Publications by authors named "Yixi Chen"

27 Publications

  • Page 1 of 1

Lipid droplets are beneficial for rabies virus replication by facilitating viral budding.

J Virol 2021 Nov 10:JVI0147321. Epub 2021 Nov 10.

Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.

Rabies is an old zoonotic disease caused by rabies virus (RABV), but the pathogenic mechanism of RABV is still not completely understood. Lipid droplets have been reported to play a role in pathogenesis of several viruses. However, its role on RABV infection remains unclear. Here, we initially found that RABV infection upregulated lipid droplet (LD) production in multiple cells and mouse brains. After the treatment of atorvastatin, a specific inhibitor of LD, RABV replication in N2a cells decreased. Then we found that RABV infection could upregulate N-myc downstream regulated gene-1 (NDRG1), which in turn enhance the expression of diacylglycerol acyltransferase 1/2 (DGAT1/2). DGAT1/2 could elevate cellular triglycerides synthesis and ultimately promote intracellular LD formation. Furthermore, we found that RABV-M and RABV-G, which were mainly involved in the viral budding process, could colocalize with LDs, indicating that RABV might utilize LDs as a carrier to facilitate viral budding and eventually increase virus production. Taken together, our study reveals that lipid droplets are beneficial for RABV replication and their biogenesis is regulated via NDRG1-DGAT1/2 pathway, which provides novel potential targets for developing anti-RABV drugs. Lipid droplets have been proven to play an important role in viral infections, but its role in RABV infection has not yet been elaborated. Here, we find that RABV infection upregulates the generation of LDs by enhancing the expression of N-myc downstream regulated gene-1 (NDRG1). Then NDRG1 elevated cellular triglycerides synthesis by increasing the activity of diacylglycerol acyltransferase 1/2 (DGAT1/2), which promotes the biogenesis of LDs. RABV-M and RABV-G, which are the major proteins involved in viral budding, could utilize LDs as a carrier and transport to cell membrane, resulting in enhanced virus budding. Our findings will extend the knowledge of lipid metabolism in RABV infection and help to explore potential therapeutic targets for RABV.
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http://dx.doi.org/10.1128/JVI.01473-21DOI Listing
November 2021

A Center of Mass Estimation and Control Strategy for Body-Weight-Support Treadmill Training.

IEEE Trans Neural Syst Rehabil Eng 2021 17;29:2388-2398. Epub 2021 Nov 17.

Walking disorders are common in post-stroke. Body weight support (BWS) systems have been proposed and proven to enhance gait training systems for recovering in individuals with hemiplegia. However, the fixed weight support and walking speed increase the risk of falling and decrease the active participation of the subjects. This paper proposes a strategy to enhance the efficiency of BWS treadmill training. It consists in regulating the height of the BWS system to track the height of the subject's center of mass (CoM), whereby the CoM is estimated through a long-short term memory (LSTM) network and a locomotion recognition system. The LSTM network takes the walking speed, body-height to leg-length ratio, hip and knee joint angles of the hemiplegic subjects' non-paretic side from the locomotion recognition system as input signals and outputs the CoM height to a BWS treadmill training robot. Besides, the hip and knee joints' ranges of motion are increased by 34.54% and 25.64% under the CoM height regulation compared to the constant weight support, respectively. With the CoM height regulation strategy, the stance phase duration of the paretic side is significantly increased by 14.6% of the gait cycle, and the symmetry of the gait is also promoted. The CoM height kinematics by adjustment strategy is in good agreement with the mean values of the 14 non-disabled subjects, which demonstrated that the adjustment strategy improves the stability of CoM height during the training.
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http://dx.doi.org/10.1109/TNSRE.2021.3126104DOI Listing
November 2021

Establishment of Full-Length cDNA Clones and an Efficient Oral Infection Model for Feline Coronavirus in Cats.

J Virol 2021 10 18;95(21):e0074521. Epub 2021 Aug 18.

State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural Universitygrid.35155.37, Wuhan, China.

Feline infectious peritonitis virus (FIPV) is the etiologic agent of feline infectious peritonitis (FIP) and causes fatal disease in cats of almost all ages. Currently, there are no clinically approved drugs or effective vaccines for FIP. Furthermore, the pathogenesis of FIP is still not fully understood. There is an urgent need for an effective infection model of feline infectious peritonitis induced by FIPV. Here, we constructed a field type I FIPV full-length cDNA clone, pBAC-QS, corresponding to the isolated FIPV QS. By replacing the FIPV QS spike gene with the commercially available type II FIPV 79-1146 (79-1146_CA) spike gene, we established and rescued a recombinant virus, designated rQS-79. Moreover, we constructed 79-1146_CA infectious full-length cDNA pBAC-79-1146_CA, corresponding to recombinant feline coronavirus (FCoV) 79-1146_CA (r79-1146_CA). In animal experiments with 1- to 2-year-old adult cats orally infected with the recombinant virus, rQS-79 induced typical FIP signs and 100% mortality. In contrast to cats infected with rQS-79, cats infected with 79-1146_CA did not show obvious signs. Furthermore, by rechallenging rQS-79 in surviving cats previously infected with 79-1146_CA, we found that there was no protection against rQS-79 with different titers of neutralizing antibodies. However, high titers of neutralizing antibodies may help prolong the cat survival time. Overall, we report the first reverse genetics of virulent recombinant FCoV (causing 100% mortality in adult cats) and attenuated FCoV (causing no mortality in adult cats), which will be powerful tools to study pathogenesis, antiviral drugs, and vaccines for FCoV. Tissue- or cell culture-adapted feline infectious peritonitis virus (FIPV) usually loses pathogenicity. To develop a highly virulent FIPV, we constructed a field isolate type I FIPV full-length clone with the spike gene replaced by the 79-1146 spike gene, corresponding to a virus named rQS-79, which induces high mortality in adult cats. rQS-79 represents the first described reverse genetics system for highly pathogenic FCoV. By further constructing the cell culture-adapted FCoV 79-1146_CA, we obtained infectious clones of virulent and attenuated FCoV. By and experiments, we established a model that can serve to study the pathogenic mechanisms of FIPV. Importantly, the wild-type FIPV replicase skeleton of serotype I will greatly facilitate the screening of antiviral drugs, both and .
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http://dx.doi.org/10.1128/JVI.00745-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513462PMC
October 2021

