objective is to learn such metrics that satisfy the following two constraints. The first minimizes pairwise, intrapersonal cross-modality distances. The second forces a margin between subject specific intrapersonal and interpersonal cross-modality distances. This is achieved by defining a hinge loss on triplet-based distance constraints for efficient optimization. It allows the proposed method to focus more on optimizing distances of those subjects whose intrapersonal and interpersonal distances are hard to separate. The proposed method is further extended to a kernelized MCML (KMCML). Both methods have been evaluated on an ID card face dataset and two other cross-modality benchmark datasets. Various feature extraction methods have also been incorporated in the study, including recent deep learned features. In extensive experiments and comparisons with the state-of-the-art methods, the MCML and KMCML methods achieved marked improvements in most cases.
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http://dx.doi.org/10.1109/TCYB.2017.2715660DOI Listing
June 2018

Suppression of microRNA-16 protects against acute myocardial infarction by reversing beta2-adrenergic receptor down-regulation in rats.

Oncotarget 2017 Mar;8(12):20122-20132

Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P.R. China.

microRNA-16 (miR-16) has been shown to be up-regulated in ischemic heart. Beta2-adrenoreceptor (β2-AR) exerts cardioprotective property in ischemic injury. This study aims to determine the effect of miR-16 in cardiac injury in rats and the possible involvement of β2-AR in this process. Acute myocardial infarction (AMI) model in rats was induced by ligation of left coronary artery. Neonatal rat ventricular cells (NRVCs) were cultured in vitro tests. The cardiomyocyte model of oxidative injury was mimicked by hydrogen peroxide. The expression of miR-16 was obviously up-regulated and β2-AR was remarkably down-regulated in both AMI rats and NRVCs under oxidative stress. miR-16 over-expression in NRVCs reduced cell viability and increased apoptosis. Conversely, inhibition of endogenous miR-16 with its specific inhibitor reversed these changes. Over-expression of miR-16 using an miR-16 lentivirus in AMI rats markedly increased cardiac infarct area, lactate dehydrogenase and creatine kinase activity, and exacerbated cardiac dysfunction. Lentivirus-mediated knockdown of miR-16 alleviated acute cardiac injury. Moreover, miR-16 over-expression significantly suppressed β2-AR protein expression in both cultured NRVCs and AMI rats, while inhibition of miR-16 displayed opposite effect on β2-AR protein expression. Luciferase assay confirmed that miR-16 could directly target the 3'untranslated region of β2-AR mRNA. miR-16 is detrimental to the infarct heart and suppression of miR-16 protects rat hearts from ischemic injury via up-regulating of β2-AR by binding to the 3'untranslated region of β2-AR gene. This study indicates that targeting miR-16/β2-AR axis may be a promising strategy for ischemic heart disease.
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http://dx.doi.org/10.18632/oncotarget.15391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386749PMC
March 2017

Etiology of acute diarrhea in the elderly in China: A six-year observational study.

PLoS One 2017 21;12(3):e0173881. Epub 2017 Mar 21.

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

Acute diarrhea leads to a substantial disease burden among the elderly worldwide. However, in the context of increasingly aging trend in China, the prevalence of etiological agents among elderly diarrheal patients was undetermined. This study aimed to explore the major enteropathogens of acute diarrhea among outpatients older than 65 years in China, and also the epidemiological features of the pathogens. Demographic and clinical data for acute diarrhea among outpatients older than 65 years were collected from 213 participating hospitals from 2009 to 2014. Stool specimens were collected and tested for 13 enteric viruses and bacteria. The proportion of outpatients positive for targeted pathogens was analyzed by residential areas and seasonal patterns. Among the 7,725 patients enrolled, 1,617 (20.9%)were positive for any one of the 13 study pathogens. The predominant pathogen was norovirus (9.0%), followed by diarrheagenic Escherichia coli (DEC) (5.5%), rotavirus (3.9%), non-typhoidal Salmonella (NTS) (2.9%), and Shigella spp. (2.5%). The prevalence of Shigella spp. among rural patients (6.9%) was higher than that among urban patients (1.6%) (p < 0.001), with opposite trend for DEC (3.6% versus 5.9%, p = 0.007). An obvious seasonal pattern was observed for major pathogens, with peak for norovirus in autumn, rotavirus in winter and DEC, NTS, and Shigella spp. in summer. A wide variety of enteropathogens were detected among the elderly with acute diarrhea in China, with norovirus and DEC being the most commonly isolated pathogens. A strong seasonal pattern was observed for major pathogens of acute diarrhea among the elderly.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173881PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360259PMC
August 2017

Bromodomain containing protein represses the Ras/Raf/MEK/ERK pathway to attenuate human hepatoma cell proliferation during HCV infection.

Cancer Lett 2016 Feb 24;371(1):107-16. Epub 2015 Nov 24.