A novel oral rabies vaccine enhances the immunogenicity through increasing dendritic cells activation and germinal center formation by expressing U-OMP19 in a mouse model.

Emerg Microbes Infect 2021 Dec;10(1):913-928

Key Laboratory of Preventive Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People's Republic of China.

Rabies remains a public health threat in most parts of the world. Dogs, especially stray dogs, are the main sources of rabies transmission in developing countries, while wild animals are primarily responsible for the spread of rabies in developed countries and play an emerging role in rabies transmission in developing countries. Oral vaccination is the most practical method for rabies control in these animals, and the greatest challenge for oral vaccination is the hostile environment and large quantity of proteases in the gastrointestinal tract. In the present study, a promising adjuvant with potential protease inhibitory activity, unlipidated outer membrane protein 19 (U-OMP19), was inserted into the genome of the recombinant rabies virus (rRABV) strain LBNSE, designated LBNSE-U-OMP19, and the immunogenicity of LBNSE-U-OMP19 was investigated. LBNSE-U-OMP19 could potentially protect viral glycoprotein from digestion by gastrointestinal fluids . The expression of U-OMP19 attenuated viral pathogenicity by restricting viral replication in the central nervous system (CNS) and repressing the production of inflammatory chemokines and cytokines. After oral vaccination, LBNSE-U-OMP19 recruited dendritic cells (DCs), follicular helper T (T) cells and germinal center (GC) B cells, promoted the formation of GCs, and increased the population of plasma cells in immunized mice, resulting in higher levels of RABV-neutralizing antibodies and better protection in mice immunized with LBNSE-U-OMP19 than in those immunized with the parent virus LBNSE. Together, our data suggest that LBNSE-U-OMP19 is a promising candidate for oral rabies vaccines.
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http://dx.doi.org/10.1080/22221751.2021.1923341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143638PMC
December 2021

The structural basis of African swine fever virus core shell protein p15 binding to DNA.

FASEB J 2021 03;35(3):e21350

State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People's Republic of China.

African swine fever (ASF) is an acute, hemorrhagic, and highly contagious disease caused by African swine fever virus (ASFV). The mortality rate of acute infection up to 100% have posed an unprecedented challenge of the swine industry. Currently no commercial antiviral drug is available for the control and treatment of ASFV. The structural resolution of ASFV virions reveals the details of ASFV morphogenesis, providing a new perspective for the research and promotion of the development of ASFV vaccines. Although the architecture of ASFV have been solved via cryo-EM, the structural details of four of the five viral layers remain unclear (except the outer capsid). In this study, we resolved the crystal structure of the ASFV core shell protein p15. The secondary structural elements of a protomer include four α-helix structures and six antiparallel β-strands. Further analysis revealed that ASFV p15 forms disulfide-linked trimers between the Cys9 from one protomer and Cys30 from other protomer. Additionally, the nucleic acid-binding property was characterized by electrophoretic mobility shift assay. Two critical amino acid Lys10 and Lys39 have been identified which is essential to the nucleic acid-binding affinity of ASFV p15. Together, these findings may provide new insight into antiviral drug development.
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http://dx.doi.org/10.1096/fj.202002145RDOI Listing
March 2021

Synaptic signalling in a network of dopamine neurons: what prevents proper intercellular crosstalk?

FEBS Lett 2020 10 30;594(20):3272-3292. Epub 2020 Aug 30.

Rowett Institute, University of Aberdeen, Aberdeen, UK.

Human embryonic stem cell (hESC)-derived midbrain dopamine (DA) neurons stand out as a cell source for transplantation with their sustainability and consistency superior to the formerly used fetal tissues. However, multiple studies of DA neurons in culture failed to register action potential (AP) generation upon synaptic input. To test whether this is due to deficiency of NMDA receptor (NMDAR) coagonists released from astroglia, we studied the functional properties of neural receptors in hESC-derived DA neuronal cultures. We find that, apart from an insufficient amount of coagonists, lack of interneuronal crosstalk is caused by hypofunction of synaptic NMDARs due to their direct inhibition by synaptically released DA. This inhibitory tone is independent of DA receptors and affects the NMDAR coagonist binding site.
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http://dx.doi.org/10.1002/1873-3468.13910DOI Listing
October 2020

Cost-Effectiveness of Tofacitinib for Patients with Moderate-to-Severe Rheumatoid Arthritis in China.

Pharmacoeconomics 2020 12 15;38(12):1345-1358. Epub 2020 Sep 15.