State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address:

Hepatitis C virus (HCV) infection facilitates the development of hepatocellular carcinoma (HCC). Activation of Ras/Raf/MEK/ERK pathway is found in more than 30% human cancers. Here, we revealed a novel mechanism underlying the regulation of hepatoma cell proliferation mediated by HCV. On one hand, hepatoma cell proliferation is facilitated by HCV infection through a positive feedback regulatory cycle. HCV promotes hepatoma cell proliferation by activating the Ras/Raf/MEK/ERK pathway, which in turn facilitates HCV replication to further enhance hepatoma cell proliferation. On the other hand, hepatoma cell proliferation is attenuated by the bromodomain containing 7 (BRD7), a tumor suppressor, through a negative feedback regulatory mechanism. After activation, the Ras/Raf/MEK/ERK pathway stimulates BRD7 production, which in turn represses the Ras/Raf/MEK/ERK pathway, leading to the attenuation of hepatoma cell proliferation. However, HCV persistent infection attenuates BRD7 gene expression and facilitates the protein degradation to release the Ras/Raf/MEK/ERK signaling, which results in the facilitation of hepatoma cell proliferation. Therefore, we proposed that the balance between BRD7 function and Ras/Raf/MEK/ERK activity is important for determining the outcomes of HCV infection and HCC development.
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http://dx.doi.org/10.1016/j.canlet.2015.11.027DOI Listing
February 2016

MRM-Lasso: A Sparse Multiview Feature Selection Method via Low-Rank Analysis.

IEEE Trans Neural Netw Learn Syst 2015 Nov 19;26(11):2801-15. Epub 2015 Feb 19.

Learning about multiview data involves many applications, such as video understanding, image classification, and social media. However, when the data dimension increases dramatically, it is important but very challenging to remove redundant features in multiview feature selection. In this paper, we propose a novel feature selection algorithm, multiview rank minimization-based Lasso (MRM-Lasso), which jointly utilizes Lasso for sparse feature selection and rank minimization for learning relevant patterns across views. Instead of simply integrating multiple Lasso from view level, we focus on the performance of sample-level (sample significance) and introduce pattern-specific weights into MRM-Lasso. The weights are utilized to measure the contribution of each sample to the labels in the current view. In addition, the latent correlation across different views is successfully captured by learning a low-rank matrix consisting of pattern-specific weights. The alternating direction method of multipliers is applied to optimize the proposed MRM-Lasso. Experiments on four real-life data sets show that features selected by MRM-Lasso have better multiview classification performance than the baselines. Moreover, pattern-specific weights are demonstrated to be significant for learning about multiview data, compared with view-specific weights.
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http://dx.doi.org/10.1109/TNNLS.2015.2396937DOI Listing
November 2015

Enhanced uptake and transport of (+)-catechin and (-)-epigallocatechin gallate in niosomal formulation by human intestinal Caco-2 cells.

Int J Nanomedicine 2014 8;9:2157-65. Epub 2014 May 8.

School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

The aim of this study was to evaluate (+)-catechin and (-)-epigallocatechin gallate (EGCG) cellular uptake and transport across human intestinal Caco-2 cell monolayer in both the absence and presence of niosomal carrier in variable conditions. The effect of free drugs and drug-loaded niosomes on the growth of Caco-2 cells was studied. The effects of time, temperature, and concentration on drug cellular uptake in the absence or presence of its niosomal delivery systems were investigated. The intestinal epithelial membrane transport of the drug-loaded niosomes was examined using the monolayer of the human Caco-2 cells. The kinetics of transport, and the effect of temperature, adenosine triphosphate inhibitor, permeability glycoprotein inhibitor, multidrug resistance-associated protein 2 inhibitor, and the absorption enhancer on transport mechanism were investigated. It was found that the uptake of catechin, EGCG, and their niosomes by Caco-2 cells was 1.22 ± 0.16, 0.90 ± 0.14, 3.25 ± 0.37, and 1.92 ± 0.22 μg/mg protein, respectively (n=3). The apparent permeability coefficient values of catechin, EGCG, and their niosomes were 1.68 ± 0.16, 0.88 ± 0.09, 2.39 ± 0.31, and 1.42 ± 0.24 cm/second (n=3) at 37°C, respectively. The transport was temperature- and energy-dependent. The inhibitors of permeability glycoprotein and multidrug resistance-associated protein 2 and the absorption enhancer significantly enhanced the uptake amount. Compared with the free drugs, niosomal formulation significantly enhanced drug absorption. Additionally, drug-loaded niosomes exhibited stronger stability and lower toxicity. These findings showed that the oral absorption of tea flavonoids could be improved by using the novel drug delivery systems.
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http://dx.doi.org/10.2147/IJN.S59331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020900PMC
December 2014

Multi-instance dictionary learning for detecting abnormal events in surveillance videos.

Int J Neural Syst 2014 May 26;24(3):1430010. Epub 2014 Jan 26.

State Key Laboratory for Novel Software Technology, Nanjing University, P. R. China.

In this paper, a novel method termed Multi-Instance Dictionary Learning (MIDL) is presented for detecting abnormal events in crowded video scenes. With respect to multi-instance learning, each event (video clip) in videos is modeled as a bag containing several sub-events (local observations); while each sub-event is regarded as an instance. The MIDL jointly learns a dictionary for sparse representations of sub-events (instances) and multi-instance classifiers for classifying events into normal or abnormal. We further adopt three different multi-instance models, yielding the Max-Pooling-based MIDL (MP-MIDL), Instance-based MIDL (Inst-MIDL) and Bag-based MIDL (Bag-MIDL), for detecting both global and local abnormalities. The MP-MIDL classifies observed events by using bag features extracted via max-pooling over sparse representations. The Inst-MIDL and Bag-MIDL classify observed events by the predicted values of corresponding instances. The proposed MIDL is evaluated and compared with the state-of-the-art methods for abnormal event detection on the UMN (for global abnormalities) and the UCSD (for local abnormalities) datasets and results show that the proposed MP-MIDL and Bag-MIDL achieve either comparable or improved detection performances. The proposed MIDL method is also compared with other multi-instance learning methods on the task and superior results are obtained by the MP-MIDL scheme.
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http://dx.doi.org/10.1142/S0129065714300101DOI Listing
May 2014
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