School of International Pharmaceutical Business, China Pharmaceutical University, 639 Longmiandadao Avenue, Nanjing, 211198, China.

Background: Patients with moderate-to-severe rheumatoid arthritis have a heavy financial burden. The cost-effectiveness of introducing tofacitinib to the current treatment sequence for patients with moderate-to-severe rheumatoid arthritis who have inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs-IR) in China remains unknown.

Objective: The objective of this study was to assess the cost-effectiveness of introducing tofacitinib into the current treatment sequence in China for patients with moderate-to-severe rheumatoid arthritis who have csDMARDs-IR.

Methods: A Markov model was constructed from the perspective of the Chinese healthcare system to compare treatment sequences with and without first-line tofacitinib for patients with rheumatoid arthritis with csDMARDs-IR. The treatment sequence without tofacitinib included adalimumab, etanercept, recombinant human tumor necrosis factor receptor-Fc fusion protein, infliximab, and tocilizumab. Costs were derived from publicly available sources. Clinical trials, network meta-analysis, and real-world data were used to generate quality-adjusted life-years (QALYs), transition probabilities, and the incidence of adverse events. Mortality probabilities were estimated from rheumatoid arthritis-based, Chinese all-cause mortality data. One-way and probabilistic sensitivity analyses were conducted to verify the robustness of the model. In addition, the cost-effectiveness of adding tofacitinib as second- and third-line treatment options was evaluated in our analyses. Costs and effects were discounted at 5% per anum.

Results: Compared to the current treatment sequence, adding tofacitinib as first-line treatment led to a cost-saving of $US880.11 (2018 values) and incremental QALYs of 1.34. Sensitivity analyses showed the results to be robust. Adding tofacitinib at second-line therapy was also a cost-saving option with a cost saving of $US653.65 and incremental QALYs of 1.34, while the incremental cost-effectiveness ratio of adding tofacitinib at third-line therapy was $US5588.14 per QALY gained.

Conclusions: Using the WHO-recommended ICER acceptability threshold of ≤ 1-time per capita Gross Domestic Product (GDP), our analysis suggests that the introduction of tofacitinib into the current treatment sequence for moderate-to-severe RA patients with csDMARDs-IR in China was a cost saving option as first- and second-line treatment, and cost-effective as a third-line treatment option. Of note, use of tofacitinib as first- and second-line treatment post-csDMARDs-IR appeared to be cost saving.
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http://dx.doi.org/10.1007/s40273-020-00961-zDOI Listing
December 2020

Machine Learning for Precision Health Economics and Outcomes Research (P-HEOR): Conceptual Review of Applications and Next Steps.

J Health Econ Outcomes Res 2020 12;7(1):35-42. Epub 2020 May 12.

Real World Evidence, Pharmerit International, Bethesda, Maryland, United States.

Precision health economics and outcomes research (P-HEOR) integrates economic and clinical value assessment by explicitly discovering distinct clinical and health care utilization phenotypes among patients. Through a conceptualized example, the objective of this review is to highlight the capabilities and limitations of machine learning (ML) applications to P-HEOR and to contextualize the potential opportunities and challenges for the wide adoption of ML for health economics. We outline a P-HEOR conceptual framework extending the ML methodology to comparatively assess the economic value of treatment regimens. Latest methodology developments on bias and confounding control in ML applications to precision medicine are also summarized.
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http://dx.doi.org/10.36469/jheor.2020.12698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299485PMC
May 2020

A novel NAC transcription factor, MdNAC42, regulates anthocyanin accumulation in red-fleshed apple by interacting with MdMYB10.

Tree Physiol 2020 03;40(3):413-423

College of Life Science, Ludong Univeristy, Hongqizhong Road 186, Zhifu District, Yantai, Shandong 264025, P.R. China.

Anthocyanin pigmentation is an important consumption trait of apple (Malus domestica Borkh.). In this study, we focused on the identification of NAC (NAM, ATAF1/2 and CUC2) proteins involved in the regulation of anthocyanin accumulation in apple flesh. A group of MdNACs was selected for comparison of expression patterns between the white-fleshed cultivar 'Granny Smith' and red-fleshed 'Redlove'. Among them, MdNAC42 was screened, which exhibited a higher expression level in red-fleshed than in white-fleshed fruit, and has a positive correlation with anthocyanin content as fruits ripened. Moreover, overexpression of MdNAC42 in apple calli resulted in the up-regulation of flavonoid pathway genes, including MdCHS, MdCHI, MdF3H, MdDFR, MdANS and MdUFGT, thereby increasing the accumulation of anthocyanins, which confirmed the roles of MdNAC42 in anthocyanin biosynthesis. Notably, MdNAC42 was demonstrated to have an obvious interaction with MdMYB10 either in vitro or in vivo by yeast two-hybrid combined with bimolecular fluorescence complementation, further suggesting that MdNAC42 is an important part of the regulatory network controlling the anthocyanin pigmentation of red-fleshed apples. To the best of our knowledge, this is the first report identifying the MdNAC gene as related to anthocyanin accumulation in red-fleshed apples. This study provides valuable information for improving the regulatory model of anthocyanin biosynthesis in apple fruit.
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http://dx.doi.org/10.1093/treephys/tpaa004DOI Listing
March 2020

Soluble epoxide hydrolase inhibitor, TUPS, attenuates isoproterenol/angiotensin II-induced cardiac hypertrophy through mammalian target of rapamycin-mediated autophagy inhibition.

J Pharm Pharmacol 2019 Aug 18;71(8):1291-1300. Epub 2019 Jun 18.

The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Objectives: To investigate the potential role and mechanism of TUPS, a soluble epoxide hydrolase inhibitor, in cardiac hypertrophy.

Methods: Rat and H9C2 cell models of cardiac hypertrophy were induced by isoproterenol and angiotensin II, respectively, followed by TUPS treatment. The expression of hypertrophic markers, ANP and BNP, was determined by quantitative real-time PCR. The abundance of Beclin-1, LC3, p-AMPK and phosphorylated-mammalian target of rapamycin (p-mTOR) proteins was analysed by Western blot and immunohistocytology. Cell morphology and viability were evaluated by F-actin staining and MTS. H9C2 cells were transfected with GFP-LC3 to evaluate autophagy flux.

Key Findings: TUPS significantly inhibited rat heart size, heart weight-to-body weight ratio, heart wall thickness, hypertrophic H9C2 cell swelling and viability suppression as well as the expression of ANP and BNP genes in hypertrophic models. In addition, autophagic markers Beclin-1 and LC3 were elevated in both cellular and animal models, which were suppressed by TUPS, with corresponding changes of autophagy flux. The abundance of p-AMPK was increased, while p-mTOR was decreased in hypertrophic cells, which were abolished by TUPS. Rapamycin decreased p-mTOR level, increased Beclin-1 and LC3 expression and induced cell size enlargement and cell viability inhibition in hypertrophic H9C2 cells treated with TUPS.

Conclusions: TUPS inhibits cardiac hypertrophy by regulating mTOR/autophagy axis.
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http://dx.doi.org/10.1111/jphp.13113DOI Listing
August 2019

Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies?

Eur J Neurosci 2019 02 23;49(4):453-462. Epub 2019 Jan 23.

MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, DD1 5EH, Dundee, UK.

Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Foetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on-going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (a) they often lack synucleinopathy, and (b) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson's, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow progressing and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson's include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy.
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http://dx.doi.org/10.1111/ejn.14314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492143PMC
February 2019

Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene.

Eur J Neurosci 2019 02 21;49(4):510-524. Epub 2018 Dec 21.

MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh, UK.

An emerging treatment for Parkinson's disease (PD) is cell replacement therapy. Authentic midbrain dopaminergic (mDA) neuronal precursors can be differentiated from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). These laboratory-generated mDA cells have been demonstrated to mature into functional dopaminergic neurons upon transplantation into preclinical models of PD. However, clinical trials with human fetal mesenchephalic cells have shown that cell replacement grafts in PD are susceptible to Lewy body formation suggesting host-to-graft transfer of α-synuclein pathology. Here, we have used CRISPR/Cas9n technology to delete the endogenous SNCA gene, encoding for α-synuclein, in a clinical-grade hESC line to generate SNCA and SNCA cell lines. These hESC lines were first differentiated into mDA neurons, and then challenged with recombinant α-synuclein preformed fibrils (PFFs) to seed the formation for Lewy-like pathology as measured by phosphorylation of serine-129 of α-synuclein (pS129-αSyn). Wild-type neurons were fully susceptible to the formation of protein aggregates positive for pS129-αSyn, while SNCA and SNCA neurons exhibited significant resistance to the formation of this pathological mark. This work demonstrates that reducing or completely removing SNCA alleles by CRISPR/Cas9n-mediated gene editing confers a measure of resistance to Lewy pathology.
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http://dx.doi.org/10.1111/ejn.14286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492083PMC
February 2019

Abrogation of Lupus Nephritis in Somatic Hypermutation-Deficient MRL/lpr Mice.

J Immunol 2018 06 4;200(12):3905-3912. Epub 2018 May 4.

Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, 130024, People's Republic of China;

Systemic lupus erythematosus (SLE) is an autoimmune disease posing threats to multiple organs in the human body. As a typical manifestation of SLE, lupus nephritis is characterized by a series of pathological changes in glomerulus as well as accumulation of pathogenic autoreactive IgG with complement in the kidney that dramatically disrupts renal functions. Activation-induced deaminase (AID), which governs both somatic hypermutation (SHM) and class-switch recombination (CSR), has been shown to be essential for the regulation of SLE. However, the relative contributions of SHM and CSR to SLE pathology have not been determined. Based on the available AID mice, we successfully established an AID MRL/lpr mouse model, in which SHM is specifically abolished, although CSR is largely unaffected. We found that the abrogation of SHM effectively alleviated SLE-associated histopathological alterations, such as expansion of the mesangial matrix and thickening of the basement membrane of Bowman's capsule as well as infiltration of inflammatory cells. Compared with SLE mice, AID MRL/lpr mice exhibited decreased proteinuria, blood urea nitrogen, and creatinine, indicating that the loss of SHM contributed to the recovery of renal functions. As a consequence, the life span of those SHM-deficient MRL/lpr mice was extended. Together, we provide direct evidence pinpointing a vital role of SHM in the control of SLE development.
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http://dx.doi.org/10.4049/jimmunol.1800115DOI Listing
June 2018

Effect of multiple drug resistance on total medical costs among patients with intra-abdominal infections in China.

PLoS One 2018 28;13(3):e0193977. Epub 2018 Mar 28.

Center for Health Policy Studies, School of Public Health, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China.

Background: Multiple drug resistant (MDR) intra-abdominal infections (IAIs) are associated with notable direct and societal costs. As previous studies have not considered the impact of MDR on the total medical costs (TMCs) of IAIs, the present one examines this, as well as further estimates the additional costs at a national level.

Methods: This is a retrospective study. Firstly, we randomly selected a sample of 40% of all inpatients discharged between 2014 and 2015 from a teaching hospital, due to limits in budget and the large number of patients. Then, we manually selected 254 patients with IAIs according to the International Classification of Disease, 10th revision, using electronic medical records. Eventually, 101 patients with IAIs (64 MDR patients and 37 non-MDR patients) were included after excluding cases without laboratory test results, any pathogens detected, or antimicrobial resistant pathogens. Univariate analysis and a generalized linear model were applied to assess the parameters associated with TMCs.

Results: Compared to non-MDR patients, those with MDR pathogens were significantly associated with higher TMCs, higher antimicrobial costs, higher antimicrobial usage, larger number of pathogens, and longer length of stay and were more likely to have insurance and combination antimicrobial therapy. In addition, the average TMC among patients with MDR pathogens was ¥ 131801, which is ¥ 90201 higher than those without MDR pathogens. If our results are applied to the whole country, the sum of all attributable TMCs was ¥ 37 billion. The societal costs, furthermore, were ¥111 billion in 2015.

Conclusion: Our results provide information that should lead to increased efforts to reduce inappropriate antimicrobial therapy, in order to decrease the emergence of MDR pathogens and to reduce their economic burden.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193977PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873998PMC
June 2018

Silencing MR-1 attenuates atherosclerosis in ApoE mice induced by angiotensin II through FAK-Akt-mTOR-NF-kappaB signaling pathway.

Korean J Physiol Pharmacol 2018 Mar 23;22(2):127-134. Epub 2018 Feb 23.

Hunan Environment-Biological Polytechnic College, Hengyang Hunan 421005, China.

Myofibrillogenesis regulator-1 (MR-1) is a novel protein involved in cellular proliferation, migration, inflammatory reaction and signal transduction. However, little information is available on the relationship between MR-1 expression and the progression of atherosclerosis. Here we report atheroprotective effects of silencing MR-1 in a model of Ang II-accelerated atherosclerosis, characterized by suppression focal adhesion kinase (FAK) and nuclear factor kappaB (NF-κB) signaling pathway, and atherosclerotic lesion macrophage content. In this model, administration of the siRNA-MR-1 substantially attenuated Ang II-accelerated atherosclerosis with stabilization of atherosclerotic plaques and inhibited FAK, Akt, mammalian target of rapamycin (mTOR) and NF-kB activation, which was associated with suppression of inflammatory factor and atherogenic gene expression in the artery. studies demonstrated similar changes in Ang II-treated vascular smooth muscle cells (VSMCs) and macrophages: siRNA-MR-1 inhibited the expression levels of proinflammatory factor. These studies uncover crucial proinflammatory mechanisms of Ang II and highlight actions of silencing MR-1 to inhibit Ang II signaling, which is atheroprotective.
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http://dx.doi.org/10.4196/kjpp.2018.22.2.127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840071PMC
March 2018

Nanowire-based thermoelectrics.

Nanotechnology 2017 Jul 19;28(28):282001. Epub 2017 Jun 19.

Artie McFerrin Department of Chemical Engineering Texas A&M University, College Station, TX 77843, United States of America.

Research on thermoelectrics has seen a huge resurgence since the early 1990s. The ability of tuning a material's electrical and thermal transport behavior upon nanostructuring has led to this revival. Nevertheless, thermoelectric performances of nanowires and related materials lag far behind those achieved with thin-film superlattices and quantum dot-based materials. This is despite the fact that nanowires offer many distinct advantages in enhancing the thermoelectric performances of materials. The simplicity of the strategy is the first and foremost advantage. For example, control of the nanowire diameters and their surface roughnesses will aid in enhancing their thermoelectric performances. Another major advantage is the possibility of obtaining high thermoelectric performances using simpler nanowire chemistries (e.g., elemental and binary compound semiconductors), paving the way for the fabrication of thermoelectric modules inexpensively from non-toxic elements. In this context, the topical review provides an overview of the current state of nanowire-based thermoelectrics. It concludes with a discussion of the future vision of nanowire-based thermoelectrics, including the need for developing strategies aimed at the mass production of nanowires and their interface-engineered assembly into devices. This eliminates the need for trial-and-error strategies and complex chemistries for enhancing the thermoelectric performances of materials.
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http://dx.doi.org/10.1088/1361-6528/aa75aeDOI Listing
July 2017

Effects of the chronic restraint stress induced depression on reward-related learning in rats.

Behav Brain Res 2017 03 5;321:185-192. Epub 2017 Jan 5.

Research Center for Pharmacology & Toxicology, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address:

Chronic mild or unpredictability stress produces a persistent depressive-like state. The main symptoms of depression include weight loss, despair, anhedonia, diminished motivation and mild cognition impairment, which could influence the ability of reward-related learning. In the present study, we aimed to evaluate the effects of chronic restraint stress on the performance of reward-related learning of rats. We used the exposure of repeated restraint stress (6h/day, for 28days) to induce depression-like behavior in rats. Then designed tasks including Pavlovian conditioning (magazine head entries), acquisition and maintenance of instrumental conditioning (lever pressing) and goal directed learning (higher fixed ratio schedule of reinforcement) to study the effects of chronic restraint stress. The results indicated that chronic restraint stress influenced rats in those aspects including the acquisition of a Pavlovian stimulus-outcome (S-O) association, the formation and maintenance of action-outcome (A-O) causal relation and the ability of learning in higher fixed ratio schedule. In conclusion, depression could influence the performances in reward-related learning obviously and the series of instrumental learning tasks may have potential as a method to evaluate cognitive changes in depression.
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http://dx.doi.org/10.1016/j.bbr.2016.12.045DOI Listing
March 2017

Precision Health Economics and Outcomes Research to Support Precision Medicine: Big Data Meets Patient Heterogeneity on the Road to Value.

J Pers Med 2016 Nov 2;6(4). Epub 2016 Nov 2.

Department of Pharmacy, University of Washington, Seattle, WA 98195, USA.

The "big data" era represents an exciting opportunity to utilize powerful new sources of information to reduce clinical and health economic uncertainty on an individual patient level. In turn, health economic outcomes research (HEOR) practices will need to evolve to accommodate individual patient-level HEOR analyses. We propose the concept of "precision HEOR", which utilizes a combination of costs and outcomes derived from big data to inform healthcare decision-making that is tailored to highly specific patient clusters or individuals. To explore this concept, we discuss the current and future roles of HEOR in health sector decision-making, big data and predictive analytics, and several key HEOR contexts in which big data and predictive analytics might transform traditional HEOR into precision HEOR. The guidance document addresses issues related to the transition from traditional to precision HEOR practices, the evaluation of patient similarity analysis and its appropriateness for precision HEOR analysis, and future challenges to precision HEOR adoption. Precision HEOR should make precision medicine more realizable by aiding and adapting healthcare resource allocation. The combined hopes for precision medicine and precision HEOR are that individual patients receive the best possible medical care while overall healthcare costs remain manageable or become more cost-efficient.
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http://dx.doi.org/10.3390/jpm6040020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198059PMC
November 2016

Economic analysis of empiric versus diagnostic-driven strategies for immunocompromised patients with suspected fungal infections in the People's Republic of China.

Clinicoecon Outcomes Res 2016 14;8:275-85. Epub 2016 Jun 14.

Pfizer International Operations, Paris, France.

Invasive fungal infections (IFIs) require rapid diagnosis and treatment. A decision-analytic model was used to estimate total costs and survival associated with a diagnostic-driven (DD) or an empiric treatment approach in neutropenic patients with hematological malignancies receiving chemotherapy or autologous/allogeneic stem cell transplants in Shanghai, Beijing, Chengdu, and Guangzhou, the People's Republic of China. Treatment initiation for the empiric approach occurred after clinical suspicion of an IFI; treatment initiation for the DD approach occurred after clinical suspicion and a positive IFI diagnostic test result. Model inputs were obtained from the literature; treatment patterns and resource use were based on clinical opinion. Total costs were lower for the DD versus the empiric approach in Shanghai (¥3,232 vs ¥4,331), Beijing (¥3,894 vs ¥4,864), Chengdu, (¥4,632 vs ¥5,795), and Guangzhou (¥8,489 vs ¥9,795). Antifungal administration was lower using the DD (5.7%) than empiric (9.8%) approach, with similar survival rates. Results from one-way and probabilistic sensitivity analyses were most sensitive to changes in diagnostic test sensitivity and IFI incidence; the DD approach dominated the empiric approach in 88% of scenarios. These results suggest that a DD compared to an empiric treatment approach in the People's Republic of China may be cost saving, with similar overall survival in immunocompromised patients with suspected IFIs.
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http://dx.doi.org/10.2147/CEOR.S101015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913884PMC
July 2016

Drug pricing reform in China: analysis of piloted approaches and potential impact of the reform.

J Mark Access Health Policy 2016 15;4. Epub 2016 Mar 15.

Faculty of Medicine, Department of Public Health, Aix-Marseille University, Marseille, France.

Objectives: In 2009, the Chinese government launched a national healthcare reform programme aiming to control healthcare expenditure and increase the quality of care. As part of this programme, a new drug pricing reform was initiated on 1 June 2015. The objective of this study was to describe the changing landscape of drug pricing policy in China and analyse the potential impact of the reform.

Methods: The authors conducted thorough research on the drug pricing reform using three Chinese databases (CNKI, Wanfang, and Weipu), Chinese health authority websites, relevant press releases, and pharmaceutical blogs and discussion forums. This research was complemented with qualitative research based on targeted interviews with key Chinese opinion leaders representing the authorities' and prescribers' perspectives.

Results: With the current reform, the government has attempted to replace its direct control over the prices of reimbursable drugs with indirect, incentive-driven influence. Although the exact implementation of the reform remains unclear at the moment, the changes introduced so far and the pilot project designs indicate that China is considering adaptation of some form of internal and external reference pricing policies, commonly used in the Organisation for Economic Co-operation and Development countries. Several challenges related to the potential new mechanism were identified: 1) the risk of hospital underfunding, if hospital funding reform is not prioritised; 2) the risk of promoting the use of cheap, low-quality drugs, if a reliable quality control system is not in place and discrepancy between the available drugs is present; 3) the risk of increasing disparity in access to care between poor and rich regions, in case of country-wide price convergence; and 4) the risk of industry underinvestment, resulting in reduced competition, issues with quality and sustainability of supply, and potentially negative social impact.

Conclusions: Foreign pricing policies cannot be transferred to China without prioritising historical, cultural, and economic contextualisation. Otherwise, the new policy may be counterproductive and affect the whole healthcare chain, as well as the health outcomes of Chinese patients.
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http://dx.doi.org/10.3402/jmahp.v4.30458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802695PMC
April 2016

Methicillin-resistant Staphylococcus aureus nosocomial pneumonia: role of linezolid in the People's Republic of China.

Clinicoecon Outcomes Res 2016 24;8:63-72. Epub 2016 Mar 24.

Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

The burden of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia in the People's Republic of China is high, with methicillin-resistance rates greater than 80% reported for patients with S. aureus pneumonia treated in intensive care units. Historically, vancomycin was the treatment of choice for patients with hospital-acquired MRSA infections. Recent evidence suggests that the minimum inhibitory concentration for vancomycin is increasing. Additionally, patients treated with vancomycin require monitoring of vancomycin trough concentrations and can develop nephrotoxicity. Linezolid is a treatment option for patients with hospital-acquired MRSA infections that can be administered either intravenously or orally. Analysis of data from a worldwide linezolid surveillance program initiated in the year 2004 shows no evidence of increasing linezolid minimum inhibitory concentrations. The clinical efficacy of linezolid for patients with gram-positive, including MRSA, nosocomial pneumonia, was evaluated in numerous studies. In general, results from these studies show higher or similar clinical success with no mortality difference for linezolid compared to vancomycin treated patients. Results from a Phase IV study enrolling patients with MRSA-confirmed nosocomial pneumonia suggest higher clinical cure rates for linezolid compared to vancomycin treated patients. Although acquisition costs are higher for linezolid compared to vancomycin therapy, evidence suggests similar overall medical costs. Cost-analysis results from a Chinese perspective show that linezolid dominated vancomycin therapy for MRSA nosocomial pneumonia in ∼35% of bootstrap simulations whereas vancomycin dominated linezolid in less than 2% of bootstrap simulations. In summary, results from both clinical and economic studies, including studies conducted from a Chinese perspective, support the use of linezolid for the treatment of patients with MRSA nosocomial pneumonia.
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http://dx.doi.org/10.2147/CEOR.S91985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818060PMC
April 2016

Linezolid for the treatment of hospital-acquired pneumonia in a Chinese tertiary hospital.

Clinicoecon Outcomes Res 2015 9;7:521-6. Epub 2015 Oct 9.

Pharmerit International, Bethesda, MD, USA.

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http://dx.doi.org/10.2147/CEOR.S89570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624059PMC
November 2015

Economic evaluation among Chinese patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus and treated with linezolid or vancomycin: a secondary, post-hoc analysis based on a Phase 4 clinical trial study.

J Med Econ 2016 22;19(1):53-62. Epub 2015 Oct 22.

a a Pharmerit International , Bethesda , MD , USA.

Objective: To assess cost-effectiveness of linezolid vs vancomycin in treating nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA-NP) in China and the impact of renal failure on healthcare resource utilization (HCRU) and costs.

Methods: Cost-effectiveness analysis was conducted based on data from the ZEPHyR trial, with efficacy measured by treatment success and costs calculated from HCRU. Confidence intervals (CI) for cost, efficacy and incremental cost-effectiveness ratios (ICER) were calculated by non-parametric bootstrap. Chi-square test was used for renal failure rate and t-test for HCRU/cost comparisons. Impact of renal failure was assessed using regression model.

Results: Data from 448 patients (1:1 linezolid:vancomycin) were analyzed. More patients treated with linezolid achieved success (55% [95% CI = 48-62%]) than with vancomycin (45% [38-52%]). Treatment cost were ¥79,551 (95% CI = ¥72,421-¥86,680) for linezolid vs ¥77,587 (¥70,656-¥84,519) for vancomycin in Beijing, ¥90,995 (¥82,598-¥99,393) vs ¥89,448 (¥81,295-¥97,601) in Guangzhou, ¥82,383 (¥74,956-¥89,810) vs ¥80,799 (¥73,545-¥88,054) in Nanjing and ¥59,413 (¥54,366-¥64,460) vs ¥57,804 (¥52,613-¥62,996) in Xi'an. Per successful treatment, the ICER of linezolid over vancomycin were ¥19,719 (-¥143,553 to ¥320,980) (Beijing), ¥15,532 (-¥185,411 to ¥349,693) (Guangzhou), ¥15,904 (-¥161,935 to ¥314,987) (Nanjing) and ¥16,145 (-¥100,738 to ¥234,412) (Xi'an). From simulations, the majority of linezolid cases had greater efficacy and higher costs and more than one third had greater efficacy and lower costs. More vancomycin patients developed renal failure (15% vs 4%, p < 0.001). Patients with renal failure had higher cost (Nanjng: ¥100,449 (SD = ¥65,080) vs ¥74,944 (SD = ¥49,632), p = 0.002).

Conclusion: Linezolid was more cost-effective than vancomycin in treating MRSA-NP from a Chinese payer's perspective, and associated with less renal failure, HCRU and cost.
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http://dx.doi.org/10.3111/13696998.2015.1088448DOI Listing
October 2016

Cost-Effectiveness of Linezolid versus Vancomycin among Patients with Methicillin-Resistant Staphylococcus aureus Confirmed Nosocomial Pneumonia in China.

Value Health Reg Issues 2014 May 10;3:94-100. Epub 2014 May 10.

HE&OR, Pharmerit International, Bethesda, MD, USA.

Objective: To estimate the cost-effectiveness of intravenous linezolid as a first-line agent against intravenous vancomycin in treating methicillin-resistant Staphylococcus aureus-confirmed nosocomial pneumonia in four Chinese cities.

Methods: A decision-analytic model of 4-week time horizon was used to conduct cost-effectiveness analyses from the payer's perspective. Clinical outcomes and resource use data were derived from a head-to-head trial, supplemented with local cost estimates based on hospital data via an expert panel. A series of scenario analyses were conducted to evaluate the impact of uncertainty around model inputs. All results were reported in 2012 Chinese Renminbi.

Results: The predicted probability of overall treatment success was 0.629 and 0.602 for linezolid and vancomycin, respectively. Total inpatient costs varied across the four cities, ranging from ¥58,835 to ¥86,894 for linezolid and ¥58,390 to ¥87,033 for vancomycin, respectively. Linezolid was demonstrated to be a dominant treatment strategy in Guangzhou. In Beijing, Nanjing, and Xi'an, incremental cost-effectiveness ratios in terms of additional successfully treated patient were ¥1,861, ¥163, and ¥16,509, respectively. Dominance by linezolid was observed in some scenario analyses with parameters such as treatment duration, inclusion of cost of managing adverse events, and drug acquisition costs being the main drivers of cost-effectiveness results.

Conclusions: Despite linezolid's higher drug acquisition cost, its superior clinical efficacy renders it a likely cost-effective alternative for the treatment of methicillin-resistant Staphylococcus aureus-confirmed nosocomial pneumonia as compared with branded vancomycin from the payer perspectives of Beijing, Guangzhou, Nanjing, and Xi'an.
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http://dx.doi.org/10.1016/j.vhri.2014.03.002DOI Listing
May 2014

Mouse precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury.

Chem Res Toxicol 2012 Sep 16;25(9):1938-47. Epub 2012 Aug 16.

Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in increased toxicity (inflammatory stress hypothesis). Aiming to develop a robust ex vivo screening method to study inflammatory stress-related IDILI mechanisms and to find biomarkers that can detect or predict IDILI, mouse precision-cut liver slices (mPCLS) were coincubated for 24 h with IDILI-related drugs and lipopolysaccharide. Lipopolysaccharide exacerbated ketoconazole (15 μM) and clozapine (45 μM) toxicity but not their non-IDILI-related comparators, voriconazole (1500 μM) and olanzapine (45 μM). However, the other IDILI-related drugs tested [diclofenac (200 μM), carbamazepine (400 μM), and troglitazone (30 μM)] did not cause synergistic toxicity with lipopolysaccharide after 24 h of incubation. Lipopolysaccharide further decreased the reduced glutathione levels caused by ketoconazole or clozapine in mPCLS after 24 h of incubation, which was not the case for the other drugs. Lipopolysaccharide significantly increased nitric oxide (NO), cytokine, and chemokine release into the mPCLS media, while the treatment with the drugs alone did not cause any substantial change. All seven drugs drastically reduced lipopolysaccharide-induced NO production. Interestingly, only ketoconazole and clozapine increased the lipopolysaccharide-induced granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Pilot experiments showed that diclofenac and troglitazone, but not carbamazepine, demonstrated synergistic toxicity with lipopolysaccharide after a longer incubation of 48 h in mPCLS. In conclusion, we have developed an ex vivo model to detect inflammatory stress-related liver toxicity and identified ketoconazole, clozapine, troglitazone, and diclofenac as drugs that showed synergistic toxicity with lipopolysaccharide. Reduced glutathione, G-CSF, and GM-CSF were identified to be potential biomarkers for IDILI-inducing drugs mediated by inflammatory stress, and mPCLS appear to be a promising screening tool to further unravel the mechanism of IDILI.
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http://dx.doi.org/10.1021/tx300248jDOI Listing
September 2012

The acylase PvdQ has a conserved function among fluorescent Pseudomonas spp.

Environ Microbiol Rep 2010 Jun 30;2(3):433-9. Epub 2010 Mar 30.

Department of Pharmaceutical Biology, 9713AV Groningen, the Netherlands. School of Molecular Medical Sciences, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.

Pyoverdine biosynthesis in fluorescent Pseudomonas spp. and especially in the opportunistic human pathogen Pseudomonas aeruginosa has been extensively studied. The acylase PvdQ is required for a maturation step in pyoverdine biosynthesis but also has been proven to be effective in degrading long-chain N-acyl homoserine lactones (AHLs). These molecules are used as quorum-sensing molecules by Gram-negative bacteria such as Pseudomonads themselves. Interestingly, the pvdQ gene is part of a pyoverdine cluster in P. aeruginosa and P. syringae but not in other fluorescent Pseudomonas spp. In this study we have compared the activities of PvdQ orthologues from various species and provide evidence for conserved functions in Pseudomonas fluorescens PfO-1, P. putida KT2440 and P. aeruginosa PA14. Despite large differences in genomic organization, expression of each of these pvdQ orthologues is regulated by iron availability. Moreover, PvdQ and its orthologues have conserved substrate specificity for AHLs and play a role in pyoverdine production in all tested Pseudomonas species. These data strongly suggest that the role of PvdQ in pyoverdine biosynthesis is conserved among Pseudomonas spp., while the control that PvdQ exerts in P. aeruginosa over its own quorum-sensing signals seems to be unique to this bacterium.
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http://dx.doi.org/10.1111/j.1758-2229.2010.00157.xDOI Listing
June 2010
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